Tag: Gulf War Illness

Verification of exercise-induced transient postural tachycardia phenotype in Gulf War Illness

Abstract:

One third of Gulf War Illness (GWI) subjects in a recent study were found to develop transient postural tachycardia after submaximal exercise stress tests. Post-exercise postural tachycardia is a previously undescribed physiological finding. A new GWI cohort was studied to verify this novel finding and characterize this cardiovascular phenomenon. Subjects followed the same protocol as before. The change in heart rate between recumbent and standing postures (ΔHR) was measured before exercise, and after submaximal bicycle exercise. About one-fourth of the verification cohort (14/57) developed transient postural tachycardia after submaximal exercise. These subjects were the Stress Test Activated Reversible Tachycardia (START) phenotype. The largest change was observed between pre-exercise and time points 2 ± 1 (mean ± SD) hours post exercise (1st Peak Effect). Eleven subjects had Postural Tachycardia Syndrome (POTS) before and after exercise. The remaining subjects had normal ΔHR (12 ± 5 bpm) and no 1st Peak Effect, and were the Stress Test Originated Phantom Perception phenotype (STOPP). These findings indicate that about one-fourth of all Gulf War Illness study participants (24/90) developed transient postural tachycardia after the submaximal exercise stress test. The START phenotype was defined as being distinctly different from POTS. Additional studies are required to examine this phenomenon in other illnesses and to determine pathological mechanisms.

Source: Garner RS, Rayhan RU, Baraniuk JN. Verification of exercise-induced transient postural tachycardia phenotype in Gulf War Illness. Am J Transl Res. 2018 Oct 15;10(10):3254-3264. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220213/ (Full article)

Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study

Editor’s comment: In the 1980s, L. O. Simpson studied abnormally shaped red blood cells in patients with ME, which he published in a paper, “Nondiscocyte Erythrocytes in Myalgic Encephalomyelitis.” He later summarized his findings in a paper entitled “The Results from Red Cell Shape Analyses of Blood Samples From Members of Myalgic Encephalomyelitis Organisations in Four Countries.” You can read it HERE.

Abstract:

BACKGROUND: Veterans with Gulf War Illness (GWI) experience chronic symptoms that include fatigue, pain, and cognitive impairment. This symptom cluster may be the consequence of impaired tissue oxygen delivery due to red blood cell (RBC) dysfunction.

OBJECTIVE: The purpose of this preliminary study was to determine whether the microrheological behavior of RBCs is altered in GWI.

METHODS: We recruited 17 cases of GWI (GWI+) and 10 age matched controls (GWI-), and examined RBC deformability and aggregation via ektacytometry along with measurement of complete blood counts.

RESULTS: RBCs were more deformable in GWI+, as indicated by higher elongation indices particularly at higher shear stress values (5.33, 9.49, and 16.89) when compared to GWI-. Aggregation formation, stability and kinetics were similar between GWI+and GWI-. Complete blood counts were also similar, with the exception of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and RBC distribution width (RDW) which was elevated in GWI+.

CONCLUSIONS: In this preliminary study, we observed increased deformability along with increased MCH, MCHC and RDW in veterans with GWI+, which may contribute to the symptomatology of GWI. Further research is required to confirm our findings and the role of RBC microrheology in GWI.

Source: Falvo MJ, Chen Y, Klein JC, Ndirangu D, Condon MR. Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study. Clin Hemorheol Microcirc. 2018;68(4):361-370. doi: 10.3233/CH-170262. https://www.ncbi.nlm.nih.gov/pubmed/29660926

VIDEO: Discovery Forum 2017 Highlights: ME/CFS and Gulf War Illness

The Solve ME/CFS Initiative presents highlights from Discovery Forum 2017 addressing the connections between Gulf War Illness and ME/CFS, featuring the presentation of Dr. Nancy Klimas of Nova Southeastern University. Dr. Klimas has more than 30 years of professional experience and has achieved international recognition for her research and clinical efforts in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf War Illness (GWI).

Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects

Abstract:

Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) have similar profiles of pain, fatigue, cognitive dysfunction and exertional exhaustion. Post-exertional malaise suggests exercise alters central nervous system functions. Lumbar punctures were performed in GWI, CFS and control subjects after (i) overnight rest (nonexercise) or (ii) submaximal bicycle exercise. Exercise induced postural tachycardia in one third of GWI subjects (Stress Test Activated Reversible Tachycardia, START). The remainder were Stress Test Originated Phantom Perception (STOPP) subjects. MicroRNAs (miRNA) in cerebrospinal fluid were amplified by quantitative PCR. Levels were equivalent between nonexercise GWI (n = 22), CFS (n = 43) and control (n = 22) groups. After exercise, START (n = 22) had significantly lower miR-22-3p than control (n = 15) and STOPP (n = 42), but higher miR-9-3p than STOPP. All post-exercise groups had significantly reduced miR-328 and miR-608 compared to nonexercise groups; these may be markers of exercise effects on the brain. Six miRNAs were significantly elevated and 12 diminished in post-exercise START, STOPP and control compared to nonexercise groups. CFS had 12 diminished miRNAs after exercise. Despite symptom overlap of CFS, GWI and other illnesses in their differential diagnosis, exercise-induced miRNA patterns in cerebrospinal fluid indicated distinct mechanisms for post-exertional malaise in CFS and START and STOPP phenotypes of GWI.

Source: James N. Baraniuk & Narayan Shivapurkar. Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects. Scientific Reports 7, Article number: 15338 (2017) doi:10.1038/s41598-017-15383-9    https://www.nature.com/articles/s41598-017-15383-9 (Full article)

Brain chemistry study shows chronic fatigue syndrome, Gulf War illness as unique disorders

WASHINGTON — Researchers at Georgetown University Medical Center have found distinct molecular signatures in two brain disorders long thought to be psychological in origin — chronic fatigue syndrome (CFS) and Gulf War Illness (GWI).

In addition, the work supports a previous observation by GUMC investigators of two variants of GWI. The disorders share commonalities, such as pain, fatigue, cognitive dysfunction and exhaustion after exercise.

Their study, published in Scientific Reports, lays groundwork needed to understand these disorders in order to diagnosis and treat them effectively, says senior investigator, James N. Baraniuk, MD, professor of medicine at Georgetown University School of Medicine. Narayan Shivapurkar, PhD, assistant professor of oncology at the medical school worked with Baraniuk on the research.

The changes in brain chemistry — observed in levels of miRNAs that turn protein production on or off — were seen 24 hours after riding a stationary bike for 25 minutes.

“We clearly see three different patterns in the brain’s production of these molecules in the CFS group and the two GWI phenotypes,” says Baraniuk. “This news will be well received by patients who suffer from these disorders who are misdiagnosed and instead may be treated for depression or other mental disorders.”

Chronic fatigue syndrome affects between 836,000 and 2.5 million Americans, according to a National Academy of Medicine report. The disorder was thought to be psychosomatic until a 2015 review of 9,000 articles over 64 years of research pointed to unspecified biological causes. Still, no definitive diagnosis or treatment is available.

Gulf War Illness has developed in more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War, Baraniuk and his colleagues have reported in earlier work.

Gulf War veterans were exposed to combinations of nerve agents, pesticides and other toxic chemicals that may have triggered the chronic pain, cognitive, gastrointestinal and other problems, Baraniuk says. Although the mechanisms remain unknown, the study provides significant insights into brain chemistry that can now be investigated.

This study focused on spinal fluid of CFS, GWI and control subjects who agreed to have a lumbar puncture. Spinal taps before exercise showed miRNA levels were the same in all participants. In contrast, miRNA levels in spinal fluid were significantly different after exercise. The CFS, control and two subtypes of GWI groups had distinct patterns of change. For example, CFS subjects who exercised had reduced levels of 12 different mRNAs, compared to those who did not exercise.

The miRNA changes in the two GWI subtypes add to other differences caused by exercise. One subgroup developed jumps in heart rate of over 30 beats when standing up that lasted for two to three days after exercise. Magnetic resonance imaging showed they had smaller brainstems in regions that control heart rate, and did not activate their brains when doing a cognitive task. In contrast, the other subgroup did not have any heart rate or brainstem changes, but did recruit additional brain regions to complete a memory test. The two groups were as different from each other as they were from the control group.

Finding two distinct pathophysiological miRNA brain patterns in patients reporting Gulf War disease “adds another layer of evidence to support neuropathology in the two different manifestations of Gulf War disease,” he says.

