[Return to digest index] --------------------------------------------- This is a special digest of Co-Cure Research & Medical posts only Problems? Write to firstname.lastname@example.org --------------------------------------------- ---------------------------------------------------------------------- Date: Tue, 3 Jul 2007 17:26:17 -0400 From: "Bernice A. Melsky"
Subject: RES: Adhesion molecules and cytokine expression in fibromyalgia patients: Increased L-selectin on monocytes and neutrophils Adhesion molecules and cytokine expression in fibromyalgia patients: Increased L-selectin on monocytes and neutrophils. J Neuroimmunol. 2007 Jun 27; [Epub ahead of print] Macedo JA, Hesse J, Turner JD, Ammerlaan W, Gierens A, Hellhammer DH, Muller CP. Institute of Immunology, Laboratoire National de Santé, 20A rue Auguste Lumičre, L-1950, Luxembourg; Department of Immunology of the Graduate School of Psychobiology, University of Trier, 54290 Trier, Germany. PMID: 17602758 Several lines of evidence implicate the immune system in the pathophysiology of fibromyalgia (FM). We investigated the role of cytokines and adhesion molecules involved in immune cell trafficking and the influence of 1.5 mg of dexamethasone (DEX) per os on their expression. L-selectin was elevated on monocytes and neutrophils of FM patients. Differences in group response to DEX were observed for CD11b on NK cells, sICAM-1 and IL-2. This study shows a slight disturbance in the innate immune system of FM patients, and suggests an enhanced adhesion and recruitment of leukocytes to inflammatory sites. [Return to top] ------------------------------ Date: Wed, 4 Jul 2007 13:16:01 -0400 From: "Bernice A. Melsky" Subject: RES: Chronic widespread pain in the spectrum of rheumatological diseases Chronic widespread pain in the spectrum of rheumatological diseases. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):391-402. Bliddal H, Danneskiold-Samsře B. The Parker Institute, Frederiksberg Hospital, Ndr Fasanvej 57, 2000 Frederiksberg, Denmark. PMID: 17602990 Chronic pain is very common in all European countries, with musculoskeletal problems predominating. About 1% of the adult population develops a syndrome of chronic muscle pain, fibromyalgia (FMS), characterized by multiple tender points, back or neck pain, and a number of associated problems from other organs, including a high frequency of fatigue. Evidence points to central sensitization as an important neurophysiological aberration in the development of FMS. Importantly, these neurological changes may result from inadequately treated chronic focal pain problems such as osteoarthritis or myofascial pain. It is important for health professionals to be aware of this syndrome and to diagnose the patients to avoid a steady increase in diagnostic tests. On the other hand, patients with chronic widespread pain have an increased risk of developing malignancies, and new or changed symptoms should be diagnosed even in FMS. In rheumatology practice it is especially important to be aware of the existence of FMS in association with immune inflammatory diseases, most commonly lupus and rheumatoid arthritis. Differential diagnoses are other causes of chronic pain, e.g. thyroid disease. The costs of this syndrome are substantial due to loss of working capability and direct expenses of medication and health-system usage. Fibromyalgia patients need recognition of their pain syndrome if they are to comply with treatment. Lack of empathy and understanding by healthcare professionals often leads to patient frustration and inappropriate illness behavior, often associated with some exaggeration of symptoms in an effort to gain some legitimacy for their problem. FMS is multifaceted, and treatment consists of both medical interventions, with emphasis on agents acting on the central nervous system, and physical exercises. [Return to top] ------------------------------ Date: Wed, 4 Jul 2007 13:20:02 -0400 From: "Bernice A. Melsky" Subject: RES: Epidemiology of chronic musculoskeletal pain Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):403-25. McBeth J, Jones K. ARC Epidemiology Unit, The Medical School, The University of Manchester, Manchester, M13 9PT, UK. PMID: 17602991 The rate of musculoskeletal pain in adolescent and adult populations is examined, with a focus on three commonly reported pain disorders: shoulder pain, low back pain and fibromyalgia/chronic widespread pain. There is a paucity of data on musculoskeletal pain in adolescent populations. Those studies available suggest that pain is common, although the actual rates are unclear. This is probably due to differences in study methodologies and populations. Pain is commonly reported among adult populations, with almost one fifth reporting widespread pain, one third shoulder pain, and up to one half reporting low back pain in a 1-month period. The prevalence of pain varies within specific population subgroups; group factors (including socioeconomic status, ethnicity and race) and individual factors (smoking, diet, and psychological status) are all associated with the reporting of musculoskeletal pain. However, the precise nature of these relationships, and particularly the mechanisms of association, are unclear and require further investigation. [Return to top] ------------------------------ Date: Wed, 4 Jul 2007 13:24:01 -0400 From: "Bernice A. Melsky" Subject: RES: Myofascial pain syndromes and their evaluation Myofascial pain syndromes and their evaluation. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):427-45. Bennett R. Oregon Health & Science University, SNORD-219, 3455 SW Veterans Road, Portland, OR 97239-2941, USA. PMID: 17602992 Myofascial pain refers to a specific form of soft-tissue rheumatism that results from irritable foci (trigger points) within skeletal muscles and their ligamentous junctions. It must be distinguished from bursitis, tendonitis, hypermobility syndromes, fibromyalgia and fasciitis. On the other hand it often exists as part of a clinical complex that includes these other soft-tissue conditions, i.e., it is not a diagnosis of exclusion. The clinical science of trigger points can be traced to the pioneering work of Kellgren in the 1930s, with his mapping of myotomal referral patterns of pain resulting from the injection of hypertonic saline into muscle and ligaments. Most muscles have characteristic myotomal patterns of referred pain; this feature forms the basis of the clinical recognition of myofascial trigger points in the form of a tender locus within a taut band of muscle which restricts the full range of motion and refers pain centrifugally when stimulated. Although myofascial pain syndromes have been described in the medical literature for about the last 100 years, it is only recently that scientific studies have revealed objective abnormalities. [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 03:11:18 +0200 From: Jan van Roijen Subject: res: Abnormal Thermoregulatory Responses in CFS Adolescents ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Send an Email for free membership ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ >>>> Help ME Circle <<<< >>>> 5 July 2007 <<<< Editorship : j.van.roijen chello.nl Outgoing mail scanned by Norton AV ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~ From: Frank Twisk http://pediatrics.aappublications.org/cgi/content/abstract/120/1/e129?rss=1 PEDIATRICS Vol. 120 No. 1 July 2007, pp. e129-e137 (doi:10.1542/peds.2006-2759) ARTICLE Abnormal Thermoregulatory Responses in Adolescents With Chronic Fatigue Syndrome: Relation to Clinical Symptoms ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Vegard Bruun Wyller, MDa,b, Kristin Godang, BScc, Lars Mrrkrid, MD, PhDd, Jerome Philip Saul, MDe, Erik Thaulow, MD, PhDa and Lars Wallre, MD, PhDb a Departments of Pediatrics c Endocrinology d Medical Biochemistry, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway b Department of Physiology, University of Oslo, Oslo, Norway e Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina OBJECTIVES. Chronic fatigue syndrome is a common and disabling disease of unknown etiology. Accumulating evidence indicates dysfunction of the autonomic nervous system. To further explore the pathophysiology of chronic fatigue syndrome, we investigated thermoregulatory responses dependent on catecholaminergic effector systems in adolescent patients with chronic fatigue syndrome. PATIENTS AND METHODS. A consecutive sample of 15 patients with chronic fatigue syndrome aged 12 to 18 years and a volunteer sample of 57 healthy control subjects of equal gender and age distribution were included. Plasma catecholamines and metanephrines were measured before and after strong cooling of 1 hand. Acral skin blood flow, tympanic temperature, heart rate, and mean blood pressure were measured during moderate cooling of 1 hand. In addition, clinical symptoms indicative of thermoregulatory disturbances were recorded. RESULTS. Patients with chronic fatigue syndrome reported significantly more shivering, sweating, sudden change of skin color, and feeling unusually warm. At baseline, patients with chronic fatigue syndrome had higher levels of norepinephrine, heart rate, epinephrine, and tympanic temperature than control subjects. During cooling of 1 hand, acral skin blood flow was less reduced, vasoconstrictor events occurred at lower temperatures, and tympanic temperature decreased more in patients with chronic fatigue syndrome compared with control subjects. Catecholamines increased and metanephrines decreased similarly in the 2 groups. CONCLUSIONS. Adolescent patients with chronic fatigue syndrome have abnormal catecholaminergic-dependent thermoregulatory responses both at rest and during local skin cooling, supporting a hypothesis of sympathetic dysfunction and possibly explaining important clinical symptoms. ` ```````` Key Words: chronic fatigue • thermal regulation • adolescents • pathogenesis Abbreviations: CFS—chronic fatigue syndrome • AVA—arteriovenous anastomosis • CDC—Centers for Disease Control and Prevention • ASBF—acral skin blood flow • TT—tympanic temperature • HR—heart rate • MBP—mean blood pressure • CI—confidence interval ```````` Accepted Jan 25, 2007. ############# Comment: In the full text of this article is stated in the *subject*-section, that the accompanying symptoms of the CDC definition (headache, muscle pain, joint pain, sore throat, tender lymph nodes, impaired memory/concentration, unrefreshing sleep, and postexertional malaise) were not required in this study. I will add the discussion section below. The Full text can be found here: pdf format:: http://pediatrics.aappublications.org/cgi/reprint/120/1/e129 html format: http://pediatrics.aappublications.org/cgi/content/full/120/1/e129 ~jvr `````````````` DISCUSSION The most important findings of this study are that (1) patients with CFS report several symptoms that might indicate thermoregulatory disturbances; (2) at baseline, patients with CFS have higher levels of norepinephrine and epinephrine and