What are the symptoms of Gulf War syndrome?
Please talk with your healthcare provider about any questions or concerns you may have regarding this condition. Health Home Conditions and Diseases. What are the symptoms of Gulf War syndrome? Symptoms may include: Fatigue Musculoskeletal pain Cognitive problems Skin rashes Diarrhea Symptoms of Gulf War syndrome may resemble other medical conditions.
How many veterans are impacted by the Gulf War syndrome? What are the possible causes of Gulf War syndrome?
Possible causes include: Chemical warfare agents, particularly nerve gas, or pyridostigmine bromide, which was given as a preventive measure to soldiers likely to be exposed to chemical warfare agents. What is the treatment for Gulf War syndrome? Increased pro-inflammatory signaling through ceramides and decreased anti-inflammatory signaling through anandamide provide one potential metabolic basis for the low-level chronic inflammation that has been reported in GWI [ 19 ]. The pattern of increased ceramides in veterans from other wars associated with post-traumatic stress disorder PTSD has also been described [ 62 ].
This is consistent with the growing understanding that serine-based sphingolipid abnormalities may represent a fundamental biochemical response to infection, cell stress, or injury [ 63 ]. Many of the metabolites that contributed to the diagnostic classifiers for GWI were found to be highly correlated with other metabolites that made up the measured metabolome Figs 2 and 3 , S3 Fig , S3 and S4 Tables. In the case of the purine xanthosine, there were positive and negative correlations with both purine and non-purine metabolites Fig 3E.
In addition to the role a metabolite plays in cellular biochemistry, there are additional connections in the metabolome that arise in part because many metabolites also have a signaling role. Such connections define a resilient network or interactome that may resist external perturbation from many dietary factors, drugs, and supplements, and can remain as a feature of chronic illness for years [ 67 ].
Such an extensively coupled metabolic network may arise from correlated adaptations to the environmental exposures that may have originally triggered the illness. However, the more tightly coupled metabolic network may come at the cost of increased autonomic, immune, cardiovascular, sensory, or responses to exposure levels of environmental triggers that fail to produce responses in individuals with a more loosely coupled metabolic network. However, in each case, the measured metabolic abnormality represents a feature of a metabolic network that can be a stable feature of chronic illness for years, and may respond dynamically to resist many external perturbations Fig 3 , S3 Fig , S3 and S4 Tables.
Indeed, some of the observed metabolic changes are compensatory—they act to oppose a problem, and are negatively correlated with clinical symptom severity. Attempts to normalize one of these compensatory metabolic changes can worsen symptoms. An improved understanding of the signaling pathways that regulate the dynamics of metabolic networks as a therapeutic target has led to a deeper understanding of pathogenesis and to new approaches to treatment [ 66 , 67 , 70 ].
Shared symptoms include fatigue, sleep problems, and cognitive impairment. The only pathway that was regulated in the same direction down in both was purine metabolism Tables 3 and 6 , Fig 4.
In addition to their broad intracellular roles as intermediates and energy carriers for metabolism, extracellular purines and pyrimidines play a critical role in purinergic signaling for regulation of energy homeostasis [ 75 ], the control of chronic pain and inflammation [ 76 ], and regulate healing [ 66 ]. Altered plasma purine pools may reflect systemic alternations in purinergic signaling [ 77 ] associated with mitochondrial metabolism, healing, and the cell danger response [ 54 , 66 , 78 ].
Animal models of GWI have been produced by exposure to pyridostigmine bromide and permethrin, with or without N,N-diethyl-m-toluamide DEET , seeking to capture the effect of exposure mixtures experienced in the Persian Gulf theater. A recent plasma lipidomic analysis in rat and mouse models, and 22 veterans with GWI showed elevations in phospholipids [ 79 ].
Increased sphingomyelin species, which are an important reservoir of choline for acetylcholine synthesis and cholinergic signaling, have also been reported in the brains of mouse models of GWI [ 80 ]. Amyotrophic lateral sclerosis, a condition that was elevated in Gulf War veterans in the early years after the conflict [ 81 ], has recently been found to have some metabolomic abnormalities that overlap with GWI, including elevations in phosphatidylcholines and sphingomyelins [ 82 ].
No single measured metabolite was diagnostic for GWI. However, a diagnostic pattern of GWI was recognizable as an increase in multiple ceramides, sphingomyelins, phosphatidylcholine lipids, and acyl-carnitines, associated with a decrease in purine nucleosides, and certain endocannabinoids. This pattern of abnormalities was diagnostic Tables 2 and 3 , Fig 2. Limitations of the current study include its small size of 20 subjects per group. The small study size limited the overall statistical power and kept the mean false discovery rate for the 30 significant metabolites to 0.
