Illness In Gulf War Veterans Research Articles

IL-17 and IL-17C Signaling Protects the Intestinal Epithelium against Diisopropyl Fluorophosphate Exposure in an Acute Model of Gulf War Veterans' Illnesses.

Gulf War Veterans' Illnesses (GWI) encompasses a broad range of unexplained symptomology specific to Veterans of the Persian Gulf War. Gastrointestinal (GI) distress is prominent in veterans with GWI and often presents as irritable bowel syndrome (IBS). Neurotoxins, including organophosphorus pesticides and sarin gas, are believed to have contributed to the development of GWI, at least in a subset of Veterans. However, the effects of such agents have not been extensively studied for their potential impact to GI disorders and immunological stability. Here we utilized an established murine model of GWI to investigate deleterious effects of diisopropyl fluorophosphate (DFP) exposure on the mucosal epithelium in vivo and in vitro. In vivo, acute DFP exposure negatively impacts the mucosal epithelium by reducing tight junction proteins and antimicrobial peptides as well as altering intestinal microbiome composition. Furthermore, DFP treatment reduced the expression of IL-17 in the colonic epithelium. Conversely, both IL-17 and IL-17C treatment could combat the negative effects of DFP and other cholinesterase inhibitors in murine intestinal organoid cells. Our findings demonstrate that acute exposure to DFP can result in rapid deterioration of mechanisms protecting the GI tract from disease. These results are relevant to suspected GWI exposures and could help explain the propensity for GI disorders in GWI Veterans.

Sex Differences in Gulf War Illness: A Reanalysis of Data From the CDC Air Force Study Using CDC and Modified Kansas Case Definitions.

Estimate and compare the prevalence of Gulf War Illness (GWI) in male and female Gulf War veterans using Centers for Disease Control and Prevention (CDC) and modified Kansas case definitions. Data from the landmark CDC Air Force Study of GW Air Force veterans is used. Nearly half of the deployed veterans met the GWI CDC case definition compared with 14% of non-deployed veterans. Only 29% met the definition using the modified Kansas criteria compared with 8% of non-deployed veterans. Deployed veterans and female veterans exhibited significantly higher GWI risk. Female GW veterans had higher rates of severe and mild-to-moderate cases of GWI. Results suggest increased GWI rates based on CDC and modified Kansas criteria among deployed and female veterans. Further research is needed to examine the chronic health outcomes of female GW veterans independently.

Medical Correlates of Chronic Multisymptom Illness in Gulf War Veterans

BackgroundChronic multisymptom illness (CMI) is more prevalent among deployed than nondeployed veterans from the first Gulf War. Objective physiologic markers of CMI are lacking. The purpose of this study is to determine whether measurable abnormalities in the autonomic nervous system or hypothalamic-pituitary adrenal axis would distinguish CMI cases (CMI+) from controls (CMI-) among deployed veterans of the 1990-1991 Gulf War. MethodsThis is a cross-sectional case-control cohort study that examined deployed veterans who participated in the Phase III study: National Health Survey of Gulf War Veterans and Their Families. Autonomic nervous system and hypothalamic-pituitary adrenal axis function-related measures included: 24-hour heart-rate variability, urinary catecholamines and cortisol, hypertension, insulin sensitivity, dyslipidemia, body fat, bone mineral density, and ultrasensitive C-reactive protein. ResultsVeterans of the first Gulf War with CMI (n = 73) and without the condition (n = 111) were studied. Sociodemographic characteristics were similar. Veterans with CMI reported poorer mental and physical functioning, greater use of prescription medications, and more nonroutine clinic visits. These veterans were also more likely to have fibromyalgia syndrome, irritable bowel syndrome, metabolic syndrome, and among males, a larger waist-to-hip ratio. Lower values for a nonlinear heart-rate-variability parameter—the short-term fractal scaling exponent (DFA1), reflecting an increased randomness of beat-to-beat changes in heart rate—were observed in veterans with CMI than those veterans without it (1.28±0.16vs 1.35±0.15; p=0.005). Hypothalamic-pituitary-adrenal axis function measures were similar between the two groups. ConclusionIn this cohort of deployed veterans from the first Gulf War, we identified abnormal heart-rate variability in veterans with CMI compared to veterans without the condition, which suggests abnormal functioning of the autonomic nervous system and possible long-term cardiovascular effects.