higher TT than control subjects; and (3) during cooling of 1 hand, the neuroendocrine responses are similar in the 2 groups, but ASBF is less reduced among patients with CFS, whereas the baseline differences in TT disappear. Furthermore, the relevance of these findings is strengthened by the strikingly homogeneous responses within the CFS group, creating significant differences from control subjects despite the small number of subjects studied. Baseline Observations The finding in this study of increased norepinephrine levels in patients with CFS seems to be novel, whereas increased levels of epinephrine have been reported sporadically.27,28 A higher level of acute emotional stress among patients with CFS might explain the epinephrine differences; however, plasma levels of norepinephrine are less influenced by such mechanisms.7 Thus, the findings seem to indicate a more substantial alteration of physiology. A high level of norepinephrine in the antecubital vein plasma might suggest increased sympathetic nerve activity to forearm skin and skeletal muscle.29 Likewise, a high plasma level of epinephrine might be a result of increased sympathetic nerve activity to the adrenals. However, there are several alternative explanations. Generally, high levels of plasma catecholamines could result from either increased spillover or reduced removal, which, in turn, depends on both sympathetic nerve activity, the capacity of different reuptake and breakdown pathways, and local blood flow.7,29 Furthermore, a high norepinephrine concentration in forearm venous blood might simply reflect increased arterial levels, which, in turn, could be because of enhanced spillover in other parts of the body. The plasma levels of metanephrines are not good markers of activity in either the adrenal medulla or the sympathetic neurons and are only weakly correlated with the plasma levels of the respective catecholamines.7,29 Thus, similar levels of metanephrines among patients with CFS and control subjects do not rule out a state of catecholamine excess in the former. The finding of increased TT in patients with CFS is in agreement with previous reports of increased skin temperature in this population30 but contrasts with 2 other studies that did not find any deviations in core body temperature.31,32 However, these latter studies focused primarily on alterations in circadian temperature rhythms. In this study, the increased TT might be partially caused by high levels of epinephrine, which increase basal metabolic rate and heat production.7 In addition, a tendency toward shivering, as reported in our patients with CFS, might contribute. Increased levels of thyroid hormone are an alternative explanation that has not been specifically addressed in this study; however, overt thyroid hyperfunction was ruled out in the patient group during routine clinical investigations. The high resting HR found in this study fits well with other studies, documenting similar hemodynamic abnormalities both at rest and during orthostatic stress.3,33 An abnormal sympathetic predominance of cardiovascular regulation is one possible interpretation of these results, which is consistent with the reduced ASBF found in the CFS group, because skin AVAs are strongly controlled by sympathetic neural activity.22,34 Taken together, our baseline observations might indicate a general enhancement of sympathetic nerve activity to different regions and organs, including the forearm, the adrenals, and the heart. Patients' report of shivering, sweating, and paleness further suggest enhanced sympathetic outflow to skeletal muscles, sweat glands, and skin arterioles, respectively, a possibility that should be the subject of further research. Observations During and After Cooling Strong, rapid cooling of 1 hand normally promotes a general enhancement of sympathetic nerve activity, causing increased plasma levels of both norepinephrine and epinephrine.7 The stimuli for this response are not only reduced skin temperature in the immersed hand but also painful sensations. The similar increase in norepinephrine and epinephrine among control subjects and patients with CFS, as documented in this study, suggests that patients with CFS have preserved response abilities toward local cooling within the sympathetic nervous system. Thus, there are no indications of gross autonomic neuropathy, as have been proposed by others.35 Although not the focus of this report, the significant reduction of normetanephrine and metanephrine on cooling observed in both groups is an interesting finding, which seems to be unique to this report. Moderate, slow cooling of 1 hand normally causes a gradual reduction of ASBF down to a certain temperature level, at which ASBF suddenly ceases, presumably because of a coordinated closure of all of the AVAs23 (Fig 1). Although the precise mechanisms behind this phenomenon have not been fully elucidated, one possible explanation is synthesis of local signal substances that increase the postsynaptic sensitivity for norepinephrine or antagonize neuronal reuptake.36,37 Still, the closure is also dependent on central sympathetic outflow.23 We have provided evidence of abnormally increased core body temperature at baseline among patients with CFS. If the part of the effector system that controls the AVAs functions normally, an adequate response would be to elicit heat loss, that is, ensuring preserved blood flow in the AVAs as the temperature in the water bath falls. Consequently, our observation of prolonged preservation of ASBF left in patients with CFS on cooling, which has not been reported before, might be interpreted as a normal regulatory response to abnormally increased core temperature at baseline. Accordingly, TT did fall in the CFS group during the experiment, indicating successful heat loss and normalization of core temperature, whereas the normal ASBF responses in the control subjects seemed to maintain TT constant in that group. Alternatively, our results might indicate a defect in local vasoconstrictor mechanisms. Interestingly, recent experimental studies applying acetylcholine to small skin areas have found stronger vasodilative responses among patients with CFS than healthy control subjects, suggesting subtle alteration of the endothelial microvascular regulatory system.38,39 Other studies have documented a strong relation between CFS and the postural orthostatic tachycardia syndrome,40 a condition that seems to be characterized by reduced norepinephrine reuptake in the sympathetic synapse.41 Altogether, the previous studies and our own results underscore the need for research specifically addressing the complicated interaction of adrenergic, cholinergic, and other microvascular control mechanism in patients with CFS. [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 16:27:23 +0200 From: "Dr. Marc-Alexander Fluks" Subject: RES,NOT: CFS genes research in Australia Source: Australian Associated Press Date: July 5, 2007 Author: Tamara McLean URL: http://www.news.com.au/adelaidenow/story/0,22606,22020918-5005962,00.html Ref: See also these reports, http://www.abc.net.au/news/stories/2007/07/05/1970542.htm http://english.people.com.cn/90001/90781/6208295.html http://www.bloomberg.com/apps/news?pid=20601102&sid=aFl3ZU6yc_qQ Gene cluster linked to chronic fatigue -------------------------------------- Australian researchers have identified a cluster of genes linked to chronic fatigue syndrome which may help finally explain the mysterious condition. The team from the University of NSW sifted through more than six million pieces of DNA information in people who had glandular fever, including half who went on to develop chronic fatigue. Their goal was to identify which genes appeared to be more active in the people who went on to get fatigue, to shed light on what triggers the unexplained condition. Professor Andrew Lloyd and his colleagues at the Centre for Infection and Inflammation Research were able to find 35 genes linked to the symptoms of the illness. 'These (35) genes might point to the nature of the disease process that underlies chronic fatigue syndrome, which is currently unknown,' said Prof Lloyd, whose findings are published in the latest Journal of Infectious Diseases. Chronic fatigue is most commonly triggered by an acute illness, like glandular fever. It is characterised by extreme tiredness but recent studies have left researchers puzzled as to what it actually is. 'We know it's not a psychiatric disorder, and doesn't appear to have anything to do with immune responses or hormones or the severity of the virus,' Prof Lloyd said. 'So that's left us thinking it's some kind of brain disorder.' The team decided to analyse brain patterns by studying blood samples of 15 people with glandular fever, including some who also developed fatigue. The work was part of a larger project tracking the long-term health of people infected by three infections - the mosquito borne Ross River virus, Q fever bacterial infection and Epstein-Barr virus, which causes glandular fever - in the central NSW city of Dubbo. Prof Lloyd said the findings were the tentative beginnings of better understanding the disease. 'It's given us the starting point for some gene expression pattern that might become a diagnostic test for the condition,' he said. 'And it's given some clues of what the disease process might be that underlies the disorder.' -------- (c) 2007 AAP [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 12:13:14 -0400 From: "Dr. Charles Shepherd (via Co-Cure Moderators)" Subject: RES,MED:Gabapentin and autonomic dysfunction MAY BE REPOSTED Gabapentin is an interesting drug in that it was originally used in the treatment of epilepsy but it has also been found to be an effective and generally well tolerated drug for the management of pain, particularly where this has a neuropathic quality (ie burning, shooting or searing) but also for some types of musculoskeletal pain. In relation to pain in ME/CFS, it is a drug that is worth considering when moderate to severe pain has not responded to more usual forms of analgesic medication. New research (1) just published from a group in Sydney, Australia suggests that a further use for gabapentin could be in the area of autonomic dysfunction. This can be a very disabling problem that affects blood vessels, bowel and bladder function in some people with ME/CFS. The Australian study involved six patients whose dysautonomia followed a traumatic brain injury. Gabapentin helped to control paroxysmal autonomic changes and posturing in the early post-acute stage following limited success with conventional medication regimes. The results cannot be adequately explained by gabapentin's effect on neuropathic pain. It is interesting to note that gabapentin has also been reported to help 'hot flashes' (ie feelings of warmth, redness, sweating) that occur in women receiving systemic therapy for breast cancer (2) - possibly in part being caused by a disturbance in hypothalamic function. Whether or not gabapentin could be helpful in autonomic dysfunction associated with ME/CFS remains a matter of speculation. But I would be interested to hear from anyone using this drug as to whether it has had any beneficial effect on ME/CFS symptoms apart from just pain. References: 1 Baguley IJ, et al. Gabapentin in the management of dysautonomia following severe traumatic brain injury: a case series. Journal of Neurology, Neurosurgery and Psychiatry 2007; 78: 539 - 541. 