Bioenergetic impairment in Gulf War illness assessed via 31P-MRS.

Time for post-exercise phosphocreatine-recovery (PCr-R), deemed a robust index of mitochondrial function in vivo, was previously reported to be elevated (signifying impaired ATP production) in veterans with Gulf War illness (GWI). Here we sought to replicate the finding and assess the impact of contravening previous eligibility requirements. The replication sample comprised white males. Cases reported ≥ moderate muscle-weakness to match the organ assessed to an organ affected; controls lacked recent headache or multiple symptoms. The expansion sample added cases without muscle-weakness, controls with recent headache, females, nonwhites. PCr-R, following pedal-depression-exercise, was compared in veterans with GWI versus controls (sample N = 38). In the replication sample, PCr-R results closely matched the prior report: PCr-R veterans with GWI mean(SD) = 47.7(16.5); control mean(SD) = 30.3(9.2), p = 0.017. (Prior-study PCr-R veterans with GWI mean(SD) = 46.1(17.9), control mean(SD) = 29.0(8.7), p = 0.023. Combined replication + prior samples: p = 0.001.) No case-control difference was observed in the expansion sample. In cases, PCr-R related to muscle-weakness: PCr-R = 29.9(7.1), 38.2(8.9), 47.8(15.2) for muscle-weakness rated none/low, intermediate, and high respectively (p for trend = 0.02), validating desirability of matching tissue assessed to tissue affected. In controls, headache/multiple symptoms, sex, and ethnicity each mattered (affecting PCr-R significantly). This study affirms mitochondrial/bioenergetic impairment in veterans with GWI. The importance of careful case/control selection is underscored.

Susceptibility to radiation adverse effects in veterans with Gulf War illness and healthy civilians.

We evaluated whether veterans with Gulf War illness (VGWI) report greater ionizing radiation adverse effects (RadAEs) than controls; whether radiation-sensitivity is tied to reported chemical-sensitivity; and whether environmental exposures are apparent risk factors for reported RadAEs (rRadAEs). 81 participants (41 VGWI, 40 controls) rated exposure to, and rRadAEs from, four radiation types. The relations of RadAE-propensity (defined as the ratio of rRadAEs to summed radiation exposures) to Gulf War illness (GWI) presence and severity, and to reported chemical-sensitivity were assessed. Ordinal logistic regression evaluated exposure prediction of RadAE-propensity in the full sample, in VGWI, and stratified by age and chemical-sensitivity. RadAE-propensity was increased in VGWI (vs. controls) and related to GWI severity (p < 0.01) and chemical-sensitivity (p < 0.01). Past carbon monoxide (CO) exposure emerged as a strong, robust predictor of RadAE-propensity on univariable and multivariable analyses (p < 0.001 on multivariable assessment, without and with adjustment for VGWI case status), retaining significance in age-stratified and chemical-sensitivity-stratified replication analyses. Thus, RadAE-propensity, a newly-described GWI-feature, relates to chemical-sensitivity, and is predicted by CO exposure-both features reported for nonionizing radiation sensitivity, consistent with shared mitochondrial/oxidative toxicity across radiation frequencies. Greater RadAE vulnerability fits an emerging picture of heightened drug/chemical susceptibility in VGWI.

Lower blood malondialdehyde is associated with past pesticide exposure: findings in Gulf War illness and healthy controls.

BACKGROUND: Malondialdehyde (MDA) is a candidate general marker of oxidative stress (OS). We sought to assess the relation of MDA to Gulf War illness (GWI) and to a variety of exposures. METHODS: This is an observational study involving subjects from Southern California recruited from October 2011 to May 2014. MDA was assessed in 81 participants (41 GWI-cases, 40 controls). General and Gulf-specific exposures were elicited. MDA case-control comparison was restricted to 40 matched pairs. The potential association between MDA and exposures was assessed using regression analyses. Gulf-specific exposures were incorporated into a case-specific model. RESULTS: Plasma MDA was significantly lower in GWI-cases than controls. Composite pesticide and fuel-solvent exposures negatively predicted MDA in the total sample, as well as in the analyses that included either GWI-cases or controls only. Self-reported exposure to organophosphate (OP) nerve gas was a strong predictor for lower MDA level in veterans with GWI. CONCLUSION: Past pesticide exposures predicted lower MDA in both veterans with GWI and in healthy controls.