Multiple Mild Traumatic Brain Injuries Are Associated with Increased Rates of Health Symptoms and Gulf War Illness in a Cohort of 1990-1991 Gulf War Veterans.

Recent research demonstrated a relation between traumatic brain injury (TBI), health symptoms and diagnosis of Gulf War Illness (GWI) in Gulf War Veterans, but no study has examined the impact of multiple mild TBIs (mTBIs). A total of 229 male Gulf War Veterans from the Ft Devens Cohort were categorized by a number of mTBIs reported. One-way ANOVA and chi-square test of independence were used to test for differences in total reported health symptoms and diagnosis of chronic multisymptom illness (CMI) or Kansas GWI criteria, two of the most common case definitions of GWI. A total of 72 veterans reported no mTBIs (31.4%), 26 reported one mTBI (11.4%), 25 reported two mTBIs (10.9%), and 106 veterans reported sustaining three or more mTBIs (46.3%). Veterans reporting two or more mTBIs (p < 0.01) or three or more mTBIs (p < 0.001) endorsed significantly higher rates of health symptoms than Veterans reporting no mTBIs. Significantly higher rates of CMI (p = 0.035) and Kansas GWI criteria (p < 0.001) were seen in the three or more mTBI group. Results suggest two mTBIs increase risk of health symptoms, but three mTBIs may be the threshold needed to sustain chronic symptom reporting needed for a formal diagnosis. These findings highlight the importance of implementing policies and procedures monitoring head injuries in military personnel.

Multisymptom Illness in Gulf War Veterans: A Systematic Review and Meta-Analysis.

The aim of this study was to conduct a systematic review and meta-analysis of multisymptom illness (MSI) in 1990 to 1991 Gulf/Afghanistan/Iraq War veterans. Electronic databases were searched from January 1990, June 2014 for studies on MSI prevalence in Gulf/Afghanistan/Iraq War veterans, based on the Centers for Disease Control and Prevention MSI case definition, and which included a military comparison group. Seven studies were identified among US, UK, and Australian Gulf War veterans; no studies were identified in Afghanistan/Iraq War veterans. MSI prevalence in Gulf War veterans and comparison groups ranged from 26 to 65% and from 12 to 37%, respectively. More recent studies were larger, with improved designs. The pooled odds ratio comparing Gulf War veterans to other military groups was 2.74 (95% confidence interval 2.15 to 3.51). The systematic review showed that MSI was most prevalent in Gulf War veterans, emphasizing the health burden of MSI in this veteran population.

A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness

No pharmacological treatments have been demonstrated to effectively treat chronic multisymptom illness (CMI) in Gulf War veterans (GWV). This study assessed the effect of the glucocorticoid receptor antagonist mifepristone in GWV with CMI. A randomized, double-blind, cross-over trial of mifepristone, with two six-week treatment phases separated by a one-month washout period, was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011. Participants were randomized to receive either 200mg of mifepristone per day or matched placebo first. The primary clinical outcome measure was change in self-reported physical health. Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes. Sixty-five participants enrolled, of whom 36 were randomized and 32 (mean age, 49.1 (7.2) years) completed the study. Physical and mental health status and neurocognitive functioning were poor at baseline. Mifepristone treatment was not associated with improvement in self-reported physical health (p=0.838) or in other self-reported measures of mental health. Mifepristone treatment was significantly associated with improvements in verbal learning (p=0.008, d=0.508), in the absence of improvement in other cognitive measures (working memory (p=0.914), visual learning (p=0.643) and a global composite measure (p=0.937). Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with endpoint verbal learning scores (p=0.012 and p=0.007, respectively). The magnitude of cortisol change during treatment mediated the improvement in verbal learning.This study was negative for the primary and secondary clinical outcomes. However, the data suggest a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI. Further study is warranted to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation.