2 Pandya K, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 2005; 366: 818 - 824. Dr Charles Shepherd Medical Adviser, ME Association (UK) http://www.meassociation.org.uk [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 17:04:14 +0200 From: "Dr. Marc-Alexander Fluks" Subject: RES,NOT: Paper: CFS genes research in Australia Source: Journal of Infectious Diseases Vol. 196, #1, p 56 - 66 Date: July 1, 2007 URL: http://www.journals.uchicago.edu/JID/journal/available.html http://www.journals.uchicago.edu/JID/journal/issues/v196n1/37954/37954.html Gene Expression Correlates of Postinfective Fatigue Syndrome after Infectious Mononucleosis ----------------------------------------------------------------------------- Barbara Cameron, Sally Galbraith, Yun Zhang, Tracey Davenport, Ute Vollmer-Conna, Denis Wakefield, Ian Hickie, William Dunsmuir, Toni Whistler, Suzanne Vernon, William C. Reeves, Andrew R. Lloyd, and Dubbo Infection Outcomes Study Abstract Background. Infectious mononucleosis (IM) commonly triggers a protracted postinfective fatigue syndrome (PIFS) of unknown pathogenesis. Methods. Seven subjects with PIFS with 6 or more months of disabling symptoms and 8 matched control subjects who had recovered promptly from documented IM were studied. The expression of 30,000 genes was examined in the peripheral blood by microarray analysis in 65 longitudinally collected samples. Gene expression patterns associated with PIFS were sought by correlation with symptom factor scores. Results. Differential expression of 733 genes was identified when samples collected early during the illness and at the late (recovered) time point were compared. Of these genes, 234 were found to be significantly correlated with the reported severity of the fatigue symptom factor, and 180 were found to be correlated with the musculoskeletal pain symptom factor. Validation by analysis of the longitudinal expression pattern revealed 35 genes for which changes in expression were consistent with the illness course. These genes included several that are involved in signal transduction pathways, metal ion binding, and ion channel activity. Conclusions. Gene expression correlates of the cardinal symptoms of PIFS after IM have been identified. Further studies of these gene products may help to elucidate the pathogenesis of PIFS. -------- (c) 2007 University of Chicago Press [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 16:51:56 +0200 From: "Dr. Marc-Alexander Fluks" Subject: RES,NOT: Press release: CFS genes research in Australia Source: University of New South Wales Date: July 5, 2007 URL: http://www.unsw.edu.au/news/pad/media/2007/jul/chronic_fatigue_syndrome.html Chronic fatigue: clues in the blood ----------------------------------- Researchers at UNSW believe that blood may hold vital insights into what is happening in the brain of patients with chronic fatigue syndrome (CFS). In a study unparalleled in its scope, a team led by UNSW Professor Andrew Lloyd of the Centre for Infection and Inflammation Research, has studied the differences in gene expression patterns in the blood of people who either recover promptly after acute glandular fever or develop the prolonged illness called post-infective syndrome. The researchers examined six million pieces of gene expression information for analysis in the project, known as the Dubbo Infection Outcomes Study. The study is named after the NSW town in which the work was conducted. The team studied the expression of 30,000 genes in the blood, testing each of the 15 individuals between four and five times over a 12-month period. The team was able to narrow its findings to the expression of just 35 genes whose pattern of expression correlated closely with the key symptoms of the illness when examined from onset through to recovery. Gene expression is significant because it is the process by which a geneâ€™s DNA sequence is converted into the proteins which ultimately determine the manifestations of disease. The research paper has been published and selected for editorial comment in the prestigious Journal of Infectious Diseases. Since 1999, the team has been tracking the long-term health of individuals infected with Ross River virus (RRV), Q fever infection and Epstein-Barr virus, which causes glandular fever. 'These  genes might point to the nature of the disease process that underlies CFS, which is currently unknown,' said Professor Lloyd, who is based in the School of Medical Sciences at UNSW. 'None of them are ones that I would have predicted, except for those relating to neurotransmitters,' he concedes. 'Some of them relate to transport of zinc and other metal ions within the cell, which may suggest a fundamental disturbance in cellular function.' The researchers now hope to narrow the focus of research onto the expression of these 35 genes in the blood of a much larger group of subjects from the Dubbo Infection Outcomes Study, with varied patterns of illness and recovery. 'There are very few complex diseases which have been comprehensively analysed, with large scale and longitudinal studies, like this,' said Professor Lloyd. 'It sets a standard for highly sophisticated, comprehensive gene expression studies in the blood of all sorts of human diseases from rheumatoid arthritis and multiple sclerosis through to schizophrenia.' Contact details: Professor Andrew Lloyd, 0413 112 701 or Susi Hamilton, UNSW media unit, 9385 1583 or 0422 934 024. -------- (c) 2007 University of New South Wales [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 21:28:31 -0400 From: "Bernice A. Melsky" Subject: RES: Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition.ccc Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):465-80. Nielsen LA, Henriksson KG. Laboratory for Experimental Pain Research, Center for Sensory-Motor Interactions (SMI), Department of Health Science and Technology, Aalborg University, Frederik Bajers Vej 7, D3DK-9220 Aalborg, Denmark. PMID: 17602994 Chronic musculoskeletal pain has biological, psychological and social components. This review deals with the biological factors, with emphasis on the fibromyalgia syndrome (FMS). Studies on central sensitization of pain-transmitting neurons, changes in endogenous pain modulation that give rise to pain disinhibition, referred pain, pain-related decrease in muscle strength and endurance, and pain generators in deep tissues are reviewed. In FMS there is strong scientific support for the statement that the biological part of the syndrome is a longstanding or permanent change in the function of the nociceptive nervous system that can be equated with a disease. Further research is necessary in order to determine which methods are best for diagnosis of the pain hypersensitivity in clinical practice. FMS may be the far end of a continuum that starts with chronic localized/regional musculoskeletal pain and ends with widespread chronic disabling pain. [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 21:35:51 -0400 From: "Bernice A. Melsky" Subject: RES: Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):481-97 Yunus MB. Section of Rheumatology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, Illinois, USA. PMID: 17602995 Patients with widespread pain or fibromyalgia syndrome have many symptoms besides musculoskeletal pain: e.g. fatigue, sleep difficulties, a swollen feeling in tissues, paresthesia, cognitive dysfunction, dizziness, and symptoms of overlapping conditions such as irritable bowel syndrome, headaches and restless legs syndrome. There is evidence for central sensitization in these conditions, but further studies are needed. Anxiety, stress and depression are also present in 30-45% of patients. Other factors that may contribute to symptoms include endocrine dysfunction, psychosocial distress, trauma, and disrupted sleep. Evaluation of a patient presenting with widespread pain includes history and physical examination to diagnose both fibromyalgia and associated or concomitant conditions. Fibromyalgia should be diagnosed by its own characteristic features. Some patients with otherwise typical symptoms of fibromyalgia may have as few as four to six tender points in clinical practice. Patients with rheumatoid arthritis and systemic lupus erythematosus should be evaluated for fibromyalgia, since 20-30% of them have associated fibromyalgia, requiring a different treatment approach. [Return to top] ------------------------------ Date: Thu, 5 Jul 2007 21:42:38 -0400 From: "Bernice A. Melsky" Subject: RES: Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):499-511. Goldenberg DL. Newton-Wellesley Hospital, Division of Rheumatology, 2000 Washington Street, Suite 304, Newton, MA 02468, USA. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):499-511. PMID: 17602996 The pharmacologic management of fibromyalgia is based on the emerging evidence that pain in this disorder is primarily related to central pain sensitization. There is strong evidence that tricyclic antidepressants are effective, and moderate evidence for the effectiveness of serotonin reuptake inhibitors and dual serotonin-norepinephrine reuptake inhibitors. Recent work suggests that the anti-seizure medications pregabalin and gabepentin are also effective. The only analgesic demonstrated to be helpful is tramadol. --------------------------------------------- Send posts to CO-CURE@listserv.nodak.edu Unsubscribe at http://www.co-cure.org/unsub.htm Co-Cure Archives: http://listserv.nodak.edu/archives/co-cure.html --------------------------------------------- Co-Cure's purpose is to provide information from across the spectrum of opinion concerning medical, research and political aspects of ME/CFS and/or FMS. We take no position on the validity of any specific scientific or political opinion expressed in Co-Cure posts, and we urge readers to research the various opinions available before assuming any one interpretation is definitive. The Co-Cure website has a link to our complete archive of posts as well as articles of central importance to the issues of our community. --------------------------------------------- --------------------------------------------- This is a special digest of Co-Cure Research & Medical posts only Problems? Write to mailto:email@example.com E-Mail mailto:Co-Cure-HMCfirstname.lastname@example.org to unsubscribe --------------------------------------------- [Return to top] ------------------------------ Date: Fri, 6 Jul 2007 19:04:59 -0400 From: "Bernice A. Melsky" Subject: RES: Non-pharmacological treatment of chronic widespread musculoskeletal pain Non-pharmacological treatment of chronic widespread musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):513-34. Mannerkorpi K, Henriksson C. Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborg University, Guldhedsgatan 10, SE-413 46 Göteborg, Sweden. PMID: 17602997 Non-pharmacological treatment for patients with chronic widespread pain (CWP) and fibromyalgia (FM) aims to enhance overall health. This chapter reviews studies of exercise, education, movement therapies and sensory stimulation. Based on a systematic review of randomized controlled trials (RCTs), we suggest that aerobic exercise of low to moderate intensity, such as walking and pool exercise, can improve symptoms and distress in patients with CWP and FM, and it may improve physical capacity in sedentary patients. Aerobic exercise of moderate to high intensity has been shown to improve aerobic capacity and tender-point status. Educational programmes have been shown to enhance self-efficacy and health perception. There is no conclusive evidence about the type of educational programme that works best, but a small-group format and interactive discussions appear to be important components. Exercise combined with education appears to produce synergies. Studies of movement therapies (such as qigong) and sensory treatments (such as acupuncture and massage) are few in number. There is today no conclusive evidence about the effects of these treatments in CWP, although positive effects have been reported in a few studies. [Return to top] ------------------------------ Date: Fri, 6 Jul 2007 19:10:01 -0400 From: "Bernice A. Melsky" Subject: RES: Genetics of chronic pain states Genetics of chronic pain states. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):535-47. Buskila D. Department of Medicine H, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, P.O.B 151, Israel 84101. PMID: 17602998 Chronic pain states are common in the general population. Genetic factors can explain a significant amount of the variability in the perception of pain. Fibromyalgia syndrome (FMS) and related conditions are syndromes characterized by generalized pain sensitivity as well as a constellation of other symptoms. Family studies show a strong familial aggregation of FMS and related conditions, suggesting the importance of genetic factors in the development of these conditions. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the pathogenesis of FMS and related conditions. Environmental factors may trigger the development of these disorders in genetically predisposed individuals. Future large well-designed studies are needed to further clarify the role of genetic factors in FMS and related conditions. The knowledge of these gene polymorphisms may help with better subgrouping of FMS patients and in designing a more specific pharmacologic treatment approach. [Return to top] ------------------------------ Date: Fri, 6 Jul 2007 19:13:54 -0400 From: "Bernice A. Melsky" Subject: RES: Future perspectives: pathogenesis of chronic muscle pain Future perspectives: pathogenesis of chronic muscle pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):581-96. Staud R. Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0221, USA. PMID: 17603001 Chronic painful muscle conditions include non-inflammatory and inflammatory illnesses. This review is focused on chronic non-inflammatory pain conditions such as myofascial pain syndrome (MPS) and fibromyalgia syndrome (FM), and will not discuss metabolic, genetic or inflammatory muscle diseases such as McArdle's disease, muscular dystrophy, polymyositis, dermatomyositis, or inclusion body myositis. [Return to top] ------------------------------ Date: Fri, 6 Jul 2007 19:31:42 -0400 From: Fred Springfield Subject: RES: A twin study of cognitive function in chronic fatigue syndrome: The effects of sudden illness onsetc A twin study of cognitive function in chronic fatigue syndrome: The effects of sudden illness onset. Journal: Neuropsychology. 2007 Jul;21(4):507-13. Authors: Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D. Affiliations: Claypoole, Keith H.: Department of Psychology, University of Hawaii, Honolulu, HI, US Noonan, Carolyn: Department of Medicine, University of Washington School of Medicine, Seattle, WA, US Mahurin, Roderick K.: Department of Neurology, University of Washington School of Medicine, Seattle, WA, US Goldberg, Jack: Department of Epidemiology, University of Washington School of Medicine, Seattle, WA, US Erickson, Tom: Regional Epilepsy Center, University of Washington School of Medicine, Seattle, WA, US Buchwald, Dedra: Department of Medicine, University of Washington School of Medicine, Seattle, WA, US NLM Citation: PMID: 17605583 Variable reports of neuropsychological deficits in individuals with chronic fatigue syndrome (CFS) may, in part, be attributable to methodological limitations. In this study, these limitations were addressed by controlling for genetic and environmental influences and by assessing the effects of comorbid depression and mode of illness onset. Specifically, the researchers conducted a co-twin control study of 22 pairs of monozygotic twins, in which 1 twin met strict criteria for CFS and the co-twin was healthy. Twins underwent a structured psychiatric interview and comprehensive neuropsychological assessment evaluating 6 cognitive domains. Results indicated that twin groups had similar intellectual and visual memory functioning, but fatigued twins exhibited decreases in motor functions (p = .05), speed of information processing (p = .02), verbal memory (p = .02), and executive functioning (p = .01). Major depression did not affect neuropsychological functioning among fatigued twins, although twins with sudden illness onset demonstrated slowed information processing compared with those with gradual onset (p = .01). Sudden onset CFS was associated with reduced speed of information processing. If confirmed, these findings suggest the need to distinguish illness onset in future CFS studies and may have implications for treatment, cognitive rehabilitation, and disability determination. ((c) 2007 APA, all rights reserved). [Return to top] ------------------------------ Date: Sat, 7 Jul 2007 16:55:16 +0200 From: "Dr. Marc-Alexander Fluks" Subject: RES,NOT: CFS conference, 4/5 oktober 2007 Source: National Network for CFS/ME Therapists Date: July 2007 URL: http://www.ppaonline.co.uk/download/Invitation_Booklet_NCCCFSME%202007.doc Poster: http://www.ppaonline.co.uk/download/Conference_poster.pdf Collaborative Conference on CFS/ME ---------------------------------- AYME and Action for ME in collaboration with the National Network for CFS/ME Therapists and the National NHS Collaboration Milton Keynes 4th - 5th October Invitation and Registration Programme You are invited to attend the first Collaborative Conference on CFS/ME, which has been developed with a broad base of support and is intended to interest a wide audience. Many of you will know that the National Network of therapists has met in October for many years, and this conference stands in the place of the meeting this year. The National NHS Collaboration grew from the national meetings of the Clinical Network and Coordinating Centres representatives, and continues to coordinate the development of effective NHS services for people with CFS/ME. There is of course an overlap in membership between the Network and the Collaboration. The programme was developed in collaboration with AYME and AfME, and we hope that the learning and networking opportunities at the conference will be stronger as a result. Programme Outline The programme will be divided into three sections. The first, on Thursday morning, involves a choice of meetings. The second, on Thursday afternoon, involves a choice of workshops. Plenary sessions and the Keynote Speaker, Professor Gijs Bleijenberg, will take place during the day on Friday. In addition, there will be a poster presentation throughout the conference, and a conference dinner on Thursday evening. Registration and registration fees You will find a registration form at the end of this document: please complete this, and return it before the first of August for an "Early Bird" discount. Registration Fees are: Early registration (until 1st August) 100 pounds for one day, 180 pounds for both Late registration 125 pounds for one day, 200 pounds for both days Paediatric Special Interest Group alone: 50 pounds Conference Dinner: 25 pounds plus wine Accommodation is not included within these costs (see below for accommodation details). CME approval is pending: attendance certificates will be supplied. Invitation To Submit Abstracts For Posters The CFS Network is inviting delegates to submit posters about their work. We would like particularly to attract work from health professionals at the grassroots level of CFS (clinical and research) and encourage those who may not have published previously in this field. The conference programme will include an â€śinteractiveâ€ť poster session when authors can give a 3-minute talk summarising their poster and answer questions. Delegates will also have the opportunity to view posters before the conference and during the breaks. The subject matter for posters should fall into one or more of the following categories: 1. Reports of evidence based practice with patients with CFS 2. Original research (which may be ongoing) which advances our theoretical understanding of CFS or its treatment 3. Issues affecting the provision of services for patients with CFS 4. CFS Service Audits Members of the executive committee will review abstract submissions. Successful submissions will be invited to display the poster at the Conference, where invited judges will choose the best poster. We are hoping to be able to offer a prize for the best poster and presentation Please submit your poster abstract in MS Word as an email attachment, by Friday 3 August 2007 to: Gabrielle.email@example.com Your abstract should contain the following information: Title Authors Affiliation Email address of contact author Body of abstract â€“ no more than 200 words. Please structure this as appropriate for the subject material, e.g. for research reports, use the following headings: Background/objectives; design/methods; results; discussion/conclusions/clinical implications. Case studies or reports of qualitative work may vary from this format. You will be informed by Friday 17th August whether your abstract has been accepted for a poster at the conference. At this time you will be sent more advice on formatting your poster. The maximum size for posters is likely to be B1 (100cm x 70cm). Conference Meetings: Thursday Morning There will be three meetings held at the same time, which are: 1. Paediatric Special Interest Group Inaugural Meeting The Royal College of Paediatrics and Child Health Paediatric CFS/ME Special Interest Group will have its inaugural meeting at the conference, chaired by Dr Tim Chambers. This will include a mixture of research and clinical practice sessions. All are welcome to join. 2. National Network for CFS/ME Therapists AGM The network membership includes general practitioners, occupational therapists, physicians, physiotherapists, psychiatrists, nurses and psychologists. The Network functions across the Primary/Secondary Care boundary, and across the Paediatric/Adult boundary. The Network is also a stakeholder group in the development of the NICE guidelines for CFS/ME. The network has met once a year for an annual autumn multiprofessional study and information day for several years, and itâ€™s meeting this year is combined with the Collaborative Conference. All are welcome. 