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INTRODUCTION: The War-Related Illness and Injury Study Center at the VA New Jersey Health Care System (WRIISC-VANJ) serves as one of the three tertiary referral centers for combat deployed Veterans of all eras with medically unexplained or difficult-to-diagnose conditions that may be related to deployment-related exposures. Many of the Veterans seen at the WRIISC experience chronic multisymptom illness (CMI), also known as Gulf War Illness (GWI). Given the complexity and interconnectedness of symptoms, Veterans with GWI are often unlikely to produce meaningful results when addressing single symptoms. Further, Veterans with GWI often have co-morbid cognitive and behavioral health conditions (e.g., TBI, PTSD, Depression), which further compromise their self-efficacy in following treatment recommendations. Thus, the WRIISC-NJ, in collaboration with Wellness Solutions Group, developed a virtual Functional Medicine-based Interdisciplinary and Integrative Intervention to improve the health of Veterans by assisting them in implementing lifestyle changes. METHODS: The 6-month telehealth program included functional medicine assessments, nutrition and adaptive exercise coaching, mindfulness meditation and yoga, guest health lectures, character strength coaching, and targeted nutritional supplements. Aspects of the program were tailored to the unique clinical needs of each Veteran. Participants completed baseline and 6 month follow-up assessments of physical and emotional symptoms and overall functioning. Follow-up scores were compared with baseline data. RESULTS: The program was well received by Veterans with attendance across all offered sessions ranging from 70 to 100%. Further, at the end of the clinical pilot program, improvements were demonstrated in physical and mental health symptoms, intentional weight loss/gain, functional movement, and sleep quality. CONCLUSIONS: These preliminary results demonstrate the possibility of creating positive health outcomes across multiple health indicators in medically complex combat-deployed Veterans. Our early success and participant enthusiasm for this clinical pilot program also illustrate an opportunity to provide individualized, innovative solutions for the evaluation and treatment of Veterans with GWI.
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Síndrome del Golfo Pérsico , Veteranos , Humanos , Síndrome del Golfo Pérsico/terapia , Síndrome del Golfo Pérsico/psicología , Síndrome del Golfo Pérsico/complicaciones , Veteranos/psicología , Veteranos/estadística & datos numéricos , Masculino , Femenino , New Jersey , Telemedicina , Adulto , Persona de Mediana Edad , Proyectos Piloto , Medicina Integrativa/métodosRESUMEN
BACKGROUND: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex®, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI. METHODS: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests. RESULTS: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus. CONCLUSIONS: The use of an FDA-approved CBD (Epidiolex®) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
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Cannabidiol , Disfunción Cognitiva , Hiperalgesia , Neurogénesis , Enfermedades Neuroinflamatorias , Síndrome del Golfo Pérsico , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Ratas , Síndrome del Golfo Pérsico/tratamiento farmacológico , Síndrome del Golfo Pérsico/complicaciones , Masculino , Hiperalgesia/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Neurogénesis/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Trastornos del Humor/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Bromuro de Piridostigmina/farmacología , Bromuro de Piridostigmina/uso terapéuticoRESUMEN
Gulf War Illness (GWI) is characterized by a wide range of symptoms that manifests largely as gastrointestinal symptoms. Among these gastrointestinal symptoms, motility disorders are highly prevalent, presenting as chronic constipation, stomach pain, indigestion, diarrhea, and other conditions that severely impact the quality of life of GWI veterans. However, despite a high prevalence of gastrointestinal impairments among these veterans, most research attention has focused on neurological disturbances. This perspective provides a comprehensive overview of current in vivo research advancements elucidating the underlying mechanisms contributing to gastrointestinal disorders in GWI. Generally, these in vivo and in vitro models propose that neuroinflammation alters gut motility and drives the gastrointestinal symptoms reported in GWI. Additionally, this perspective highlights the potential and challenges of in vitro bioengineering models, which could be a crucial contributor to understanding and treating the pathology of gastrointestinal related-GWI.