Baraniuk adds that miRNA levels in these disorders were different from the ones that are altered in depression, fibromyalgia, and Alzheimer’s disease, further suggesting CFS and GWI are distinct diseases.

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The study was supported by funding from The Sergeant Sullivan Center, Dr. Barbara Cottone, Dean Clarke Bridge Prize, Department of Defense Congressionally Directed Medical Research Program (CDMRP) W81XWH-15-1-0679, and National Institute of Neurological Diseases and Stroke R21NS088138 and RO1NS085131.

Baraniuk and Shivapurkar are named as inventors on a patent application that has been filed by Georgetown University related to the technology described.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness patients exhibit increased humoral responses to the Herpesviruses-encoded dUTPase: Implications in disease pathophysiology

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) are debilitating diseases with overlapping symptomology and there are currently no validated tests for definitive diagnosis of either syndrome. While there is evidence supporting the premise that some herpesviruses may act as possible triggers of ME/CFS, the involvement of herpesviruses in the pathophysiology of GWI has not been studied in spite of a higher prevalence of ME/CFS in these patients.

We have previously demonstrated that the deoxyuridine triphosphate nucleotidohydrolases (dUTPase) encoded by Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and varicella-zoster virus (VZV) possess novel functions in innate and adaptive immunity. The results of this study demonstrate that a significant percentage of patients with ME/CFS (30.91-52.7%) and GWI (29.34%) are simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or the human dUTPase when compared to controls (17.21%). GWI patients exhibited significantly higher levels of antibodies to the HHV-6 and human dUTPases than controls (p = 0.0053 and p = 0.0036, respectively), while the ME/CFS cohort had higher anti-EBV-dUTPase antibodies than in both GWI patients (p = 0.0008) and controls (p < 0.0001) as well as significantly higher anti-human dUTPase antibodies than in controls (p = 0.0241).

These results suggest that screening of patients’ sera for the presence of various combinations of anti-dUTPase antibodies could be used as potential biomarkers to help identify/distinguish patients with these syndromes and better direct treatment. This article is protected by copyright. All rights reserved.

Source: Halpin P, Williams MV, Klimas NG, Fletcher MA, Barnes Z, Ariza ME.Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness patients exhibit increased humoral responses to the Herpesviruses-encoded dUTPase: Implications in disease pathophysiology. J Med Virol. 2017 Mar 17. doi: 10.1002/jmv.24810. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28303641

 

Research Provides More Evidence That Chronic Fatigue Syndrome Is A Legitimate Medical Condition

Press Release: Researchers at Georgetown University Medical Center have found that chronic fatigue syndrome (CFS) may be rooted in distinct neurological abnormalities that can be medically tested. Although the sample studied was small, this research provides objective, physiological evidence that the controversial disorder can be considered a legitimate medical condition.

Chronic fatigue syndrome defines a range of illnesses including fibromyalgia and Gulf War syndrome, all of which have fatigue as a major symptom. Even among medical professionals, there is a disagreement about the causes, diagnosis and treatment of CFS because so much about the disorder remains unknown. One reason CFS is difficult to diagnose is because it shares symptoms with many other diseases, including multiple sclerosis and lupus. Even when other illnesses are ruled out and a CFS diagnosis is given, there is not a standardized course of treatment and it’s difficult for doctors to measure patient improvement. Estimates are that two to four times as many women as men are diagnosed with CFS.

The Georgetown study, published in the November edition of the BMC Neurology Journal, an online publication, reveals that patients diagnosed with CFS and its family of illnesses have a set of proteins in their spinal cord fluid that were not detected in healthy individuals. These proteins might give insight into the causes of CFS and could someday be used as markers to diagnose patients with the disorder.

“For years, patients with chronic fatigue syndrome have suffered from painful symptoms for which there is no blood test, diagnosable physical condition or any method for doctors to measure improvement,” said James Baraniuk, MD, assistant professor of medicine at Georgetown University Medical Center and first author on the study. “Our research provides initial evidence that chronic fatigue syndrome and its family of illnesses may be legitimate, neurological diseases and that at least part of the pathology involves the central nervous system.”