3. CFS/ME Champions and Co-ordinators Meeting This is a closed meeting for the current clinical champions and network coordinators, scheduled following our last meeting in May 2007. Workshops: Thursday Afternoon Delegates can choose to attend two out of the following workshops: - Vincent Deary: Using CBT with adults - Dr Esther Crawley: collecting data to understand CFS/ME - Facilitator tbc: implementation of the NICE Guidelines - Dr Hugh Rickards: Depression, anxiety and the problems with differential diagnosis - Chris Daniels/Rosanne Walton: Innovations in service delivery for severely affected users - Professor Trudie Chalder and Dr Mary Burgess: Working with adolescents Friday: Keynote Speaker and Plenary Sessions - Keynote Speaker: Professor Gijs Bleijenberg Head of the Nijmegen Expert Centre for Chronic Fatigue, Netherlands Cognitive behavioural therapy for chronic fatigue syndrome: the role of pain and the effects of guided self-management. - Dr Brian Marien The evidence supporting an integrated (mind/body) explanatory model for CFS/ME. - Professor George Davey-Smith The future of genetic research and CFS/ME - Dr Manny Bagary Sleep and CFS/ME research - Dr Julia Newton Standing up for Fatigue: Autonomic Nervous System Dysfunction in CFS/ME Speaker Information and Biographies - Keynote speaker: Professor Gijs Bleijenberg Clinical psychologist and Head of the Nijmegen Expert Centre for Chronic Fatigue, Radboud University Nijmegen Medical CentreÂ in the Netherlands. The Expert Centre for Chronic Fatigue is a multidisciplinary collaboration focussing on the study of chronic fatigue. Furthermore,Â the ECCF isalso a nationalÂ referral centre for patients withÂ chronic fatigue.Â Abo300 patients a year can be seen for fatigue diagnostics, not only CFS patients but also patients with cancer related fatigue or withÂ fatigue and a chronic disease. AboutÂ 200 of themÂ are treated with diverse forms of cognitive behavioural therapy. - Professor George Davey-Smith Professor of Clinical Epidemiology and head of the new MRC centre for genetic research in Bristol University, Director of ALSPAC, and Honorary Consultant with North Bristol NHS Trust, from October 1994. A world leader in epidemiology and genetic epidemiology, George Davey Smith has led the way in discovering which genes are important in traits such as obesity and height. He thinks we can do the same for fatigue and discover some of the important biological pathways for CFS/ME. Come and find out if this is true! - Dr Julia Newton Senior Lecturer in the Institute for Cellular Medicine, Newcastle University. She is the academic lead of the internationally renowned Cardiovascular Investigation Unit (Falls and Syncope Unit), which is arguably the largest autonomic nervous system testing laboratory in Europe. She has a reputation in the investigation of autonomic function in the pathogenesis of fatigue with a research programme funded by the MRC, ME Research UK, and Liver North. She founded and chairs the local multidisciplinary Fatigue Interest Group. The talk will focus on the physiological changes that occur when humans stand, and how autonomic nervous system responses to assuming the upright position may be impaired in those with CFS/ME. - Professor Trudie Chalder Professor of Cognitive Behavioural Psychotherapy in the Dept. of Psychological Medicine at Kingâ€™s College London. She has worked as a clinician and a researcher in the area of chronic fatigue syndrome for about 18 years and has in the last decade turned her attention to the needs of adolescents. - Dr Mary Burgess Works in the Chronic Fatigue Syndrome Research and Treatment Unit at King's. She is specifically interested in the needs of the severely affected and is currently piloting and evaluating a home based treatment for this group. - Vincent Deary Is currently MRC Research Fellow at the University of Newcastle conducting research into medically unexplained dysphonia (hoarseness and voice the loss). He has been researching and treating (so called) medically unexplained symptoms for 12 years and, with Trudie Chalder, has pioneered the use of cognitive behavioural therapy to treat children and adolescents with chronic fatigue syndrome. - Rosanne Walton Acting Head OT with the chronic pain and fatigue management team based at Rayners Hedge in Aylesbury. She was involved in setting up the fatigue component of the team in 1998 and has worked in it since. They run interdisciplinary chronic fatigue management programmes using a cognitive behavioural therapy approach with graded exercise therapy. They also offer a limited amount of individual outpatient fatigue management. She initially trained as a biologist, then did an OT degree and has since done a postgraduate diploma in psychology. Rosanna is currently trialling the use of Videophone with people at home. This means the client has a hands-free videophone at their house connected to one in the hospital. - Chris Daniels A qualified counsellor and previously the Clinical service Manager for Action for ME, Chris now manages the NHS counselling and information telephone service for Avon Gloucester Wiltshire, and more recently Greater Manchester. This telephone service is targeted at the severely affected. Chris also works as a counsellor in the Bristol CFS/NHS Adult team. - Dr Hugh Rickards Dr Rickards is a Consultant in Neuropsychiatry who is part of an interdisciplinary neuropsychiatry team based in Birmingham and in the West Midlands. He leads the CFS/ME Service in this region. Accommodation The link below (which you need to click on to open) will take you to a Milton Keynes website which lists various hotels in Milton Keynes. Jurys Hotel (the conference venue) is listed/flagged as 'B'. http://maps.google.co.uk/maps?hl=en&q=hotels&near=Milton+Keynes,+UK&ie=UTF8&z=13&ll=52.032746,-0.738659&spn=0.076883,0.159645&om=1 --------------------------------------------------------------------- Registration Form: Collaborative Conference on CFS/ME 2007 Jurys Hotel, Milton Keynes, Bucks Thursday 4th and Friday 5th October 2007 Please print clearly in block capitals. Your name, place of work and Profession/position held: these will be used for your name badge, the attendance list and your certificate of attendance. Full name and title ............................................ Place of employment ............................................ Profession/Position held ............................................ Postal address ............................................ County ............................................ Postcode .................. Tel No................... Email ............................................ Special dietary requirements or other special needs ................. ............................................ Please tick the boxes as appropriate. (O) I have enclosed a cheque for: Until 1st August 07 100 pounds for one day, 180 pounds for both days. After 1st August 07 (late registration) 125 pounds for one day, 200 pounds for both days. This does not include your hotel accommodation which you need to book independently. Paediatric SIG only 50 (Please note that this is the only form of payment we are able to accept and cheques must be made payable to North Bristol NHS Trust budget code B09052) (O) I would like attend the conference dinner at 25 pounds per head plus wine (O) I would like to be sent directions and/or a map. Please return your completed form to: Sue Webb 9 Osterley Close Newport Pagnell Bucks MK16 0EZ Reservation is a contract. Cancellations must be made in writing and will be subject to a 10% administration charge. No refunds will be made for cancellations notified within fourteen days of the event, but substitute delegates will be accepted at any time. For further information please email: firstname.lastname@example.org --------------------------------------------------------------------- [Return to top] ------------------------------ Date: Sun, 8 Jul 2007 10:40:23 -0400 From: "Bernice A. Melsky" Subject: RES: Cranial electrotherapy stimulation and fibromyalgia Cranial electrotherapy stimulation and fibromyalgia. Expert Rev Med Devices. 2007 Jul;4(4):489-95. Gilula MF. President and Director, Life Energies Research Institute, 2510 Inagua Avenue, Miami, FL 33133, USA. email@example.com. PMID: 17605684 Cranial electrotherapy stimulation (CES) is a well-documented neuroelectrical modality that has been proven effective in some good studies of fibromyalgia (FM) patients. CES is no panacea but, for some FM patients, the modality can be valuable. This article discusses aspects of both CES and FM and how they relate to the individual with the condition. FM frequently has many comorbidities such as anxiety, depression, insomnia and a great variety of different rheumatologic and neurological symptoms that often resemble multiple sclerosis, dysautonomias, chronic fatigue syndrome and others. However, despite long-standing criteria from the American College of Rheumatology for FM, some physicians believe there is probably no single homogeneous condition that can be labeled as FM. Whether it is a disease, a syndrome or something else, sufferers feel like they are living one disaster after another. Active self-involvement in care usually enhances the therapeutic results of various treatments and also improves the patient's sense of being in control of the condition. D-ribose supplementation may prove to significantly enhance energy, sleep, mental clarity, pain control and well-being in FM patients. A form of evoked potential biofeedback, the EPFX [Electro-Physio-Feedback-Xrroid], is a powerful stress reduction technique which assesses the chief stressors and risk factors for illness that can impede the FM patient's built-in healing abilities. Future healthcare will likely expand the diagnostic criteria of FM and/or illuminate a group of related conditions and the ways in which the conditions relate to each other. Future medicine for FM and related conditions may increasingly involve multimodality treatment that features CES as one significant part of the therapeutic regimen. Future medicine may also include CES as an invaluable, cost-effective add-on to many facets of clinical pharmacology and medical therapeutics. [Return to top] ------------------------------ Date: Sun, 8 Jul 2007 13:33:35 -0400 From: "Bernice A. Melsky" Subject: RES: Randomized controlled study of the antinociceptive effect of ultrasound on trigger point sensitivity: novel applications in myofascial therapy? Randomized controlled study of the antinociceptive effect of ultrasound on trigger point sensitivity: novel applications in myofascial therapy? Clin Rehabil. 