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Bioingeniería , Enfermedades Gastrointestinales , Síndrome del Golfo Pérsico , Humanos , Síndrome del Golfo Pérsico/fisiopatología , Síndrome del Golfo Pérsico/complicaciones , Bioingeniería/métodos , Bioingeniería/tendencias , Enfermedades Gastrointestinales/fisiopatología , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/complicaciones , Tracto Gastrointestinal/fisiopatologíaRESUMEN
Gulf War Illness (GWI) is a chronic multi-symptom neurological disorder affecting veterans of the Gulf War that is commonly comorbid with depression. A secondary data analysis was conducted to examine serum homocysteine and inflammatory cytokines (IFN-γ, IL-6, IL-1ß, TNF-α) as potential biomarkers of depression improvement among veterans with GWI after a one-month dietary intervention aimed at reducing excitotoxicity and increasing micronutrients. Analyses, including multiple linear and logistic regression, were conducted in R studio. Dietary adherence was estimated using a specialized excitotoxin food frequency questionnaire (FFQ), and depression was measured using the Center for Epidemiologic Studies Depression (CES-D) scale. After one month on the diet, 52% of participants reported a significant decrease in depression (p < 0.01). Greater dietary adherence (FFQ) was associated with increased likelihood of depression improvement; OR (95% CI) = 1.06 (1.01, 1.11), (p = 0.02). Reduced homocysteine was associated with depression improvement after adjusting for FFQ change (ß = 2.58, p = 0.04), and serum folate and vitamin B12 were not mediators of this association. Reduction in IFN-γ was marginally associated with likelihood of depression improvement (OR (95% CI) = 1.11 (0.00, 1.42), (p = 0.06)), after adjustment for potential confounders. Findings suggest that homocysteine, and possibly IFN-γ, may serve as biomarkers for depression improvement in GWI. Larger trials are needed to replicate this work.
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Biomarcadores , Depresión , Homocisteína , Síndrome del Golfo Pérsico , Veteranos , Humanos , Masculino , Biomarcadores/sangre , Síndrome del Golfo Pérsico/sangre , Síndrome del Golfo Pérsico/dietoterapia , Síndrome del Golfo Pérsico/complicaciones , Persona de Mediana Edad , Depresión/sangre , Femenino , Homocisteína/sangre , Adulto , Citocinas/sangre , DietaRESUMEN
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.
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Demencia , Enfermedad de Parkinson , Síndrome del Golfo Pérsico , Veteranos , Masculino , Humanos , Femenino , Persona de Mediana Edad , Anciano , Guerra del Golfo , Olfato , Síndrome del Golfo Pérsico/epidemiología , Síndrome del Golfo Pérsico/complicaciones , CogniciónRESUMEN
BACKGROUND: One-third of veterans returning from the 1990-1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI. METHODS: Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine & cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWIH) and GWI with low probability of PTSD symptoms (GWIL). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWIH, GWIL, and healthy control groups. RESULTS: GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWIL subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWIL subgroup was found to be delineated from both GWIH and HC on measures of IL-15 across an exercise challenge (ANOVA F > 3.75, P < 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms. CONCLUSION: We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.
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Síndrome del Golfo Pérsico , Trastornos por Estrés Postraumático , Veteranos , Humanos , Masculino , Trastornos por Estrés Postraumático/complicaciones , Trastornos por Estrés Postraumático/epidemiología , Interleucina-15 , Guerra del Golfo , Citocinas , Síndrome del Golfo Pérsico/complicaciones , Biomarcadores , FatigaRESUMEN
OBJECTIVE: The aim of the study is to investigate relationships between inflammatory analytes and symptoms of pain and fatigue in Gulf War illness (GWI). METHODS: In this preliminary study, 12 male veterans meeting GWI criteria provided daily blood samples and symptom ratings over 25 days. Linear mixed models were used to analyze associations between symptoms and sera concentrations of cytokines, acute phase proteins, insulin, and brain-derived neurotropic factor. RESULTS: Analyses included 277 days with both blood draws and self-reports. Days with worse fatigue severity were associated with higher C-reactive protein and serum amyloid A, and lower eotaxin 1. Muscle pain and joint pain were associated with leptin, monocyte chemoattractant protein 1, and interferon γ-induced protein. Joint pain was further associated with serum amyloid A and eotaxin 3. CONCLUSIONS: Gulf War illness involves fatigue and pain associated with inflammation. Conventional and novel anti-inflammatories should be further explored for the treatment of GWI.