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.

Diplomats' Mystery Illness and Pulsed Radiofrequency/Microwave Radiation.

Importance: A mystery illness striking U.S. and Canadian diplomats to Cuba (and now China) "has confounded the FBI, the State Department and US intelligence agencies" (Lederman, Weissenstein, & Lee, 2017). Sonic explanations for the so-called health attacks have long dominated media reports, propelled by peculiar sounds heard and auditory symptoms experienced. Sonic mediation was justly rejected by experts. We assessed whether pulsed radiofrequency/microwave radiation (RF/MW) exposure can accommodate reported facts in diplomats, including unusual ones. Observations: (1) Noises: Many diplomats heard chirping, ringing or grinding noises at night during episodes reportedly triggering health problems. Some reported that noises were localized with laser-like precision or said the sounds seemed to follow them (within the territory in which they were perceived). Pulsed RF/MW engenders just these apparent "sounds" via the Frey effect. Perceived "sounds" differ by head dimensions and pulse characteristics and can be perceived as located behind in or above the head. Ability to hear the "sounds" depends on high-frequency hearing and low ambient noise. (2) Signs/symptoms: Hearing loss and tinnitus are prominent in affected diplomats and in RF/MW-affected individuals. Each of the protean symptoms that diplomats report also affect persons reporting symptoms from RF/MW: sleep problems, headaches, and cognitive problems dominate in both groups. Sensations of pressure or vibration figure in each. Both encompass vision, balance, and speech problems and nosebleeds. Brain injury and brain swelling are reported in both. (3) Mechanisms: Oxidative stress provides a documented mechanism of RF/MW injury compatible with reported signs and symptoms; sequelae of endothelial dysfunction (yielding blood flow compromise), membrane damage, blood-brain barrier disruption, mitochondrial injury, apoptosis, and autoimmune triggering afford downstream mechanisms, of varying persistence, that merit investigation. (4) Of note, microwaving of the U.S. embassy in Moscow is historically documented. Conclusions and relevance: Reported facts appear consistent with pulsed RF/MW as the source of injury in affected diplomats. Nondiplomats citing symptoms from RF/MW, often with an inciting pulsed-RF/MW exposure, report compatible health conditions. Under the RF/MW hypothesis, lessons learned for diplomats and for RF/MW-affected civilians may each aid the other.

Physicians' Experiences as Patients with Statin Side Effects: A Case Series.