Power analysis based on the mean effect size of 0. Sample sizes might be reduced to about 25—30 with the same power by using plasma instead of serum because of improved sample processing control [ 83 ]. This study was restricted to males, and sex differences are well known in metabolomic studies [ 31 ]. Future studies should include, or focus on, females with GWI, to identify shared and disparate metabolic features. This study used nonveteran controls. This choice was made in part because many Gulf War veterans who were not initially diagnosed with GWI, continued to accrue symptoms and newly meet GWI diagnostic criteria in the years after the war [ 3 ].
Each choice of a control population will have attendant pros and cons. In addition, metabolomics studies regularly benefit from a validated quality of life or clinical severity score that permits the change in specific metabolites to be correlated with symptom severity or functional performance [ 31 , 84 ].
Not every metabolite can be measured with a single mass spectrometry method. Some metabolites that are abundant inside cells may be undetectable in plasma. It is possible that unmeasured metabolites, cytokines, or cellular differences would add further to diagnostic accuracy, or offer added insights into mechanism of disease in GWI. In characterizing the roles for different metabolites, not all known roles have been cited, those that are cited need not be relevant to GWI, and scientific understanding of the roles each metabolite plays continues to evolve. Although we applied the usual statistical validation methods in omics studies such as repeated double cross validation and permutation analysis [ 38 ], no metabolomic signature of a disease can be considered confirmed until it has been validated in geographically independent cohorts of the same and related disorders.
Future studies will be required to test the generalizability of specific metabolic classifiers in other GWI cohorts.
Chronic fatiguing illness has been reported after non-military exposure to organophosphate pesticides [ 86 ]. Organophosphate pesticides are inhibitors of acetylcholinesterase. Exposures to acetylcholinesterase inhibitors, including organophosphate pesticides themselves [ 87 ], occurred in the Gulf, and have been implicated in GWI [ 5 ]. These data suggest several testable hypotheses with treatment implications, and may revise our understanding of the mechanisms of existing treatments. For instance, coenzyme Q10 coQ10 , reported to significantly improve symptoms and function in veterans with GWI [ 89 ], is known to support electron transport in mitochondria, inhibit redox changes under cell stress, and protect the cell against free radical injury.
Cell culture experiments have demonstrated that coQ10 can also prevent apoptosis by decreasing ceramide release [ 90 ], and both in vivo and in vitro studies showed that coQ10 can decrease apoptosis in response to ceramide exposure [ 91 ]. The prominence of purine and pyrimidine metabolism in the signature of GWI Table 3 , Fig 1B , the importance of purinergic signaling in the molecular stages of healing [ 66 ], and the adaptation of energy use to energy availability, suggest that therapies directed at purinergic signaling might constitute a fresh approach to treatment [ 66 , 77 ].
Similarly, the reductions of measured endocannabinoids may support an appraisal of cannabinoid therapy. With regard to potential surrogate markers of disease, the robust increase in nearly a dozen plasma ceramides in GWI veterans suggests that a reduction in ceramides might merit assessment as a biochemical marker of treatment benefit in new clinical trials. The metabolomic signature of GWI was dominated by increases in ceramides, sphingomyelins, and phosphatidylcholine lipids, and a decrease in plasma purines Figs 1 , 2 , 3 and 4 , Tables 2 and 3 , S1 Table , S1 , S2 and S3 Figs.
These differences offer novel insights into the underlying biology and have implications for new approaches to treatment. Metabolomic findings in this human study are buttressed by concordant findings in mouse and rat models of GWI. Future studies should encompass geographically distinct samples, larger sample numbers, include a measure of clinical severity, and extend assessment to female veterans. Colored circles reflect metabolite changes measured as Z-scores.
Red shaded metabolites were increased, green shaded metabolites were decreased in GWI. Yellow circles were measured but found to be unchanged. White circles reflect metabolites that were not measured in this study. Scree Plot. The green line represents the cumulative variance explained by each added component.
The blue line represents the individual percent variance explained by each component. Gulf War illness, B. Gray colored connectors represent positive correlations. Black colored connectors represent negative correlations. Same-colored metabolites in each subnetwork are from the same biochemical pathway. We thank the veterans and healthy volunteers who gave their time and effort to make this study possible. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field.