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Síndrome del Golfo Pérsico , Veteranos , Masculino , Humanos , Síndrome del Golfo Pérsico/complicaciones , Citocinas , Dimensión del Dolor , Proteínas de Fase Aguda , Proteína Amiloide A Sérica , Guerra del Golfo , Fatiga , Dolor , ArtralgiaRESUMEN
BACKGROUND: Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder characterized by fatigue, muscle pain, cognitive problems, insomnia, rashes, and gastrointestinal issues affecting an estimated 30% of the ~ 750,000 returning military Veterans of the 1990-1991 Persian Gulf War. Female Veterans deployed to combat in this war report medical symptoms, like cognition and respiratory troubles, at twice the rate compared to non-deployed female Veterans of the same era. The heterogeneity of GWI symptom presentation complicates diagnosis as well as the identification of effective treatments. This is exacerbated by the presence of co-morbidities. Defining subgroups of the illness may help alleviate these complications. One clear grouping is along the lines of gender. Our aim is to determine if women with GWI can be further subdivided into distinct subgroups based on post-traumatic stress disorder (PTSD) symptom presentation. METHODS: Veterans diagnosed with GWI (n = 35) and healthy sedentary controls (n = 35) were recruited through the Miami Veterans Affairs Medical Health Center. Symptoms were assessed via the RAND short form health survey, the multidimensional fatigue inventory, and the Davidson trauma scale. Hierarchal regression modeling was performed on measures of health and fatigue with PTSD symptoms as a covariate. This was followed by univariate analyses conducted with two separate GWI groups based on a cut-point of 70 for their total Davidson trauma scale value and performing heteroscedastic t-tests across all measures. RESULTS: Based on the distinct differences found in PTSD symptomology regarding all health and trauma symptoms, two subgroups were derived within female GWI Veterans. Hierarchical regression models displayed the comorbid effects of GWI and PTSD, as both conditions had measurable impacts on quality of life and fatigue (ΔR2 = 0.08-0.672), with notable differences in mental and emotional measures. Overall, a cut point analysis indicated poorer quality of life and greater fatigue within all measures for women with GWI and PTSD symptoms in comparison to those women with GWI without PTSD symptoms and healthy controls. CONCLUSIONS: Our current findings support the understanding that comorbid symptoms of GWI and PTSD subsequently result in poorer quality of life and fatigue, along with establishing the possibility of varying clinical presentations.
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Síndrome del Golfo Pérsico , Trastornos por Estrés Postraumático , Fatiga/etiología , Femenino , Guerra del Golfo , Humanos , Síndrome del Golfo Pérsico/complicaciones , Síndrome del Golfo Pérsico/diagnóstico , Calidad de VidaRESUMEN
By its nature, Gulf war illness (GWI) is multisymptomatic and affects several organ systems in the body. Along with other symptoms, veterans who suffer from GWI commonly report chronic gastrointestinal issues such as constipation, pain, indigestion, etc. However, until recently, most attention has been focused on neurological disturbances such as cognitive impairments, chronic fatigue, and chronic pain among affected veterans. With such high prevalence of gastrointestinal problems among Gulf war (GW) veterans, it is surprising that there is little research to investigate the mechanisms behind these issues. This review summarizes all the available works on the mechanisms behind gastrointestinal problems in GWI that have been published to date in various databases. Generally, these studies, which were done in rodent models, in vitro and human cohorts propose that an altered microbiome, a reactive enteric nervous system or a leaky gut among other possible mechanisms are the major drivers of gastrointestinal problems reported in GWI. This review aims to draw attention to the gastrointestinal tract as an important player in GWI disease pathology and a potential therapeutic target.
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Enfermedades Gastrointestinales/etiología , Síndrome del Golfo Pérsico/complicaciones , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/fisiopatología , Enfermedades Gastrointestinales/fisiopatología , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Humanos , Síndrome del Golfo Pérsico/fisiopatología , Veteranos/estadística & datos numéricosRESUMEN
AIMS: Widespread pain and headache are common in Gulf War Illness with suboptimal treatments available. We tested the efficacy of non-invasive, transcutaneous vagal nerve stimulation (nVNS) for relief of widespread pain and migraine in Gulf War Veterans with GWI. MAIN METHODS: A 10-week double-blind, randomized controlled trial of nVNS used the gammaCore (ElectroCore, Inc.) compared to sham stimulation with the same device followed by a 10-week open-label follow up with active nVNS. The primary outcome was a numerical pain rating at the end of the blinded period. Secondary outcomes included physical function, migraine frequency and severity, and impression of change during the blinded and open-label periods. Two-factor MANOVA models tested for significant differences between groups from baseline to end of the blinded period and during the open-label period. KEY FINDINGS: Among 27 participants enrolled and issued a nVNS device, there was a slight improvement in pain ratings from baseline to the end of the blinded phase [6.18 (±0.82) vs. 5.05 (±2.3); p = 0.040] which did not differ between active and sham nVNS. Physical function was also slightly improved overall without group differences. There were no significant changes in migraine frequency or severity during the blinded period. Twenty participants started in the open-label phase; no statistically significant changes in pain, physical function, migraine measures, or impression of change were noted during this phase. SIGNIFICANCE: Veterans with GWI actively treated with nVNS reported no improvement in either widespread pain or migraine frequency or severity relative to Veterans with GWI who received sham nVNS.