Physicians are among those prescribed statins and therefore, subject to potential statin adverse effects (AEs). There is little information on the impact of statin AEs on physicians affected by them. We sought to assess the character and impact of statin AEs occurring in physicians and retired physicians, and to ascertain whether/how personal experience of AEs moderated physicians' attitude toward statin use. Seven active or retired physicians from the United States communicated with the Statin Effects Study group regarding their personal experience of statin AEs. AE characteristics, experience with (their own) physicians, and impact of AE was ascertained. We inquired whether or how their experience altered their own attitude toward statins or statin AEs. Patient A: Atorvastatin 40 then 80 mg was followed by cognitive problems, neuropathy, and glucose intolerance in a Radiologist in his 50s (Naranjo criteria: probable causality). Patient B: Atorvastatin 10 mg was followed in 2 months by muscle weakness and myalgia in an Internist in his 40s (probable causality). Patient C: Atorvastatin, ezetimibe/simvastatin, rosuvastatin at varying doses was followed shortly after by irritability, myalgia, and fatigue in a Cardiac Surgeon in his 40s (probable causality). Patient D: Simvastatin 20 then 40 mg was followed in 4 years by mitochondriopathy, myopathy, neuropathy, and exercise intolerance in an Emergency Medicine physician in his 50s (definite causality). Patient E: Simvastatin 20 mg and niacin 1000 mg was followed in one month by muscle weakness and myalgia in a Physical Medicine and Rehabilitation physician in his 50s (probable causality). Patient F: Lovastatin 20 mg then simvastatin 20 mg, atorvastatin 20 mg, rosuvastatin 5 mg, niacin 20 mg and ezetimbe 10 mg was followed by muscle weakness and myalgia in an Obstetrician/Gynecologist in his 70s (definite causality). Patient G: Ezetimibe/simvastatin and atorvastatin (dose unavailable) was followed shortly after by cognitive problems in a Radiologist in her 80s (probable causality). Thus AEs affected multiple quality-of-life relevant domains, often in combination, encompassing muscle (N = 5), fatigue (N = 2), peripheral neuropathy (N = 2), cognitive (N = 2), dysglycemia (N = 1) and behavioral manifestations (N = 1). In five, the AEs affected the physician professionally. Five physicians experienced dismissive attitudes in some of their own healthcare encounters. One noted that his experience helped not only his own attention to statin AEs, but that of other physicians in his community. Several stated that their experience altered their understanding of and/or attitude toward statin AEs, and/or their view of settings in which statin use is warranted. Statin AEs can have profound impact in high functioning professionals with implications to the individual, their professional life, and those whom they serve professionally.

Fluoroquinolone-induced serious, persistent, multisymptom adverse effects.

We present a case series of four previously healthy, employed adults without significant prior medical history in each of whom symptoms developed while on fluoroquinolones (FQs), with progression that continued following discontinuation evolving to a severe, disabling multisymptom profile variably involving tendinopathy, muscle weakness, peripheral neuropathy, autonomic dysfunction, sleep disorder, cognitive dysfunction and psychiatric disturbance. Physicians and patients should be alert to the potential for FQ-induced severe disabling multisymptom pathology that may persist and progress following FQ use. Known induction by FQs of delayed mitochondrial toxicity provides a compatible mechanism, with symptom profiles (and documented mechanisms of FQ toxicity) compatible with the hypothesis of an exposure-induced mitochondrial neurogastrointestinal encephalomyopathy.

A Fat to Forget: Trans Fat Consumption and Memory.

PURPOSE: We sought to assess the relation of dietary trans fatty acid (dTFA) consumption to word-memory. METHODS: We analyzed cross-sectional data from the 1999-2005 UCSD Statin Study. Participants were 1018 adult men and non-procreative women age ≥20 without diagnosed diabetes, CVD, or extreme LDL-cholesterol. Primary analyses focused on men, as only men (N = 694) were effectively represented in younger adult ages. "Recurrent words" assessed word memory. dTFA (grams/day) estimates were calculated from the Fred Hutchinson Food Frequency Questionnaire. Regression, stratified at age 45, assessed the relation between memory and dTFA in various adjustment models. Major findings were replicated in the full sample (including women). Potential mediators were examined. RESULTS: An age-by-dTFA interaction was significant. dTFA adversely predicted memory in younger adults (only), robust to adjustment model. Each gram/day dTFA was associated with an estimated 0.76 fewer words recalled (full model) (SE = 0.27, 95%CI = 0.22,1.3, P = 0.006). Adjustment for systolic blood pressure, waist circumference and BMI (but not lipid or glycemic variables) attenuated the relationship, consistent with mediation by factors involving, relating to, or concurrently influencing, these factors. CONCLUSION: Greater dTFA was significantly associated with worse word recall in younger adults. Prooxidant and energetic detriments of dTFA and triangulation with other evidence offer prospects for causality.

First-degree relatives with behavioural adverse effects on statins.