2007 May;21(5):411-7. Srbely JZ, Dickey JP. Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. firstname.lastname@example.org. PMID: 17613561 OBJECTIVE: To investigate whether therapeutic ultrasound modulates the pain sensitivity of myofascial trigger points. DESIGN: Repeated measures, single-blinded randomized controlled trial of ultrasound treatment of trigger points. SETTING: Outpatient injury rehabilitation clinic. SUBJECTS : Forty-four patients (22 males, 22 females) with trigger points identified within the trapezius muscle. INTERVENTIONS: Five-minute therapeutic intensity of ultrasound versus 5-min low-intensity application of ultrasound to a trapezius myofascial trigger point locus. MAIN MEASURES: Pain pressure threshold readings were measured at the trapezius trigger point site before and after exposure to the ultrasound intervention. RESULTS: Pain pressure threshold scores increased an average of 44.4 (14.2)% after therapeutic exposure to ultrasound (pre-ultrasound test 35.4 (8.5) N, post-ultrasound test 51.1 (12.8) N). No significant difference in pain pressure threshold scores was observed with low-intensity ultrasound exposures (pre-ultrasound 36.1 (6.1) N, post-ultrasound 36.6 (4.8) N). CONCLUSIONS : Therapeutic exposures to ultrasound reduce short-term trigger point sensitivity. Ultrasound may be a useful clinical tool for the treatment and management of trigger points and myofascial pain syndromes. [Return to top] ------------------------------ Date: Sun, 8 Jul 2007 14:23:45 +0200 From: "Dr. Marc-Alexander Fluks" Subject: RES,NOT: Paper: CFS genes research in Australia (Full text version) Source: The Journal of Infectious Diseases Vol. 196, #1, p 56-66 Date: July 1, 2007 URL: http://www.journals.uchicago.edu/JID/journal/available.html http://www.journals.uchicago.edu/JID/journal/issues/v196n1/37954/37954.html Gene Expression Correlates of Postinfective Fatigue Syndrome after Infectious Mononucleosis ------------------------------------------------------------------ Barbara Cameron(1), Sally Galbraith(2), Yun Zhang(2) Tracey Davenport(4), Ute Vollmer-Conna(3), Denis Wakefield(1), Ian Hickie(4), William Dunsmuir(2), Toni Whistler(5), Suzanne Vernon(5), William C. Reeves(5), and Andrew R. Lloyd(1) for the Dubbo Infection Outcomes Study 1 School of Medical Sciences, 2 School of Mathematics, and 3 School of Psychiatry, University of New South Wales, and 4 Brain and Mind Research Institute, Sydney University, Sydney, Australia; 5 Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Received 5 December 2006; accepted 12 January 2007; electronically published 24 May 2007. Potential conflicts of interest: none reported. Financial support: National Health and Medical Research Council of Australia (project grants 157092 and 157062); US Centers for Disease Control and Prevention (cooperative research agreement U50/CCU019851-01). Correspondence: Prof. Andrew Lloyd, Centre for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney 2052, Australia (A.Lloyd@unsw.edu.au). See the editorial commentary by White, on pages 4-5. Background. Infectious mononucleosis (IM) commonly triggers a protracted postinfective fatigue syndrome (PIFS) of unknown pathogenesis. Methods. Seven subjects with PIFS with 6 or more months of disabling symptoms and 8 matched control subjects who had recovered promptly from documented IM were studied. The expression of 30,000 genes was examined in the peripheral blood by microarray analysis in 65 longitudinally collected samples. Gene expression patterns associated with PIFS were sought by correlation with symptom factor scores. Results. Differential expression of 733 genes was identified when samples collected early during the illness and at the late (recovered) time point were compared. Of these genes, 234 were found to be significantly correlated with the reported severity of the fatigue symptom factor, and 180 were found to be correlated with the muscu- loskeletal pain symptom factor. Validation by analysis of the longitudinal expression pattern revealed 35 genes for which changes in expression were consistent with the illness course. These genes included several that are involved in signal transduction pathways, metal ion binding, and ion channel activity. Conclusions. Gene expression correlates of the cardinal symptoms of PIFS after IM have been identified. Further studies of these gene products may help to elucidate the pathogenesis of PIFS. In industrialized countries, 40%-65% of primary Epstein-Barr virus (EBV) infections occur asymptomatically during early childhood [1, 2]. In contrast, primary EBV infection in young adults often causes symptomatic infectious mononucleosis (IM). Most cases of acute IM resolve within several weeks without sequelae, but some individuals experience a prolonged and disabling illness marked by fatigue extending over weeks or months. Prospective cohort studies examining the kinetics of recovery from acute IM [3-5] have revealed that almost 50% of subjects had ongoing symptoms at 2 months after onset and that ~10% had disabling symptoms marked by fatigue lasting 6 months or more. These subjects did not have clinical features of chronic, active EBV (CAEBV) infection, which is attributable to congenital  or acquired [7, 8] impairments of T cell immunity. Similarly, detailed medical and psychiatric assessments conducted in the Dubbo Infection Outcomes Study (DIOS)  did not reveal an alternative medical or psychiatric explanation for this postinfective fatigue syndrome (PIFS), indicating that subjects with PIFS represent a subset of the more heterogeneous and enigmatic clinical disorder termed "chronic fatigue syndrome" (CFS) [9, 10]. We recently reported the outcomes of a detailed assessment of virological and immunological correlates of PIFS in a case-control series of DIOS subjects followed from the onset of acute IM . There was no difference in cellular EBV load at any time point between the case subjects, who developed PIFS, and the control subjects, who recovered promptly. Although minor alterations in the kinetics of both antibody and T cell responses to EBV were evident, these did not correlate with the timing of recovery, arguing against the popular immunological and virological hypotheses of the pathogenesis of PIFS [12, 13]. In combination with available evidence from other studies of patients with CFS, these data point to the central nervous system (CNS) as the likely site of the pathophysiological disturbance [13-16]. Thus, we predicted that neurochemical and neuroinflammatory genes would be differen- tially expressed in the peripheral blood of subjects with PIFS. Accordingly, the present study adopted a gene discovery approach as a novel strategy to elucidate the pathophysiology of PIFS. Peripheral blood was chosen for study, first because it was readily available; second because the utility of peripheral blood gene expression to explore the pathogenesis of complex diseases of the CNS has recently been demonstrated in predicting emergent posttraumatic stress disorder  and in distinguishing subjects with schizophrenia or bipolar disorder from healthy control subjects ; and finally because preliminary studies examining samples collected from a group of subjects during acute IM discovered novel gene expression correlates of the symptoms of the acute sickness response . Thus, the present study used microarray technology to examine gene expression in a matched case-control series of subjects followed from shortly after the onset of acute IM that was of short duration or that persisted into PIFS. SUBJECTS, MATERIALS, AND METHODS Subjects. Participants were enrolled in DIOS after presentation with symptoms of acute IM and detection of IgM antibodies against EBV capsid antigen. Follow-up was conducted at regular intervals for 12 months or more. Provisional serological diagnoses were confirmed by testing longitudinally collected serum samples . At each visit, detailed self-report and interview assessments of physical and psychological health were recorded. The severity and duration of symptoms were monitored using a self-report questionnaire, the Somatic and Psychological Health Report [21, 22]. A score of 3 or more (of a possible 12) on a validated subscale (called "the SOMA") was used to designate clinically significant fatigue states [23-25]. In those subjects with persistent symptoms beyond 3 months (designated as having provisional PIFS cases), structured medical and psychiatric assessments as well as laboratory investi- gations to exclude CAEBV infection or unrelated causes of illness were undertaken in accordance with the diagnostic criteria for CFS [9, 10]. Seven subjects with PIFS (i.e., those who had unexplained illness persisting for 6 months or more after onset of symptoms and met the diagnostic criteria for CFS) and 8 control subjects who had recovered more promptly, matched as a group by age and sex, were selected for the present study . To allow investigation of the gene expression correlates of the symptom complex, scores for each subject at each time point for the 6 symptom factors (as described elsewhere ) - fatigue, musculoskeletal pain, mood disturbance, neurocognitive disturbance, acute sickness, and irritability - were calculated from their self-report data sets. The study protocol was approved by the relevant institutional review boards. Written, informed consent was provided by all subjects. Specimens and laboratory methods. Blood samples were collected in the morning and transported to the laboratory within 6 h. Then, peripheral blood mononuclear cells (PBMCs) were separated (Lymphoprep; AXIS-SHIELD) and cryopreserved with 10% DMSO (Sigma) and 50% autologous plasma, and aliquots were stored in the vapor phase of liquid nitrogen. Subsequently, the thawed PBMCs were lysed in Tri Reagent (Sigma). RNA was extracted and quantified by spectrophotometry, and quality was evaluated by denaturing gel electrophoresis. Glass arrays (MWG Biotech) carrying 50mer oligonucleotides for 30,000 genes (10,000 on each of the 3 arrays, designated A, B, and C) were used. The A array bore 10,000 well-characterized genes; the B array carried a mix of known genes and expressed sequence tags (ESTs); and the C array bore all ESTs. Biotinylated cDNA probes were prepared from 1 mg of sample RNA as described elsewhere  and were hybridized to the arrays on the Ventana instrument (Ventana Medical Systems). Hybridization was for 8 h at 42 C with the ChipMap kit, with three 10-min stringency washes at 42 C (NaCl-Na citrate buffer at 2x 1x, and 0.1x ). This was followed by a 30-min incubation in streptavidin- labeled gold-particle solution (RLS system; Invitrogen [previously Genicon Sciences]) before vigorous washing to remove the oil, application of a liquid optical coating, and air drying. A total of 65 samples were