CFS/ME Literature Review (Jan 2004 – Jun 2009) A literature review has been included to help inform the workshop participants of the current state of research in the field. A search on Scopus was run using the following search terms and limits: Limits Articles published or entered onto Scopus from 2004 – 2009. Search Terms A search was run using the following search terms: CFS/ME OR chronic fatigue syndrome OR myalgic encephalomyelitis OR myalgic encephalopathy. Autonomic dysfunction inc. cardiovascular abnormalities Van Houdenhove B., Eede F.V.D., Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a 'crash' in the stress system? 2009 Medical Hypotheses 72 (6); 701 - 705 http://www.scopus.com/inward/record.url?eid=2-s2.0-62949099218&partnerID=40 Department of Liaison Psychiatry, University Hospitals K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium; Collaborative Antwerp Psychiatric Research Institute, Department of Psychiatry, Antwerp University Hospital, Antwerp, Belgium; Department of Psychology, K.U. Leuven, Leuven, Belgium The etiopathogenesis of chronic fatigue syndrome (CFS) remains poorly understood. Although neuroendocrine disturbances - and hypothalamic-pituitary-adrenal (HPA) axis hypofunction in particular - have been found in a large proportion of CFS patients, it is not clear whether these disturbances are cause or consequence of the illness. After a review of the available evidence we hypothesize that that HPA axis hypofunction in CFS, conceptualized within a system-biological perspective, primarily reflects a fundamental and persistent dysregulation of the neurobiological stress system. As a result, a disturbed balance between glucocorticoid and inflammatory signaling pathways may give rise to a pathological cytokine-induced sickness response that may be the final common pathway underlying central CFS symptoms, i.e. effort/stress intolerance and pain hypersensitivity. This comprehensive hypothesis on HPA axis hypofunction in CFS may stimulate diagnostic refinement of the illness, inform treatment approaches and suggest directions for future research, particularly focusing on the neuroendocrine-immune interface and possible links between CFS, early and recent life stress, and depression. © 2009 Elsevier Ltd. All rights reserved. Smith A.K., Maloney E.M., Falkenberg V.R., Dimulescu I., Rajeevan M.S. An angiotensin-1 converting enzyme polymorphism is associated with allostatic load mediated by C- reactive protein, interleukin-6 and cortisol 2009 Psychoneuroendocrinology 34 (4); 597 – 606 http://www.scopus.com/inward/record.url?eid=2-s2.0-62549098578&partnerID=40 Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, 1600 Clifton Road, MSG41, Atlanta, GA 30333, United States; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States Allostatic load (AL) is a theoretical framework that describes the cumulative physiologic effects of adaptation to change or stress throughout the lifespan. AL is operationalized by a composite index of multiple biomarkers. Accordingly, genes, behavior and environment contribute to AL. To determine if individual differences in AL may be influenced by inherent genetic variation, we calculated an allostatic load index (ALI) for 182 Caucasian subjects derived from a population-based study of chronic fatigue syndrome. Nearly 65% of the subjects in this study sample reported fatiguing illness. ALI was calculated based on 11 measures representing metabolic, cardiovascular, inflammatory, hypothalamic- pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activities. Subjects were dichotomized into high (ALI ≥ 3) or low (ALI < 3) AL groups, and the association between high AL and 129 polymorphisms in 32 genes related to the HPA axis, neurotransmission, inflammation, cardiovascular and metabolic functions were evaluated. Polymorphisms in angiotensin-1 converting enzyme (ACE), corticotropin-releasing hormone receptor 1 (CRHR1), and serotonin receptors (HTR3A and HTR4) were associated with AL (p = 0.0007-0.0486), but only one polymorphism, rs4968591, in ACE remained significant after correction for multiple comparisons. The T allele of ACE rs4968591 was more common in subjects with high AL (67.5%) than in subjects with low AL (49.3%) (p = 0.0007), and this effect appeared independent of age, sex, body mass index and fatigue status. Additionally, high interleukin-6 (IL-6; ptrend = 0.04), and C-reactive protein (CRP; ptrend = 0.01) levels, as well as low urinary cortisol levels in females (p = 0.03) were associated with the T allele, which may result in allele-specific binding of the transcription factor, E2F1. Our results suggest a role for ACE in the bidirectional communication