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Dolor Crónico/terapia , Síndrome del Golfo Pérsico/terapia , Estimulación del Nervio Vago/métodos , Adulto , Dolor Crónico/etiología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome del Golfo Pérsico/complicaciones , Resultado del Tratamiento , Estimulación del Nervio Vago/efectos adversos , Estimulación del Nervio Vago/instrumentación , VeteranosRESUMEN
AIMS: Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. MATERIALS AND METHODS: We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. KEY FINDINGS: Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. SIGNIFICANCE: These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.
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Tronco Encefálico/fisiopatología , Dolor/etiología , Síndrome del Golfo Pérsico/complicaciones , Síndrome del Golfo Pérsico/fisiopatología , Trastornos del Sueño-Vigilia/etiología , Tronco Encefálico/patología , Enfermedad Crónica , Femenino , Guerra del Golfo , Humanos , Masculino , Persona de Mediana Edad , Dolor/patología , Dolor/fisiopatología , Síndrome del Golfo Pérsico/patología , Sueño , Trastornos del Sueño-Vigilia/patología , Trastornos del Sueño-Vigilia/fisiopatología , VeteranosRESUMEN
AIMS: Post-exertional malaise (PEM) is poorly understood in Gulf War Illness (GWI). Exercise challenges have emerged as stimuli to study PEM; however, little attention has been paid to unique cardiorespiratory and perceptual responses during exercise. This study tested whether select exercise parameters explained variability in PEM responses. MAIN METHODS: Visual analog scale (0-100) versions of the Kansas questionnaire were used for daily symptom measurements one week before and one week after 30-min of cycling at 70% heart rate reserve in 43 Veterans with GWI and 31 Veteran controls (CON). Cardiopulmonary exercise testing (CPET) methods were used to measure oxygen (VO2), carbon dioxide (VCO2), ventilation (VE), heart rate, work rate, and leg muscle pain. Symptom changes and CPET parameters were compared between groups with independent samples t-tests. Linear regression (GLM) with VE/VCO2, cumulative work, leg muscle pain, and self-reported physical function treated as independent variables and peak symptom response as the dependent variable tested whether exercise responses predicted PEM. KEY FINDINGS: Compared to CON, Veterans with GWI had greater ventilatory equivalent for oxygen (VE/VO2), peak leg muscle pain, fatigue, and lower VCO2, VO2, power, and cumulative work during exercise (p < 0.05), and greater peak symptom responses (GWI = 38.90 ± 29.06, CON = 17.84 ± 28.26, g = 0.70, p < 0.01). The final GLM did not explain significant variance in PEM (Pooled R2 = 0.15, Adjusted R2 = 0.03, p = 0.34). SIGNIFICANCE: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise.
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Ejercicio Físico , Síndrome del Golfo Pérsico/fisiopatología , Anciano , Prueba de Esfuerzo , Fatiga/complicaciones , Fatiga/fisiopatología , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Mialgia/complicaciones , Mialgia/fisiopatología , Síndrome del Golfo Pérsico/complicacionesRESUMEN
Gulf war illness (GWI) is a chronic disorder of unknown etiology characterized by multiple symptoms such as pain, fatigue, gastrointestinal disturbances and neurocognitive problems. Increasing evidence suggests that gut microbiome perturbations play a key role in the pathology of this disorder. GWI courses with gut microbiota alterations and their metabolites (e.g. short chain fatty acids -SCFA-), which can be aggravated by lifestyle risk factors such as a high fat diet (HF). To investigate the causative role of the gut microbiome, non-absorbable antibiotics (Abx) were administered to mice treated with GWI agents and concomitantly fed with a HF. In light of the wide use of Abx as pseudo-germ-free models, we evaluated the effects of Abx exposure on GWI and HF on body weight, food intake, gut microbiota changes and levels of the SCFA acetate. Results show that HF decreased food intake while increasing body weight in both controls and GWI. Exposure to Abx prevented these HF effects by offsetting the body weight gain in GWI. GWI and HF led to decreases in α-diversity, disruptions in the composition and structure of the gut bacterial community and decreases in acetate levels. This Abx-induced remodeling of the gut microbiome was characterized by an expansion of Proteobacteria, decreases in Bacteroidetes and Firmicutes, and overall increases in acetate levels, as well as by the proliferation of potential pathobionts. Therefore, the use of Abx may not represent a dependable approach to deplete the gut microbiome and its advantages as a pseudo germ-free model warrant further investigation.