The disorder is characterized by profound fatigue that is not improved by bed rest and that may get worse with physical or mental activity, according to the Centers for Disease Control and Prevention. Persons with CFS usually function at a lower level of activity than they were capable of before the onset of illness, feeling too tired to perform normal activities or easily exhausted with no apparent reason. Patients also report various nonspecific symptoms, including weakness, muscle pain, impaired memory and/or mental concentration, insomnia and post-exertional fatigue lasting more than 24 hours.

The study looked at 50 individuals suffering from at least two disorders related to CFS, including fibromyalgia and Gulf War syndrome. By examining spinal cord fluid in patients with CFS and in healthy individuals, the researchers found that CFS patients have 16 proteins that healthy individuals do not. Five of these 16 proteins are found in all patients with the illnesses but in none of the controls. The results indicate that those 16 proteins could possibly serve as a “biosignature” for the disease and could someday be used to diagnose CFS.

“Although this is a small study and more research on the subject is necessary, these results indicate it might be possible to develop a simple laboratory test to diagnose these disorders in the future,” Baraniuk said.

Other co-authors on the paper include Begona Casada, PhD, and Hilda Maibach, MS, of Georgetown University Medical Center; Daniel J. Clauw, MD, of the University of Michigan; and Lewis K. Pannell, PhD, of the University of South Carolina; and Sonya Hess, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases.

 

Source: Georgetown University Medical Center. “Research Provides More Evidence That Chronic Fatigue Syndrome Is A Legitimate Medical Condition.” ScienceDaily. ScienceDaily, 10 January 2006. www.sciencedaily.com/releases/2006/01/060110013424.htm

Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis

Abstract:

Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined.

Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME.

To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls.

Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology.

Copyright © 2014 Elsevier Ltd. All rights reserved.

 

Source: Khaiboullina SF, DeMeirleir KL, Rawat S, Berk GS, Gaynor-Berk RS, Mijatovic T, Blatt N, Rizvanov AA, Young SG, Lombardi VC. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. Cytokine. 2015 Mar;72(1):1-8. doi: 10.1016/j.cyto.2014.11.019. Epub 2014 Dec 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410698/ (Full article)

 

A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome

Erratum in

  • PLoS One. 2014;9(4):e94161.
  • PLoS One. 2014;9(6):e100355.

Abstract:

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.

 

Source: Craddock TJ, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, Klimas NG, Broderick G. A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome. PLoS One. 2014 Jan 8;9(1):e84839. doi: 10.1371/journal.pone.0084839. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885655/ (Full article)

 

Migraine in gulf war illness and chronic fatigue syndrome: prevalence, potential mechanisms, and evaluation

Abstract:

OBJECTIVE: To assess the prevalence of headache subtypes in Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) compared to controls.

BACKGROUND: Approximately, 25% of the military personnel who served in the 1990-1991 Persian Gulf War have developed GWI. Symptoms of GWI and CFS have considerable overlap, including headache complaints. Migraines are reported in CFS. The type and prevalence of headaches in GWI have not been adequately assessed.

METHODS: 50 GWI, 39 CFS and 45 controls had structured headache evaluations based on the 2004 International Headache Society criteria. All subjects had history and physical examinations, fatigue and symptom related questionnaires, measurements of systemic hyperalgesia (dolorimetry), and assessments for exclusionary conditions.

RESULTS: Migraines were detected in 64% of GWI (odds ratio = 11.6 [4.1-32.5]) (mean [±95% CI]) and 82% of CFS subjects (odds ratio = 22.5 [7.8-64.8]) compared to only 13% of controls. There was a predominance of females in the CFS compared to GWI and controls. However, migraine status was independent of gender in GWI and CFS groups (x (2) = 2.7; P = 0.101). Measures of fatigue, pain, and other ancillary criteria were comparable between GWI and CFS subjects with and without headache.

CONCLUSION: The high prevalence of migraine in CFS was confirmed and extended to GWI subjects. GWI and CFS may share dysfunctional central pathophysiological pathways that contribute to migraine and subjective symptoms. The high migraine prevalence warrants the inclusion of a structured headache evaluation in GWI and CFS subjects, and treatment when present.

 

Source: Rayhan RU, Ravindran MK, Baraniuk JN. Migraine in gulf war illness and chronic fatigue syndrome: prevalence, potential mechanisms, and evaluation. Front Physiol. 2013 Jul 24;4:181. doi: 10.3389/fphys.2013.00181. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721020/ (Full article)