Metabolic features of Gulf War illness.

BACKGROUND: More than 230,000 veterans-about 1/3 of US personnel deployed in the 1990-1991 Persian Gulf War-developed chronic, multi-symptom health problems now called "Gulf War illness" (GWI), for which mechanisms and objective diagnostic signatures continue to be sought. METHODS: Targeted, broad-spectrum serum metabolomics was used to gain insights into the biology of GWI. 40 male participants, included 20 veterans who met both Kansas and CDC diagnostic criteria for GWI and 20 nonveteran controls without similar symptoms that were 1:1 matched to GWI cases by age, sex, and ethnicity. Serum samples were collected and archived at -80° C prior to testing. 358 metabolites from 46 biochemical pathways were measured by hydrophilic interaction liquid chromatography and tandem mass spectrometry. RESULTS: Veterans with GWI, compared to healthy controls, had abnormalities in 8 of 46 biochemical pathways interrogated. Lipid abnormalities accounted for 78% of the metabolic impact. Fifteen ceramides and sphingomyelins, and four phosphatidylcholine lipids were increased. Five of the 8 pathways were shared with the previously reported metabolic phenotype of males with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, 4 of the 5 shared pathways were regulated in opposite directions; key pathways that were up-regulated in GWI were down-regulated in ME/CFS. The single pathway regulated in the same direction was purines, which were decreased. CONCLUSIONS: Our data show that despite heterogeneous exposure histories, a metabolic phenotype of GWI was clearly distinguished from controls. Metabolomic differences between GWI and ME/CFS show that common clinical symptoms like fatigue can have different chemical mechanisms and different diagnostic implications. Larger studies will be needed to validate these findings.

Depressed prostaglandins and leukotrienes in veterans with Gulf War illness.

Background: There is need to understand biological markers and mechanisms in Gulf War illness (GWI). Goal: To examine whether and how eicosanoids - prostaglandins and leukotrienes - are altered in veterans with GWI. Methods: Seventy participants including 37 GWI and 33 healthy controls, shared exposure information, and had plasma eicosanoids assessed - prostaglandin F2 alpha (pgf2α), prostaglandin D2 (pgd2), leukotriene B4 (lb4) among others. Values were compared for GWI versus controls. Eicosanoid intercorrelations were compared in cases vs. controls. For the most significantly altered eicosanoid in GWI, exposure and symptom relations were assessed. Results: Prostaglandins and leukotrienes were depressed in GWI, strongest for pgf2α, then lb4. Eicosanoid intercorrelations differed in GWI vs. controls. Fuel-solvent, pesticide, radioactive chemicals and metal exposures related negatively to pgf2α; as, in GWI, did chemical attack and vaccines. Multivariate predictors included fuels-solvents and radioactive chemicals (negative); tetanus vaccine and herbicides (positive). Fuels-solvents and radioactive chemicals predicted lower pgf2α in cases, controls, and all participants controlled for case status. Lower pgf2α related to GWI "Kansas criteria" domains of pain, respiratory, and (borderline significantly) skin symptoms. Conclusion: Multiple eicosanoids are depressed in GWI, particularly pgf2α and lb4. Prior fuel-solvent exposures, radioactive chemicals, and (in GWI cases) vaccines were linked to lower pgf2α.

Coenzyme Q10 benefits symptoms in Gulf War veterans: results of a randomized double-blind study.

We sought to assess whether coenzyme Q10 (CoQ10) benefits the chronic multisymptom problems that affect one-quarter to one-third of 1990-1 Gulf War veterans, using a randomized, double-blind, placebo-controlled study. Participants were 46 veterans meeting Kansas and Centers for Disease Control criteria for Gulf War illness. Intervention was PharmaNord (Denmark) CoQ10 100 mg per day (Q100), 300 mg per day (Q300), or an identical-appearing placebo for 3.5 ± 0.5 months. General self-rated health (GSRH), the primary outcome, differed across randomization arms at baseline, and sex significantly predicted GSRH change, compelling adjustment for baseline GSRH and prompting sex-stratified analysis. GSRH showed no significant benefit in the combined-sex sample. Among males (85% of participants), Q100 significantly benefited GSRH versus placebo and versus Q300, providing emphasis on Q100. Physical function (summary performance score, SPS) improved on Q100 versus placebo. A rise in CoQ10 approached significance as a predictor of improvement in GSRH and significantly predicted SPS improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on Q100 versus placebo was favorable for all except sleep problems; sign test 19:1, p=0.00004) with several symptoms individually significant. Significance for these symptoms despite the small sample underscores large effect sizes, and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. In conclusion, Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness. Examination in a larger sample is warranted, and findings from this study can inform the conduct of a larger trial.