Developing a brief depression screen and identifying associations with comorbid physical and psychological illness in Australian Gulf War veterans

Objective: Major depression occurs frequently in veterans, and is associated with comorbid psychological and physical disorders and poorer quality of life. Depression can be difficult to detect in primary care, while lengthy assessment instruments can deter use. Our study aimed to develop a brief depression screen that could be used by veterans and caregivers, and then to compare the association between the brief screen and comorbidities and quality of life with that of a longer instrument. Methods: Our dataset comprised 1204 male Royal Australian Navy veterans of the 1990/91 Gulf War. Depressive symptoms were assessed using the General Health Questionnaire (GHQ-12), health-related quality of life by the Short-Form Health Survey (SF-12), major depression and comorbid psychiatric diagnoses such as posttraumatic disorder (PTSD) using Diagnostic and Statistical Manual (DSM-IV) criteria. Comorbid physical illnesses including musculoskeletal disorders, chronic fatigue and diabetes were examined. Results: A brief depression screen of three key self-reported symptoms was identified. Veterans with major depression present according to the screen were over four times more likely to have multisymptom illness or PTSD, and almost twice as likely to have musculoskeletal disorders. Having depression according to the brief screen and having at least one other physical or psychological condition was associated with poorer quality of life. Similar results were obtained for a longer screen based on all GHQ-12 items. Conclusion: A 3 item depression screen performed as well as a 12 item one in identifying major depression, comorbid physical and psychological illness and poorer quality of life in veterans.

Persistent Na+ and K+ channel dysfunctions after chronic exposure to insecticides and pyridostigmine bromide

Many soldiers that served in the 1991 Gulf War developed widespread chronic pain. Exposure to insecticides and the nerve gas prophylactic pyridostigmine bromide (PB) was identified as risk factors by the Research Advisory Committee on Gulf War Veterans’ Illnesses (GWI). We examined whether a 60 day exposure to neurotoxicants/PB (NTPB) produced behavioral, molecular and cellular indices of chronic pain in the rat. Male rats were exposed to chlorpyrifos (120mg/kg; SC), permethrin (2.6mg/kg; topical), and PB (13.0mg/kg; oral) or their respective vehicles (corn oil, ethanol, and water). Permethrin can exert profound influences on voltage activated Na+ channel proteins; while chlorpyrifos and PB can increase absorption and/or retard metabolism of permethrin as well as inhibit cholinesterases. During and after exposure to these agents, we assessed muscle pressure pain thresholds and activity (distance and rest time). Eight and 12 weeks after treatments ceased, we used whole cell patch electrophysiology to examine the physiology of tissue specific DRG nociceptor channel proteins expressed in muscle and putative vascular nociceptors (voltage dependent, activation, inactivation, and deactivation). Behavioral indices were unchanged after treatment with NTPB. Eight weeks after treatments ended, the peak and average conductance of Kv7 mediated K+ currents were significantly increased in vascular nociceptors. When a specific Kv7 inhibitor was applied (linopirdine, 10μM) NTPB treated vascular nociceptors emitted significantly more spontaneous APs than vehicle treated neurons. Changes to Kv7 channel physiology were resolved 12 weeks after treatment. The molecular alterations to Kv7 channel proteins and the specific susceptibility of the vascular nociceptor population could be important for the etiology of GWI pain.

Gulf War Illness

To further elucidate the nature of illness in veterans of the 1990 to 1991 Gulf War (GW) by examining the GW Illness (GWI) definition advanced by the Centers for Disease Control and Prevention, which specified caseness as having at least one symptom from two of the three factors: fatigue, mood-cognition, and musculoskeletal. A total of 311 male and female GW veterans drawn from across the nation were assessed in a survey-based study approximately 10 years after deployment. A total of 33.8% of the probability-weighted sample met GWI criteria. Multiple symptom profiles were found, with more than half of GWI cases endorsing a symptom on all the three factors, and almost all cases endorsing at least one mood-cognition symptom. Although the Centers for Disease Control and Prevention definition has some limitations that should be considered, it remains a useful tool for assessing the presence of illness in GW veterans.

