The Antibiotic Treatment Trial of Gulf War Veterans' Illnesses

Collins, Joseph F.; Donta, Sam T.; Engel, Charles C.; Baseman, Joel B.; Dever, Lisa L.; Taylor, Thomas N.; Boardman, Kathy D.; Martin, Suzanne E.; Wiseman, Annette L.; Feussner, John R.

doi:10.1016/s0197-2456(02)00192-7

Cited by 23 publications

(8 citation statements)

References 27 publications

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“…Subjects were in good health prior to 1990, and had no current exclusionary diagnoses [50]. Collins et al [51] supports the use of the Fukuda definition in GWI. Control subjects consisted of gulf war era sedentary veterans and were matched to GWI subjects by age, body mass index (BMI) and ethnicity.…”

Section: Methodsmentioning

confidence: 93%

A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

et al. 2014

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A key component in the body's stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses. Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

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Section: Methodsmentioning

confidence: 93%

A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

et al. 2014

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“…Medications that could have impacted immune function were excluded. Use of the Fukuda definition in GWI is supported by Collins et al [ 12 ]. Additional details may be found in Broderick et al [ 13 ].…”

Section: Methodsmentioning

confidence: 99%

Using gene expression signatures to identify novel treatment strategies in gulf war illness

et al. 2015

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BackgroundGulf War Illness (GWI) is a complex multi-symptom disorder that affects up to one in three veterans of this 1991 conflict and for which no effective treatment has been found. Discovering novel treatment strategies for such a complex chronic illness is extremely expensive, carries a high probability of failure and a lengthy cycle time. Repurposing Food and Drug Administration approved drugs offers a cost-effective solution with a significantly abbreviated timeline.MethodsHere, we explore drug re-purposing opportunities in GWI by combining systems biology and bioinformatics techniques with pharmacogenomic information to find overlapping elements in gene expression linking GWI to successfully treated diseases. Gene modules were defined based on cellular function and their activation estimated from the differential expression of each module’s constituent genes. These gene modules were then cross-referenced with drug atlas and pharmacogenomic databases to identify agents currently used successfully for treatment in other diseases. To explore the clinical use of these drugs in illnesses similar to GWI we compared gene expression patterns in modules that were significantly expressed in GWI with expression patterns in those same modules in other illnesses.ResultsWe found 19 functional modules with significantly altered gene expression patterns in GWI. Within these modules, 45 genes were documented drug targets. Illnesses with highly correlated gene expression patterns overlapping considerably with GWI were found in 18 of the disease conditions studied. Brain, muscular and autoimmune disorders composed the bulk of these.ConclusionOf the associated drugs, immunosuppressants currently used in treating rheumatoid arthritis, and hormone based therapies were identified as the best available candidates for treating GWI symptoms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0111-3) contains supplementary material, which is available to authorized users.

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“…With regard to pesticides or herbicide exposure, this was an urban population and we relied on GWI registry data available to survey this aspect. The use of the Fukuda definition in GWI is supported by Collins et al (2002) [32]. …”

Section: Methodsmentioning

confidence: 99%

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome

et al. 2013

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BackgroundThough potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating condition presenting complex immune, endocrine and neurological symptoms. Here we compared male (n = 20) and female (n = 10) veterans with GWI separately against their healthy counterparts (n = 21 male, n = 9 female) as well as subjects with chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) (n = 12 male, n = 10 female).MethodsSubjects were assessed using a Graded eXercise Test (GXT) with blood drawn prior to exercise, at peak effort (VO2 max) and 4-hours post exercise. Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFNγ, TNFα and TNFβ in plasma samples from each phase of exercise. Linear classification models were constructed using stepwise variable selection to identify cytokine co-expression patterns characteristic of each subject group.ResultsClassification accuracies in excess of 80% were obtained using between 2 and 5 cytokine markers. Common to both GWI and CFS, IL-10 and IL-23 expression contributed in an illness and time-dependent manner, accompanied in male subjects by NK and Th1 markers IL-12, IL-15, IL-2 and IFNγ. In female GWI and CFS subjects IL-10 was again identified as a delineator but this time in the context of IL-17 and Th2 markers IL-4 and IL-5. Exercise response also differed between sexes: male GWI subjects presented characteristic cytokine signatures at rest but not at peak effort whereas the opposite was true for female subjects.ConclusionsThough individual markers varied, results collectively supported involvement of the IL-23/Th17/IL-17 axis in the delineation of GWI and CFS in a sex-specific way.

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The Antibiotic Treatment Trial of Gulf War Veterans' Illnesses

Cited by 23 publications

References 27 publications

A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

Using gene expression signatures to identify novel treatment strategies in gulf war illness

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome

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