included, representing from 3 to 7 time points per subject (table 1). RNA of sufficient yield and quality (a 28S:18S ratio of 1.8-2.0) was available to hybridize with all 3 arrays for 43 sampling points, whereas only hybridization with the A and B arrays was conducted for 13 samples, and, for a further 9 samples, hybridization with the A array alone was performed. All subjects had hybridizations preformed with all 3 arrays for at least 2 sampling points. For each subject, probe synthesis and hybridizations for all samples were performed in a single run. Arrays from a case and a control subject were run together where possible, to control for run-to-run effects. Data handling and analysis. Arrays were scanned (GSD-501; Invitrogen [previously Genicon Sciences]) with settings chosen to saturate a minimum of 1 feature on each array. Array images were analyzed (ArrayVision RLS; Imaging Research) to remove unacceptable features (i.e., "flags" due to dust or other technical artifacts) after manual confirmation as well as to quantify the relative expression of each feature in comparison to background. The raw intensity values ranged from 0 to 64,000. Flagged features as well as blanks and Arabidopsis con- trols were removed from the analysis . Normalization. The data were normalized within each array by assuming that the intensity values plus an array-specific constant, after log_2 transformation, followed a normal distribution, with zero values representing left-censored observa- tions. Parameters of the distribution were estimated by maximum likelihood (S.G. and W.D., submitted manuscript). This approach transformed the data to normality, removed artificial array-specific effects, and recognized left censoring of intensity values at zero. Filtering. It was assumed that the majority of the genes would not be differentially expressed and that including these noninformative genes might distort the clustering and correlation analyses . In addition, it was assumed that the genes of interest in relation to PIFS would be differentially expressed when comparing the early illness phase with recovery, consistent with our recent evidence that all of the phenotypic characteristics of the PIFS illness are present from onset but resolve slowly . The filtering procedure therefore compared expression levels in samples collected from subjects with a SOMA score of 3 or more at baseline (T1; representing data from samples collected during the early symptomatic phase of IM) with levels in subjects with a SOMA score <3 by 9 months (T4) and also during the preceding 3 months (representing data from samples collected well after recovery from IM and PIFS) (table 1). A feature was deemed to be differentially expressed if a 2-sample t test for equality of the means of normalized expression levels between the 2 groups (not assuming equality of variances) resulted in a P value of .01 or less. Outlying data points in the second group (expression levels 11.5 times the interquartile range below the first quartile or above the third quartile) were excluded before performing the t test. Overabundance analysis. To assess the significance of the correlations between symptom scores and expression data of the filtered set of features, overabundance analysis was performed as described elsewhere . This technique compared the number of features designated as being differentially expressed with the number expected by chance, which was ob- tained by randomly permuting the group labels 1000 times for different P value cutoffs. The 2-sample t test was performed for each permutation, and the number of P values less than each cutoff, averaged over all permutations, represented the expected number of features "differentially expressed" under the null hypothesis of no difference in expression levels between the 2 groups. Clustering. Clustering was used to determine whether expression levels for the filtered features at baseline (T1) were able to classify subjects correctly according to case/control status. Clustering was performed using DoublePCluster software (available in the public domain ScoreGenes package [version December 2002]; see http://www.compbio.cs.huji.ac.il/ scoregenes/), which implements an unsupervised hierarchical biclustering approach . For subjects with 11 array at T1, the first array was used. Correlation analyses. For each of the 6 symptom domains, Pearson correlations between symptom factor scores and expression levels were calculated for each feature. All subjects and time points were included in this analysis. To test the null hypothesis of zero correlation, an upper 1-sided t test was performed. Features with a P value <.05 were deemed to be significantly positively correlated, and those with a P value >.95 were deemed to be significantly negatively correlated. To assess the significance of the resulting sets of features, overabundance analyses were again performed using 1000 random permutations of the group labels. Bioinformatics. The National Center for Biotechnology Information UniGene cluster ID as well as the RefSeq (reference sequence) and GenBank accession numbers were sought for each feature on the arrays by use of the SOURCE automated-annotation Web site (http://source.stanford.edu/). Of the original 30,000 features, 13,956 with gene annotations were identified. WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) software (http://bioinfo.vanderbilt.edu/webgestalt/) , which includes GOTree Machine software, was used for comparative functional analysis. Gene ontology (GO) terms were sought for each annotated feature. For each GO term, the total number of features on the array belonging to that category was determined, before comparisons were made with the lists of symptom factor-correlated features identified in the analyses described above. Statistical analysis of the enrichment by GO category was completed using the hypergeometric test, which accounts for the problem of sampling without replacement associated with comparison of the filtered and symptom factor-correlated genes from the remaining features on the arrays. A GO category was considered to be differentially regulated if the significance level was <.01. Finally, to validate the biological relevance of the symptom factorcorrelated genes, the subject group was divided into 3 subgroups on the basis of the course of illness: those who remained symptomatic throughout the 9 months or more of follow-up (n=4; subjects PIFS13 and PIFS7 in table 1); those who were symptomatic on enrollment but subsequently recovered (n=8; subjects PIFS4-6 and C1-5); and those who had already recovered from IM shortly before enrollment in the cohort and remained symptom free over the period of prolonged follow-up (n=3; subjects C6-8). For each gene, the mean normalized expression values and mean symptom factor scores for these 3 subject subgroups were plotted. Candidate genes were retained if (1) the pattern of change in expression over time was consistent with that predicted from the categorization of the subjects--that is, the mean intensity was highest in those who were symptomatic and lowest in those were not (or the converse for negatively correlated genes) - and (2) the pattern of recovery from illness over time was reflected by a 1.5-fold or greater (>=log_2 0.59) change in mean expression levels between the extremes of the data set. A single outlying data point in the mean trend lines was ignored, but the presence of 2 or more outlying data points led to the exclusion of that gene from further interest. Functional and pathway information for the finalized list of genes was obtained from the BioCarta (http://www.biocarta.com/) and Kyoto Encyclopedia of Genes and Genomes (http://www.genome.ad.jp/kegg/kegg4.html) databases. Figure 1 provides a schematic summary of the complete data analysis process. RESULTS The subjects with PIFS included 2 males and 5 females with a mean age of 24 years (table 1). At enrollment, these subjects reported a mean of 22 days out of role and 14 days in bed since the onset of IM, whereas the control group, which included 5 males and 3 females with a mean age of 24 years, reported a mean of 17 days out of role and 9 days in bed. With the exception of 1 Hispanic individual, all subjects were white. All subjects had a clinical illness consistent with IM, featuring fever and pharyngitis. Generalized lymphadenopathy was evident in 10 subjects, splenomegaly in 1, and rash in 1. None of the group had preexisting medical illnesses that might have contributed to the symptom complex or influenced gene expression, with the possible exception of 1 case subject who had idiopathic epilepsy well controlled by sodium valproate therapy. Five subjects reported recent use of prescribed antibiotics (1 case and 4 control subjects) at baseline. Two females (1 case and 1 control subject) were taking the oral contraceptive pill. All subjects reported occasional use of simple analgesics, typically paracetamol, during the illness. The cluster analysis sought a gene expression signature to distinguish case from control subjects during early illness (T1), to allow prediction of the subsequent development of PIFS. The solution dendrogram (figure 2) categorized the subjects into 2 broad groups, with 6 of the 7 case subjects in one arm and the remaining case subject (PIFS1) in the other arm. This subject was significantly older (49 years) than the other case subjects and was 1 of the 2 who had sustained illness over 12 months or more of follow-up. The 6 clustered PIFS cases were associated with 3 control subjects (C1, C3, and C5), who had no apparent distinguishing features. Cluster analysis of the T3 data set, which included the case subjects with 6 months or more of illness and the recovered control subjects, did not provide a coherent gene expression signature for PIFS. Gene expression correlates of the 6 symptom domains were sought by analysis of the filtered gene list and the symptom factor scores for all subjects at all time points (figure 3). The fatigue factor was correlated, positively or negatively, with 197 genes, and the musculoskeletal pain factor was correlated with 138 genes. Overabundance analyses revealed that these 2, but not the other 4, symptom factors were associated significantly more commonly than by chance alone (P<.0001 for fatigue and P=.007 for musculoskeletal pain). Of these genes, 83 were associated with both factors, giving a combined list of 252 genes. Of the 252 fatigue- and/or pain-associated genes, 35 were validated by analysis of the temporal course of the illness in relation to the gene expression pattern (figure 4). Analysis of the enrichment of these 35 genes by GO category did not identify recognized biological processes, molecular functions, or cellular components in which 11 gene from the diseaseassociated list was implicated, indicating significant enrichment in comparison to the GO categories associated with all annotated features on the arrays. Nevertheless, it is apparent that several members of the gene list are involved in similar