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Bacterias/patogenicidad , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Disbiosis/patología , Microbioma Gastrointestinal , Inflamación/patología , Síndrome del Golfo Pérsico/complicaciones , Animales , Disbiosis/etiología , Inflamación/etiología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
AIMS: Nearly a third of U.S. veterans who deployed in support of the 1990-1991 Persian Gulf War are affected by Gulf War illness (GWI). Here we aimed to characterize whether subjective sleep complaints in GWI veterans are associated with objective sleep EEG disturbances relative to healthy veterans and controls; and whether Gulf War veterans show alterations in neural activity during sleep that differentiate them from healthy subjects. MAIN METHODS: We used high-density EEG (HDEEG) to assess regional patterns of rapid eye movement (REM) sleep and non-REM (NREM) sleep between three groups: Gulf War male veterans with fatigue and GWI, Gulf War male veterans without fatigue or GWI, and control males. The groups were matched relative to age, sex and obstructive sleep apnea. Topographic comparisons of nocturnal NREM and REM sleep were made between groups for all frequency bands. KEY FINDINGS: Topographic analysis revealed a broadband reduction in EEG power in a circumscribed region overlying the frontal lobe in both groups of Gulf War veterans, regardless of GWI and fatigue. This frontal reduction in neural activity was present, to some extent, across all frequency bands in NREM and REM sleep. SIGNIFICANCE: Given that our findings were observed in all Gulf War veterans, it appears unlikely that frontal sleep HDEEG power reductions prove wholly responsible for fatigue symptoms. These results provide avenues for research which may someday contribute to improved clinical care of formerly deployed veterans of the Persian Gulf War.
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Lóbulo Frontal/fisiopatología , Síndrome del Golfo Pérsico/fisiopatología , Apnea Obstructiva del Sueño/fisiopatología , Sueño , Adulto , Estudios de Casos y Controles , Electroencefalografía , Fatiga/etiología , Fatiga/fisiopatología , Guerra del Golfo , Humanos , Masculino , Persona de Mediana Edad , Síndrome del Golfo Pérsico/complicaciones , Polisomnografía , Estudios Prospectivos , Apnea Obstructiva del Sueño/etiologíaRESUMEN
Gulf War illness (GWI) is a chronic and multi-symptomatic disorder affecting veterans who served in the Gulf War. The commonly reported symptoms in GWI veterans include mood problems, cognitive impairment, muscle and joint pain, migraine/headache, chronic fatigue, gastrointestinal complaints, skin rashes, and respiratory problems. Neuroimaging studies have revealed significant brain structure alterations in GWI veterans, including subcortical atrophy, decreased volume of the hippocampus, reduced total grey and white matter, and increased brain white matter axial diffusivity. These brain changes may contribute to or increase the severities of the GWI-related symptoms. Epidemiological studies have revealed that neurotoxic exposures and stress may be significant contributors to the development of GWI. However, the mechanism underlying how the exposure and stress could contribute to the multi-symptomatic disorder of GWI remains unclear. We and others have demonstrated that rodent models exposed to GW-related agents and stress exhibited higher extracellular glutamate levels, as well as impaired structure and function of glutamatergic synapses. Restoration of the glutamatergic synapses ameliorated the GWI-related pathological and behavioral deficits. Moreover, recent studies showed that a low-glutamate diet reduced multiple symptoms in GWI veterans, suggesting an important role of the glutamatergic system in GWI. Currently, growing evidence has indicated that abnormal glutamate neurotransmission may contribute to the GWI symptoms. This review summarizes the potential roles of glutamate dyshomeostasis and dysfunction of the glutamatergic system in linking the initial cause to the multi-symptomatic outcomes in GWI and suggests the glutamatergic system as a therapeutic target for GWI.
