Carnosine treatment for gulf war illness: a randomized controlled trial.
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ABSTRACT:
SUBMITTER: Baraniuk JN
PROVIDER: S-EPMC4209301 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Approximately 30% of the 700,000 US veterans of the 1990-1991 Persian Gulf War developed multiple persistent symptoms called Gulf War illness. While the etiology is uncertain, several toxic exposures including pesticides and chemical warfare agents have shown associations. There is no effective medical treatment. An intervention to enhance detoxification developed by Hubbard has improved quality of life and/or reduced body burdens in other cohorts. We evaluated its feasibility and efficacy in ill Gulf War (GW) veterans in a randomized, waitlist-controlled, pilot study at a community-based rehabilitation facility in the United States. Eligible participants (n = 32) were randomly assigned to the intervention (n = 22) or a four-week waitlist control (n = 10). The daily 4-6 week intervention consisted of exercise, sauna-induced sweating, crystalline nicotinic acid and other supplements. Primary outcomes included recruitment, retention and safety; and efficacy was measured via Veteran's Short Form-36 (SF-36) quality of life, McGill pain, multidimensional fatigue inventory questionnaires and neuropsychological batteries. Scoring of outcomes was blinded. All 32 completed the trial and 21 completed 3-month follow-up. Mean SF-36 physical component summary score after the intervention was 6.9 (95% CI; -0.3, 14.2) points higher compared to waitlist control and 11 of 16 quality of life, pain and fatigue measures improved, with no serious adverse events. Most improvements were retained after 3 months. The Hubbard regimen was feasible, safe and might offer relief for symptoms of GW illness.
| S-EPMC6862571 | biostudies-literature
Project description:BackgroundMany Gulf War (GW) Veterans report chronic symptoms including pain, fatigue, and cognitive impairment, commonly defined as Gulf War Illness (GWI). Complementary and integrative health (CIH) therapies may potentially improve multiple symptoms of GWI.ObjectiveTo examine the effectiveness of combining 2 commonly available CIH therapies, mindfulness meditation and auricular acupuncture, in improving health-related functioning and multiple symptom domains of GWI (e.g., pain, fatigue).MethodsThis study was a randomized controlled trial in which Veterans with GWI were randomly assigned to either the intervention group (n = 75), wherein they received 2 distinct CIH therapies - mindfulness meditation and auricular acupuncture, or the active control group, wherein they received a GW Health Education (GWHE) program (n = 74), each lasting 8 weeks. Self-report health measures were assessed at baseline, endpoint, and 3 month follow-up.ResultsIn the intention-to-treat analyses, there were significant between-group differences for mental-health related functioning, fatigue, depression symptoms, and Kansas total severity scores for symptoms in which the CIH group had improved scores for these outcomes at endpoint compared to the GWHE group (all P ≤ .05). The CIH group also had significant reductions in pain interference at endpoint and follow-up compared to baseline (estimated marginal mean difference: -2.52 and -2.22, respectively; all P = .01), whereas no significant changes were observed in the GWHE group. For pain characteristics, the GWHE group had a worsening of pain at endpoint compared to baseline (estimated marginal mean difference: +2.83; P = .01), while no change was observed in the CIH group.ConclusionFindings suggest a possible beneficial effect of combining 2 CIH therapies, mindfulness meditation and auricular acupuncture, in reducing overall symptom severity and individual symptom domains of fatigue, musculoskeletal, and mood/cognition in Veterans with GWI.Trial registrationClinical Trials identifier NCT02180243.
| S-EPMC10161299 | biostudies-literature
Project description: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.
| S-EPMC8217272 | biostudies-literature
Project description:Long term consequences of combined pyridostigmine bromide and permethrin exposure in C57BL6/J mice using a well characterized mouse model of exposure to these Gulf War agents. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semi-acute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches – stable isotope dimethyl labeling (SIDL) and isobaric tags for relative and absolute quantitation (iTRAQ). The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW-agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at five months post exposure to PB+PER
2017-02-01 | PXD005185 | Pride
Project description:BACKGROUND:Gulf War Illness is a Complex Medical Illness characterized by multiple symptoms, including fatigue, sleep and mood disturbances, cognitive dysfunction, and musculoskeletal pain affecting veterans of the first Gulf War. No standard of care treatment exists. METHODS:This pragmatic Randomized Clinical Trial tested the effects of individualized acupuncture treatments offered in extant acupuncture practices in the community; practitioners had at least 5 years of experience plus additional training provided by the study. Veterans with diagnosed symptoms of Gulf War Illness were randomized to either six months of biweekly acupuncture treatments (group 1, n = 52) or 2 months of waitlist followed by weekly acupuncture treatments (group 2, n = 52). Measurements were taken at baseline, 2, 4 and 6 months. The primary outcome is the SF-36 physical component scale score (SF-36P) and the secondary outcome is the McGill Pain scale. RESULTS:Of the 104 subjects who underwent randomization, 85 completed the protocol (82%). A clinically and statistically significant average improvement of 9.4 points (p = 0.03) in the SF-36P was observed for group 1 at month 6 compared to group 2, adjusting for baseline pain. The secondary outcome of McGill pain index produced similar results; at 6 months, group 1 was estimated to experience a reduction of approximately 3.6 points (p = 0.04) compared to group 2. CONCLUSIONS:Individualized acupuncture treatment of sufficient dose appears to offer significant relief of physical disability and pain for veterans with Gulf War Illness. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Gulf War Illness Research Program under Award No. W81XWH-09-2-0064. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. TRIAL REGISTRATION:ClinicalTrials.gov NCT01305811.