between the central nervous and immune systems in response to stress. Further studies will be needed (a) to replicate the association between AL and ACE polymorphisms in population studies designed to differentiate the effects of sex, age and racial/ethnic background, (b) to evaluate the effect of allele-specific binding of E2F1 at rs4968591, and (c) to examine the role of ACE in the co-regulation of CRP, IL-6 and cortisol. Sakudo A., Kato Y.H., Tajima S., Kuratsune H., Ikuta K. Visible and near-infrared spectral changes in the thumb of patients with chronic fatigue syndrome 2009 Clinica Chimica Acta 403 (01-Feb); 163 – 166 http://www.scopus.com/inward/record.url?eid=2-s2.0-64849104310&partnerID=40 Department of Virology, Center for Infectious Disease Control, Research Institute for Microbial Diseases, Yamadaoka, Suita, Osaka, 565-0871, Japan; Fatigue Clinical Center, 21st Century COE Program, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, 545-8585, Japan; Department of Health Science, Faculty of Health Science for Welfare, Kansai University of Welfare Science, Kashihara, Osaka, 582-0026, Japan Background: Chronic fatigue syndrome (CFS) patients show a persistent fatigue condition with muscle pain and impairment of concentration, memory, and sleep. Presently, the physiological basis of CFS remains unclear. In this study, spectroscopic differences in the thumb were compared between 103 CFS patients and 122 healthy controls to examine possible changes of levels of oxygenated or deoxygenated hemoglobin. Methods: Visible and near-infrared (Vis-NIR) spectroscopy was used to examine possible changes in the region of 600-1100 nm. Results: Vis-NIR spectra showed sharp peaks at 694, 970 and 1060 nm and broad peaks in the regions of 740-760 and 830-850 nm. As these peaks are possibly related to oxyhemoglobin, cytochrome c oxidase and water, levels of these factors were compared between the two groups. Statistical analysis of the absorbance of Vis-NIR spectra showed a significant decrease in water content, a significant increase in oxyhemoglobin content, and a significant increase in the oxidation of heme a + a3 and copper in cytochrome c oxidase in CFS patients. Conclusions: These changes imply accelerated blood flow and energy metabolism in the thumbs of CFS patients. © 2009 Elsevier B.V. All rights reserved. Newton J.L., Sheth A., Shin J., Pairman J., Wilton K., Burt J.A., Jones D.E. Lower ambulatory blood pressure in chronic fatigue syndrome. 2009 Psychosomatic medicine 71 (3); 361 – 365 http://www.scopus.com/inward/record.url?eid=2-s2.0-68549122686&partnerID=40 Cardiovascular Investigation Unit, Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK. OBJECTIVE: To examine blood pressure circadian rhythm in subjects with chronic fatigue syndrome (CFS) and appropriate normal and fatigued controls to correlate parameters of blood pressure regulation with perception of fatigue in an observational cohort study. The cause of CFS remains unknown and there are no effective treatments. METHODS: To address whether inactivity was a confounder, we performed a 24-hour ambulatory blood pressure monitoring in the following three subject groups: 1) CFS patients (Fukuda Diagnostic criteria) (n = 38); 2) normal controls (n = 120); and 3) a fatigue comparison group (n = 47) with the autoimmune liver disease primary biliary cirrhosis (PBC). All patients completed a measure of fatigue severity (Fatigue Impact Scale). In view of the different demographics between the patient groups, patients were age- and sex-matched on a case-by- case basis to normal controls and blood pressure parameters were compared. RESULTS: Compared with the control population, the CFS group had significantly lower systolic blood pressure (p < .0001) and mean arterial blood pressure (p = .0002) and exaggerated diurnal variation (p = .009). There was a significant inverse relationship between increasing fatigue and diurnal variation of blood pressure in both the CFS and PBC groups (p < .05). CONCLUSION: Lower blood pressure and abnormal diurnal blood pressure regulation occur in patients with CFS. We would suggest the need for a randomized, placebo-controlled trial of agents to increase blood pressure such as midodrine in CFS patients with an autonomic phenotype. Myhill S., Booth N.E., McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction 2009 International Journal of Clinical and Experimental Medicine 2 (1); 1 – 16 http://www.scopus.com/inward/record.url?eid=2-s2.0-65549089718&partnerID=40 Sarah Myhill Limited, Llangunllo -acty Knighton, Powys LD7 1SL, United Kingdom; Department of Physics, Mansfield College, University of Oxford, Oxford OX1 3RH, United