Irritability, aggression and other adverse behavioural effects have been associated with the use of statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) and other drug classes. A number of studies have also linked low cholesterol with aggression and violence. This paper presents the cases of two first-degree male relative patients (father and son) identified by self-referral to the University of California in San Diego Statin Effects Study. Both patients experienced behavioural adverse effects on statins including irritability and aggression, however neither patient recognised a significant change in their behaviour. This may be the first report of behavioural adverse effects manifested on statins by first-degree male relatives, which may suggest possible familial/biological predisposition. These cases also highlight the issue of externalisation by patients of the origin of interpersonal discord, which may serve as an obstacle to adverse effects reporting and lead to negative outcomes for patients, and for those around them.

Improvement in sleep apnoea associated with switch from simvastatin to pravastatin.

Sleep problems have been reported as an adverse effect of statins. In a randomised trial, simvastatin at 20 mg produced significantly worse sleep quality than either placebo or pravastatin 40 mg. A possible relation to sleep apnoea was hypothesised. Here, the case of a 67-year-old man who experienced sleep apnoea on simvastatin 20 mg is presented. Objective nightly testing showed a prompt, marked, sustained and statistically significant improvement in the obstructive apnoea index when the patient switched to pravastatin 20 mg.

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.

Implications of statin adverse effects in the elderly.

The elderly differ from younger people in the relation of cholesterol to heart disease and mortality. Clinical trial evidence supports epidemiological findings in showing that high cholesterol weakens in its relationship to heart disease with age and loses (and in older age reverses) its relation to mortality. Randomised trial data confirm that lowering cholesterol no longer extends life in the elderly, even those at high risk of heart disease, and no evidence supports the presumption that the impact on all-cause morbidity is any more favourable. These findings increase the importance of statin adverse effects (AEs) in this group. Furthermore, the elderly may be more vulnerable to known AEs, and evidence provides cause for concern that new risks may supervene, including cancer, neurodegenerative disease and heart failure. Physiological evidence regarding the impact of statins on mitochondrial function, and mitochondrial function on ageing, support these concerns. Additionally, the impact of statin AEs (e.g., muscle and cognitive problems) may be amplified in this group. Effects may be misattributed to ageing. Even modestly lower cognitive and physical function in older elderly prognosticates increased disability, hospitalisation, institutionalisation, and mortality. Disability, once present, is less likely to recover. Because the risk for AEs is unattended by evidence of net benefit to the person, the use of statins in the elderly should be undertaken, if at all, with circumspection and close scrutiny for adverse effects.

Conceptual foundations of the UCSD Statin Study: a randomized controlled trial assessing the impact of statins on cognition, behavior, and biochemistry.

BACKGROUND: Statin cholesterol-lowering drugs are among the most prescribed drugs in the United States. Their cardiac benefits are substantial and well supported. However, there has been persistent controversy regarding possible favorable or adverse effects of statins or of cholesterol reduction on cognition, mood, and behavior (including aggressive or violent behavior). METHODS: The literature pertaining to the relationship of cholesterol or statins to several noncardiac domains was reviewed, including the link between statins (or cholesterol) and cognition, aggression, and serotonin. RESULTS: There are reasons to think both favorable and adverse effects of statins and low cholesterol on cognition may pertain; the balance of these factors requires further elucidation. A substantial body of literature links low cholesterol level to aggressive behavior; statin randomized trials have not supported a connection, but they have not been designed to address this issue. A limited number of reports suggest a connection between reduced cholesterol level and reduced serotonin level, but more information is needed with serotonin measures that are practical for clinical use. Whether lipophilic and hydrophilic statins differ in their impact should be assessed. CONCLUSION: There is a strong need for randomized controlled trial data to more clearly establish the impact of hydrophilic and lipophilic statins on cognition, aggression, and serotonin, as well as on other measures relevant to risks and quality-of-life impact in noncardiac domains.