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Ácido Glutámico/metabolismo , Síndrome del Golfo Pérsico/metabolismo , Síndrome del Golfo Pérsico/terapia , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Dietoterapia , Manejo de la Enfermedad , Guerra del Golfo , Humanos , Síndrome del Golfo Pérsico/complicaciones , Síndrome del Golfo Pérsico/fisiopatología , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
AIMS: Gulf War Illness (GWI) is a prevalent and disabling condition characterized by persistent physical symptoms. Clinical practice guidelines recommend self-management to reduce the disability from GWI. This study evaluated which GWI self-management strategies patients currently utilize and view as most effective and ineffective. MATERIALS AND METHODS: Data were collected from 267 Veterans during the baseline assessment of a randomized clinical trial for GWI. Respondents answered 3 open-ended questions regarding which self-management strategies they use, view as effective, and view as ineffective. Response themes were coded, and code frequencies were analyzed. KEY FINDINGS: Response frequencies varied across questions (in-use: n = 578; effective: n = 470; ineffective: n = 297). Healthcare use was the most commonly used management strategy (38.6% of 578), followed by lifestyle changes (28.5% of 578), positive coping (13% of 578), and avoidance (13.7% of 578). When asked about effective strategies, healthcare use (25.9% of 470), lifestyle change (35.7% of 470), and positive coping (17.4% of 470) were identified. Avoidance was frequently identified as ineffective (20.2% of 297 codes), as was invalidating experiences (14.1% of 297) and negative coping (10.4% of 297). SIGNIFICANCE: Patients with GWI use a variety of self-management strategies, many of which are consistent with clinical practice guidelines for treating GWI, including lifestyle change and non-pharmacological strategies. This suggests opportunities for providers to encourage effective self-management approaches that patients want to use.
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Terapia Cognitivo-Conductual/métodos , Síndrome del Golfo Pérsico/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Veteranos/psicología , Adulto , Anciano , Manejo de la Enfermedad , Femenino , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Percepción , Síndrome del Golfo Pérsico/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Encuestas y CuestionariosRESUMEN
AIMS: To examine whether cognitive behavioral therapy for insomnia (CBT-I), delivered by telephone, improves sleep and non-sleep symptoms of Gulf War Illness (GWI). MAIN METHODS: Eighty-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 FINDINGS: Compared 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. SIGNIFICANCE: GWI 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.
Asunto(s)
Terapia Cognitivo-Conductual/métodos , Síndrome del Golfo Pérsico/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Veteranos/psicología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome del Golfo Pérsico/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Encuestas y CuestionariosRESUMEN
Chronic diffuse body pain is unequivocally highly prevalent in Veterans who served in the 1990-91 Persian Gulf War and diagnosed with Gulf War Illness (GWI). Diminished motor cortical excitability, as a measurement of increased resting motor threshold (RMT) with transcranial magnetic stimulation (TMS), is known to be associated with chronic pain conditions. This study compared RMT in Veterans with GWI related diffuse body pain including headache, muscle and joint pain with their military counterparts without GWI related diffuse body pain. Single pulse TMS was administered over the left motor cortex, using anatomical scans of each subject to guide the TMS coil, starting at 25% of maximum stimulator output (MSO) and increasing in steps of 2% until a motor response with a 50 µV peak to peak amplitude, defined as the RMT, was evoked at the contralateral flexor pollicis brevis muscle. RMT was then analyzed using Repeated Measures Analysis of Variance (RM-ANOVA). Veterans with GWI related chronic headaches and body pain (N = 20, all males) had a significantly (P < 0.001) higher average RMT (% ± SD) of 77.2% ± 16.7% compared to age and gender matched military controls (N = 20, all males), whose average was 55.6% ± 8.8%. Veterans with GWI related diffuse body pain demonstrated a state of diminished corticomotor excitability, suggesting a maladaptive supraspinal pain modulatory state. The impact of this observed supraspinal functional impairment on other GWI related symptoms and the potential use of TMS in rectifying this abnormality and providing relief for pain and co-morbid symptoms requires further investigation.Trial registration: This study was registered on January 25, 2017, on ClinicalTrials.gov with the identifier: NCT03030794. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03030794 .
Asunto(s)
Dolor Crónico/fisiopatología , Corteza Motora/fisiopatología , Síndrome del Golfo Pérsico/fisiopatología , Adulto , Estudios de Casos y Controles , Guerra del Golfo , Humanos , Masculino , Personal Militar , Corteza Motora/metabolismo , Manejo del Dolor/métodos , Síndrome del Golfo Pérsico/complicaciones , Estimulación Magnética Transcraneal/métodos , VeteranosRESUMEN
Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1ß in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1ß, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.