Acetylcholinesterase inhibitors and Gulf War illnesses

Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose-response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV.

Acetylcholinesterase Activity in Veterans of the First Gulf War

BackgroundFactors affecting acetylcholine-mediated neurotransmission have been proposed as possible explanations for physical and mental health symptoms among veterans of the 1990-1991 Gulf War. This study was designed to examine relationships...

Predictors of Exercise Compliance in Individuals with Gulf War Veterans Illnesses: Department of Veterans Affairs Cooperative Study 470

Although the health benefits of exercise for individuals with Persian Gulf War veterans illnesses (GWVI) are documented, many of these individuals do not exercise regularly enough to obtain benefits. The purpose of this study was to investigate factors predicting exercise compliance among individuals with GWVI in a multicenter, randomized, clinical trial. Participants were 1,092 veterans who reported at least two of the following cardinal symptoms of GWVI: (1) fatigue, (2) musculoskeletal pain, and (3) cognitive problems. Participants received exercise alone or exercise and cognitive-behavioral therapy. The overall level of compliance was relatively low during the exercise treatment phase (46.2%) and decreased by one-half during the follow-up period (23.0%). Predictors of compliance during treatment included less pain and greater age, motivation, and body mass index. Predictors of compliance during the follow-up period included less pain and greater age. The results highlight factors that affect adoption and maintenance of physical activity in a population with GWVI.

The Antibiotic Treatment Trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics

Many veterans who were deployed to the Persian Gulf during the 1990–1991 Gulf War developed multiple unexplained symptoms such as pain, fatigue, and neurocognitive problems. This constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI). Although there is no proven explanation for the cause of GWVI, one fairly widespread explanation is systemic Mycoplasma fermentans infection. The Antibiotic Treatment Trial of GWVI is a randomized placebo-controlled trial to determine whether a 1-year course of doxycycline treatment in deployed Gulf War veterans with GWVI and testing as Mycoplasma species positive will improve their overall functional status as measured by the Physical Component Summary of the SF-36V questionnaire. The study of a multisymptom illness such as GWVI is complicated by the nonspecific nature of the illness, the unknown etiology, and the lack of a widely accepted outcome measure. The presumption of mycoplasma infection raises concerns regarding the methodology for determination of mycoplasma infection, the choice of treatment, and the duration of treatment. However, such a presumption allows the formulation of a clear testable hypothesis that can be tested with treatments with known rates of adverse events and known activity against Mycoplasma species. This paper describes the major issues faced by the investigators during planning, the study design, the patient screening results, and the baseline characteristics of the study patients. There were 2712 patients screened for study entry at 26 Department of Veterans Affairs and two Department of Defense medical centers. Of these, 491 met all study entry criteria and were randomized to either 1 year of doxycycline (200 mg/day) or 1 year of placebo. All patients were seen monthly during treatment and at 6 months after the end of treatment. Study patients had a mean age of 41 years and were mostly male (86%), white (64%), married (68%), and employed full-time (71%).

Self-reported exposures and their association with unexplained illness in a population-based case-control study of Gulf War veterans.

Many factors have been considered as possible causes of the unexplained illness reported by veterans of the Gulf War (GW). In this study, we report an analysis of risk factors and unexplained illness in a population-based sample of GW veterans who underwent clinical evaluation. Multiple risk factors were compared in 241 veterans who met criteria for unexplained illness and 113 healthy controls. Results suggest that GW unexplained illness is most highly associated with combat conditions, heat stress, and having sought medical attention during the GW. When controlling for multiple simultaneous exposures during the GW, interactions around pyridostigmine bromide, insecticides and repellents, and stress were not significant. These results indicate that most unexplained illness in GW veterans cannot be explained by neurotoxic effects of exposures to chemicals that inhibit cholinesterase activity.