Recruiting a special sample with sparse resources: lessons from a study of Gulf War veterans.

BACKGROUND: Recruitment is the most common failure point for clinical studies, with recruitment failure adversely affecting science, dollar costs, human capital, and the ethical risk-benefit trade-off to study participants. Added problems attend recruitment of special and/or challenging candidate populations, particularly in settings of sparse recruitment resources. Obstacles to study recruitment and participation of ill Gulf War veterans (GWVs) include health barriers, work and family obligations, mistrust of the medical/scientific community, and challenges to identifying/reaching potential participants. PURPOSE: We sought to identify and implement a minimal-cost multipronged recruitment approach for a small single-site (<50 participants) study of a special group, ill GWVs, with approaches substantially applicable to other recruitment settings and larger multisite studies. METHODS: Categories of recruitment approach included directed as well as general media, collaborations with support groups/interest groups, local free advertising resources (Craigslist and Backpage), physician outreach, Internet-based approaches, and referrals from study participants and screenees. We describe the subcategories and yield of each approach within each approach. RESULTS: Each approach contributed candidates to the final recruitment tally, with the largest fractional contribution by directed media (52%). Among the remainder, no other individual approach was clearly dominant (largest contribution: 13%). LIMITATIONS: Special population subsamples present special challenges; all approaches cited may not be useful in all settings and subpopulations. CONCLUSIONS: A multipronged suite of minimal-cost approaches led to successful recruitment to target for this single-site clinical trial for a special population with significant recruitment challenges. It additionally yielded a nation-wide corpus of several hundred individuals interested in participation in future studies of GWVs. While certain approaches produced disproportionate yield, it was not possible to predict these a priori. We suggest that this model, which incorporates a suite of approaches, and delineates backup approaches in the event of recruitment shortfall, may provide a template applicable to recruitment of other special samples in settings of limited resources and also is germane to cost-effective recruitment in studies more generally.

Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial.

BACKGROUND: Some studies have suggested reductions in blood pressure (BP)with statin treatment, particularly in persons with hypertension. Randomized trial evidence is limited. METHODS: We performed a randomized, double-blind, placebo-controlled trial with equal allocation to simvastatin, 20 mg; pravastatin sodium,40 mg; or placebo for 6 months. Nine hundred seventy-three men and women without known cardiovascular disease or diabetes mellitus, with low-density lipoprotein cholesterol screening levels of 115 to 190 mg/dL, had assessment of systolic and diastolic BP (SBP and DBP, respectively). Blood pressure values were compared for placebo vs statins by intention-to-treat (ITT) analysis. Additional analyses were performed that (1) were confined to subjects with neither high baseline BP (SBP>140 mm Hg or DBP>90 mm Hg) nor receiving BP medications, to exclude groups in whom BP medications or medication changes may have influenced results, and (2) separately evaluated simvastatin and pravastatin (vs placebo). The time course of BP changes after statin initiation and the effect of stopping statins on BP were examined. RESULTS: Statins modestly but significantly reduced BP relative to placebo,by 2.2 mm Hg for SBP (P=.02) and 2.4 mm Hg for DBP (P<.001) in ITT analysis. Blood pressure reductions ranged from 2.4 to 2.8 mm Hg for both SBP and DBP with both simvastatin and pravastatin, in those subjects with full follow-up, and without potential for influence by BP medications (ie, neither receiving nor meriting BP medications). CONCLUSIONS: Reductions in SBP and DBP occurred with hydrophilic and lipophilic statins and extended to normotensive subjects. These modest effects may contribute to the reduced risk of stroke and cardiovascular events reported on statins. Trial Registration clinicaltrials.gov Identifier: NCT00330980.