| S-EPMC4816551 | biostudies-literature
Project description:Altered gut microbiome in a mouse model of gulf war illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation
| PRJEB19474 | ENA
Project description:Approximately 30 percent of U.S. veterans deployed during the Gulf War (1990-1991) have been diagnosed with Gulf War Illness (GWI), a chronic multi-symptom disorder without widely available specific treatments. We investigated whether the consumption of Concord grape juice (CGJ), rich in anti-inflammatory flavonoids, would be tolerated and safe in individuals with GWI and explored improvement in cognitive function and fatigue. Thirty-six veterans with GWI enrolled in a 24-week randomized, double-blind, Phase I/IIA clinical trial to explore safety, tolerability, and feasibility of 16 ounces daily of commercially available CGJ compared to placebo. Participants completed neurocognitive tests and self-reported surveys at baseline, 12 and 24 weeks. Thirty-one participants (86%) completed the study; no dropouts were related to side effects. Thirty participants (83%) documented ≥80% adherence. There were no statistically significant unadjusted differences between CGJ and placebo groups in change in efficacy measures from baseline to endpoint. We employed general linear regression models controlling for baseline differences between groups which indicated statistically significant improvement in the Halstead Category Test-Russell Revised Version (RCAT) at endpoint in the CGJ group compared to placebo (8.4 points, p = 0.04). Other measures of cognitive functioning did not indicate significant improvements in the adjusted analyses (p-values: 0.09-0.32), nor did the fatigue variable (p = 0.67). CGJ was safe and well-tolerated by veterans with GWI. Our data suggest high tolerability and potential benefit from CGJ in veterans with GWI and can be used to inform future studies of efficacy.
| S-EPMC7277758 | biostudies-literature
Project description:ImportanceFew evidence-based treatments are available for Gulf War illness (GWI). Behavioral treatments that target factors known to maintain the disability from GWI, such as problem-solving impairment, may be beneficial. Problem-solving treatment (PST) targets problem-solving impairment and is an evidence-based treatment for other conditions.ObjectiveTo examine the efficacy of PST to reduce disability, problem-solving impairment, and physical symptoms in GWI.Design, setting, and participantsThis multicenter randomized clinical trial conducted in the US Department of Veterans Affairs compared PST with health education in a volunteer sample of 511 Gulf War veterans with GWI and disability (January 1, 2015, to September 1, 2019); outcomes were assessed at 12 weeks and 6 months. Statistical analysis was conducted between January 1, 2019, and December 31, 2020.InterventionsProblem-solving treatment taught skills to improve problem-solving. Health education provided didactic health information. Both were delivered by telephone weekly for 12 weeks.Main outcomes and measuresThe primary outcome was reduction from baseline to 12 weeks in self-report of disability (World Health Organization Disability Assessment Schedule). Secondary outcomes were reductions in self-report of problem-solving impairment and objective problem-solving. Exploratory outcomes were reductions in pain, pain disability, and fatigue.ResultsA total of 268 veterans (mean [SD] age, 52.9 [7.3] years; 88.4% male; 66.8% White) were randomized to PST (n = 135) or health education (n = 133). Most participants completed all 12 sessions of PST (114 of 135 [84.4%]) and health education (120 of 133 [90.2%]). No difference was found between groups in reductions in disability at the end of treatment. Results suggested that PST reduced problem-solving impairment (moderate effect, 0.42; P = .01) and disability at 6 months (moderate effect, 0.39; P = .06) compared with health education.Conclusions and relevanceIn this randomized clinical trial of the efficacy of PST for GWI, no difference was found between groups in reduction in disability at 12 weeks. Problem-solving treatment had high adherence and reduced problem-solving impairment and potentially reduced disability at 6 months compared with health education. These findings should be confirmed in future studies.Trial registrationClinicalTrials.gov Identifier: NCT02161133.
| S-EPMC9856484 | biostudies-literature
Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.
2019-03-15 | GSE112905 | GEO
Project description:Low level sarin nerve gas and other anti-cholinesterase agents have been implicated in Gulf War illness (GWI), a chronic multi-symptom disorder characterized by cognitive, pain and fatigue symptoms that continues to afflict roughly 32% of veterans from the 1990-1991 Gulf War. How disrupting cholinergic synaptic transmission could produce chronic illness is unclear, but recent research indicates that acetylcholine also mediates communication between axons and oligodendrocytes. Here we investigated the hypothesis that oligodendrocyte development is disrupted by Gulf War agents, by experiments using the sarin-surrogate acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP). The effects of corticosterone, which is used in some GWI animal models, were also investigated. The data show that DFP decreased both the number of mature and dividing oligodendrocytes in the rat prefrontal cortex (PFC), but differences were found between PFC and corpus callosum. The differences seen between the PFC and corpus callosum likely reflect the higher percentage of proliferating oligodendroglia in the adult PFC. In cell culture, DFP also decreased oligodendrocyte survival through a non-cholinergic mechanism. Corticosterone promoted maturation of oligodendrocytes, and when used in combination with DFP it had protective effects by increasing the pool of mature oligodendrocytes and decreasing proliferation. Cell culture studies indicate direct effects of both DFP and corticosterone on OPCs, and by comparison with in vivo results, we conclude that in addition to direct effects, systemic effects and interruption of neuron-glia interactions contribute to the detrimental effects of GW agents on oligodendrocytes. Our results demonstrate that oligodendrocytes are an important component of the pathophysiology of GWI.
| S-EPMC6899710 | biostudies-literature