A Multicenter Two by Two Factorial Trial of Cognitive Behavioral Therapy and Aerobic Exercise for Gulf War Veterans' Illnesses: Design of a Veterans Affairs Cooperative Study (CSP #470)

The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #470 is a 2 × 2 factorial trial designed to evaluate the hypothesis that both cognitive behavioral therapy (CBT) and aerobic exercise will significantly improve physical function in participants with Gulf War veterans' illnesses (GWVI), and that adding CBT to aerobic exercise will provide further incremental benefit. One thousand three hundred fifty-six veterans will be randomized to one of four treatment arms: CBT plus aerobic exercise plus usual and customary care, aerobic exercise plus usual and customary care, CBT plus usual and customary care, or usual and customary care alone. The study duration is 2.5 years with 1.5 years of intake and 1 year of follow-up. The primary outcome measure is the proportion of veterans improved more than seven units on the physical component summary (PCS) scale of the Short Form Health Survey for Veterans (SF-36V) measured 12 months after randomization. This generic quality-of-life measure was chosen because there is no disease-specific measure for GWVI and the symptoms of GWVI span a wide range of physical manifestations that are related to the domains covered by the PCS scale. Sample size was determined to detect all six pairwise comparisons between the four treatment arms with 90% power and a Bonferroni adjustment for an overall type I error of 0.05 or 0.05/6 = 0.0083. CSP #470 was initiated in May 1999 in 18 VA and two Department of Defense medical centers. To date this represents the largest randomized trial designed to evaluate treatments for individuals with unexplained physical symptoms. This paper will focus on the rationale and unique features of the study design. Control Clin Trials 2001;22:310–332

Stress and immune dysfunction in Gulf War veterans.

The role of stress and immunological abnormalities, as well as the neuroendocrine regulation of these two variables, in illnesses in Gulf War veterans (GWVs) is unknown. Many GWV patients complain of skin and joint problems, that is, disorders that may have a common immunological basis. Post-traumatic stress disorder (PTSD), an anxiety disorder associated with chronic stress, is diagnosed in approximately 10% of the Alabama GWVs. Chronic stress can lead to a reduced capacity to resist disease. Recent work suggests that a dysregulated balance of cytokines produced by T helper cells of the immune system can play a significant role in stress-related illnesses. Indeed, a balanced immune response (cell-mediated and humoral immunity) is an important defense mechanism, and cytokines can regulate this balance. It is therefore plausible that stress-induced changes in hormones (such as cortisol and catecholamines) and cytokines, both of which have been implicated in altering levels of cellular or humoral immunity, may play a role in GWV illnesses.

Clinical findings for the first 1000 Gulf war veterans in the Ministry of Defence's medical assessment programme

Objective: To review the clinical findings in the first 1000 veterans seen in the Ministry of Defence's Gulf war medical assessment programme to examine whether there was a particular illness...

Illness in Gulf War Veterans&lt;subtitle&gt;Causes and Consequences&lt;/subtitle&gt;

In 1990 and 1991, 697 000 men and women of the US armed forces served in the Persian Gulf. During their service these veterans were exposed to a wide array of known and potential hazards to health. These risk factors included extremes of heat and cold, blowing dust, smoke from oil well fires, petroleum fuels and their combustion products, pyridostigmine bromide (administered as pretreatment for potential poison gas exposure), anthrax and botulinum toxoid vaccines, depleted uranium (used in certain artillery shells), infectious diseases, chemical warfare agents, pesticides, and pervasive psychological and physiological stress. 1 See also pp 215, 223, 231, and 238. Since returning home, many Persian Gulf War veterans have developed illness. Some have specific diseases that clearly resulted from their military service. 2 For example, 32 veterans have been diagnosed with leishmaniasis, and 7 have developed malaria. Several dozen retain fragments of depleted uranium embedded in their bodies,