Methods Targeted, broad-spectrum serum metabolomics was used to gain insights into the biology of GWI. Results Veterans with GWI, compared to healthy controls, had abnormalities in 8 of 46 biochemical pathways interrogated. Conclusions Our data show that despite heterogeneous exposure histories, a metabolic phenotype of GWI was clearly distinguished from controls. Sample collection, transport, processing, and storage Samples were collected by venipuncture into 6 ml, red top vacutainer tubes. Results Participant characteristics Table 1 shows participant characteristics.
Download: PPT. Metabolomics pathway overview Multivariate analysis of the metabolomic profile of clearly discriminated veterans with GWI from healthy controls Fig 1. Fig 1. Metabolite and biochemical pathway abnormalities in Gulf War illness. Ceramides and sphingomyelins were increased The three most-altered biochemical pathways were ceramides, sphingomyelins, and phosphatidylcholines. Assessment of metabolomics as a diagnostic tool in Gulf War illness The top 25 metabolites that were most correlated by univariate analysis with a diagnosis of GWI are shown in Fig 2.
Table 4. Performance of metabolomics as a diagnostic tool in Gulf War illness. Fig 2. Top 25 metabolites most correlated with Gulf War illness vs healthy civilian controls. Fig 3.
Gulf War Syndrome | hesosemypu.tk
Intermetabolome correlations of the 6 metabolites selected as a classifier for the discrimination of Gulf War illness from healthy civilian controls. Discussion Veterans with GWI had objective chemical abnormalities that distinguished them from controls. Metabolic networks Many of the metabolites that contributed to the diagnostic classifiers for GWI were found to be highly correlated with other metabolites that made up the measured metabolome Figs 2 and 3 , S3 Fig , S3 and S4 Tables.
Table 6. Metabolic features of Gulf War illness and chronic fatigue syndrome.
Fig 4. Metabolic similarities and differences between Gulf War illness and chronic fatigue syndrome.
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Lipidomic findings support and extend findings from mouse and rat models of GWI Animal models of GWI have been produced by exposure to pyridostigmine bromide and permethrin, with or without N,N-diethyl-m-toluamide DEET , seeking to capture the effect of exposure mixtures experienced in the Persian Gulf theater. Diagnostic utility No single measured metabolite was diagnostic for GWI. Study limitations Limitations of the current study include its small size of 20 subjects per group.
General caveats for metabolomics studies Not every metabolite can be measured with a single mass spectrometry method. Implications for differential diagnosis, pathogenesis, and treatment The finding of metabolic pathways that are regulated in opposite directions in GWI and CFS Fig 4 , Table 3 , and the lipidomic differences that distinguish GWI from PTSD and TBI suggest that metabolomic analysis holds promise as a diagnostic tool for distinguishing these disorders.
Conclusions The metabolomic signature of GWI was dominated by increases in ceramides, sphingomyelins, and phosphatidylcholine lipids, and a decrease in plasma purines Figs 1 , 2 , 3 and 4 , Tables 2 and 3 , S1 Table , S1 , S2 and S3 Figs. Supporting information. S1 Table. Discriminating metabolites. S2 Table. S3 Table. Pairwise spearman correlations of metabolite Z-scores in veterans with Gulf War illness.
Chronic Multisymptom Illness Affecting Air Force Veterans of the Gulf War
S4 Table. Pairwise spearman correlations of metabolite Z-scores in controls. S5 Table. S1 Fig. Metabolic map of pathways disturbed in Gulf War illness. S2 Fig. Principal components analysis. S3 Fig. Metabolomic networks in Gulf War illness. Acknowledgments We thank the veterans and healthy volunteers who gave their time and effort to make this study possible.
References 1. Washington, D.
Institute of Medicine. Symptoms in 18, Persian Gulf War veterans. Latency of onset and lack of association with self-reported exposures. J Occup Environ Med. The researchers examined vestibular function in 60 veterans who participated in Operation Desert Storm, of which 54 suffered with Gulf War illnesses and six of whom were healthy - as well as 36 civilians who were of the same age and sex. They found that reduced vestibular function and poor balance appear to be prevalent in veterans with Gulf War Illness.
Gulf War Illness
To examine if vestibular function and balance could be improved, the researchers developed an electrical stimulator clipped to the earlobe and attached to a Walkman-size box that generated a low-level, random electrical noise pattern that was imperceptible to the wearer. Prof Serrador said: "The electrical stimulation added a random noise pattern into the veterans' vestibular systems that travelled through the earlobes into the inner ear, which acts like the body's accelerometer.
The findings suggest that correcting the vestibular system may treat other conditions associated with Gulf War illnesses.