biological themes, including signal transduction pathways, metal ion binding, and ion channel activity (table 2). DISCUSSION The present study provides the first comprehensive and longitudinal examination of the peripheral blood transcriptome in patients with well-characterized PIFS. Although peripheral blood is a complex tissue, a previous study revealed relatively restricted interindividual and within-individual variability in gene expression when studied by microarray analysis and also showed that this variance was markedly less than that observed in disease states . In addition, recent data from the Microarray Quality Control project indicates good intraplatform consistency across test sites as well as a high level of interplatform concordance in terms of genes identified as being differentially expressed . Several of the recognized confounding influences on peripheral blood gene expression were controlled for in the present study , including age (by matching in the case-control series), medication use (generally none), and time of day at which blood sampling was conducted (standardized). In addition, we previously reported no significant differences in leukocyte subpopulations between these subject groups . In the DIOS cohort, we have already established that PIFS is a stereotyped illness complex, consistent with the diagnostic criteria for CFS, with a case rate of 11% of subjects at 6 months after the onset of infection . The prospective, population-based research design in the present study can be contrasted with traditional CFS research, which has focused almost exclusively on cross-sectional studies of subjects recruited from tertiary referral clinics. Such subjects feature clinical heterogeneity and chronicity, which are likely to reflect diversity in risk factors, illness course, and pathophysiology [9, 32, 33]. This heterogeneity is likely to be a major reason why the pathogenesis of CFS remains largely unknown, despite several de- cades of hypothesis-driven research [13, 14]. The PIFS model used here therefore provides a unique opportunity to critically examine the popular hypotheses on the pathogenesis of CFS. The findings of the present study provide preliminary evidence for the potential of studies of peripheral blood gene expression to identify biomarkers for the major symptoms of the PIFS illness and to open new investigative pathways for studies of pathogenesis. The gene expression signature identified by cluster analysis on the baseline samples generally predicted subsequent PIFS status. However, this signature should be regarded as exploratory only, because it was not unique to the subjects who went on to a PIFS illness. In addition, a cross0sectional analysis of the gene expression data set at 6-9 months after the onset of infection could not reliably distinguish subjects with PIFS from those who had recovered uneventfully from IM. The genes of interest associated with the major symptoms of PIFS included several with functional roles in metal ion binding within the cell (CBFA2T2, NDUFS2, CHEK2, ZNF596, MT1X, ZBTB41, and ZDHHC3); immune response pathways (PRDX1, SCARB1, SH2D1B, RAE1, ASAH2, and IL11RA); hormonal responses (IGF2AS and ACBD3); and neuronal pathways (SORCS3 and KCND3). The association between each of these genes and PIFS was validated by demonstrating first that the expression in subjects who had recovered from IM differed from those with ongoing symptoms and second that the pattern of change in gene expression over time was associated in a consistent fashion with the longitudinal course of illness (either with ongoing PIFS or with recovery). It may be noteworthy that none of these candidate genes are shared with those identified in previous studies of patients with CFS, although similar biological processes have been implicated [34-38]. However, these previous studies were cross-sectional and were based on comparison of patients with long-standing CFS, with the likely heterogeneity inherent in that patient group [9, 32]. For instance, a recent analysis of the clinical phenotypes within the diagnosis of CFS in a population-based sample and the associated peripheral blood gene expression pattern revealed at least 5 patient subgroups, each associated with relatively distinct gene expression signatures . Nevertheless, the common biological process identified in these various studies is the transport of iron, zinc, and copper ions, and, in terms of functional pathway, it appears that immune response genes and neuronal genes are commonly expressed. Because these processes and pathways constitute a large proportion of all well-characterized genes in the transcriptome, the fundamental premise of this study - that peripheral blood gene expression will inform a better understanding of the pathogenesis of CFS - remains speculative. Additional factors beyond alterations in the pattern of peripheral blood gene expression reflecting the host response to the initial infection are likely to contribute to the duration of illness after IM. These may include behavioral response patterns such as alterations in sleep, exercise, and mood as well as the modulating influences of sex , which in turn may also influence peripheral blood gene expression [37, 41]. There were no genes identified here that were shared with those previously identified as exercise induced, either in control subjects or in patients with CFS . Further studies of the genes of interest identified here in an expanded case-control series of subjects followed from the onset of acute IM are therefore needed to verify the association with the illness complex of PIFS and to investigate the impact of behavioral changes on gene expression. Confirmation of these gene expression correlates by real-time polymerase chain reaction in the subjects reported here and in subjects who developed PIFS after having other infections included in the DIOS cohort - as well as in independent postinfective cohorts - may make possible novel investigative approaches to elucidate the pathophysiology of PIFS and CFS. Acknowledgments The support of the general practitioners and the diagnostic pathology services in the Dubbo region and the enduring cooperation of the subjects who participated in this research are gratefully acknowledged. Tables Table 1. Subject groups, symptom scores, and sampling time points (T1T4) for the microarray analysis. --------------------------------------------------------------------------------------- Symptom scores^b by time after onset ---------------------------------------------------------------------- T1 T2 T3 T4 -------------- -------------- -------------- ---------------------- Subjecta (sex, 0-3 3-6 6-9 9-12 3-6 6-9 9-12 >12 >12 age in years) weeks weeks weeks weeks months months months months months PIFS1 (F, 49) 8 7 8 8 8 4 5 PIFS2 (F, 17) 3 6 9 10 11 10 5 PIFS3 (F, 23) 11 8 10 6 PIFS4 (F, 17) 6 9 4 7 0 PIFS5 (M, 18) 11 NA 8 7 3 2 0 PIFS6 (M, 23) 4 5 0 PIFS7 (F, 19) 5 8 3 C1 (F, 34) 5 4 0 C2 (M, 17) 8 0 C3 (M, 19) 9 2 0 0 C4 (M, 48) 3 NA 0 1 C5 (M, 18) 3 1 0 0 C6 (M, 18) 0 2 0 1 C7 (F, 19) 2 2 1 0 C8 (F, 18) 1 0 0 0 --------------------------------------------------------------------------------------- NOTE. Shaded and unshaded areas indicate the illness and the recovery period, respectively, for each subject. NA, not available. a Case patients with postinfective fatigue syndrome are indicated by "PIFS"; matched control subjects who recovered within 6 weeks of onset are indicated by "C." b Symptom score on the SOMA subscale of the Somatic and Psychological Health Report (possible range, 012; a score of 3 or more indicates a clinically significant fatigue state). Table 2. Postinfective fatigue syndromeassociated genes: function, subcellular localization, tissue expression, and disease associations. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- GenBank Gene name Gene symbol Gene function Subcellular Tissue expression Associated phenotype(s) accession no. localization ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- NM_003171 Suppressor of var 1, 3-like 1 (S. cerevisiae) SUPV3L1 Cofactor of survivin in apoptosis suppression; Mitochondrion Ubiquitous ATP and RNA binding; helicase activity NM_182961 Spectrin repeat containing, nuclear SYNE1 Actin binding; laminin binding; Golgi and nuclear Golgi apparatus; Ubiquitous envelope 1 organization and biogenesis; myocyte cytoskeleton; differentiation nuclear envelope AC013478 Phospholipase C-like 1 PLCL1 Calcium ion binding; hydrolase activity; Ubiquitous phospholipase C activity AL034421 Core-binding factor; runt domain, CBFA2T2 Metal ion binding; regulation of transcription; Nucleus Ubiquitous Translocation in acute myeloid leukemia produces alpha subunit 2 cell proliferation a chimeric gene product associated with nuclear corepressor/histone deacetylase complex to block hematopoietic differentiation AF013160 NADH dehydrogenase (ubiquinone) Fe-S NDUFS2 Metal ion binding; mitochondrial electron Mitochondrial Ubiquitous Mitochondrial complex I deficiency protein 2, 49 kDa (NADH-coenzyme transport; NADH dehydrogenase inner membrane Q reductase) (ubiquinone) activity; oxidative phosphorylation NM_002574 Peroxiredoxin 1 PRDX1 Antioxidant enzyme activity; antiviral activity Cytoplasm Ubiquitous Increased expression in Alzheimer disease, Down in CD8 T cells; cell proliferation; skeletal syndrome, and lung injury development AL117330 CHK2 checkpoint homolog (S. pombe) CHEK2 (also ATP, Mg, nucleotide, and protein binding; Nucleus Ubiquitous Associated with cancer susceptibility, including breast, CDS1) serine/threonine kinase activity; colorectal, and prostate cancer response to DNA damage; cell cycle regulation NM_005938 Myeloid/lymphoid or mixed-lineage MLLT7 Transcription factor; cell cycle arrest; cell Nucleus; Ubiquitous leukemia differentiation; negative regulation of cytoplasm angiogenesis, cell proliferation, and muscle cell differentiation; AKT and Ras signaling pathways AC004908 Zinc finger protein 596 ZNF596 DNA and metal ion binding; DNA-dependent Nucleus Ubiquitous regulation of transcription AF351784 DnaJ (Hsp40) homolog, subfamily C, DNAJC14 Heat shock protein and unfolded protein Membranes of the Ubiquitous member 14 binding; interacts with angiotensin receptor1 endoplasmic (AGTR1), dopamine receptor1 (DRD1), and reticulum lysosomal trafficking regulator (LYTR) NM_016412 Insulin-like growth factor 2 antisense IGF2AS Growth factor inhibition Brain; liver; placenta; plasma; pancreas NM_005505 Scavenger receptor class B, member 1 SCARB1 Apoptosis; cell adhesion; cholesterol Plasma membrane Ubiquitous HCV entry cofactor; amyloid B protein interaction metabolism AL365449 Sortilin-related VPS10 domain SORCS3 Neuropeptide signaling pathway Membranes of the Brain; testis; cranial nerve; blood; liver; containing receptor 3 endosomes, stomach; colon; muscle; larynx; Golgi, lysosomes tonsil; mammary gland and nucleus NM_053282 SH2 domain containing 1B SH2D1B Intracellular signaling; NK cellmediated Blood; spleen; thymus; kidney; cytotoxicity; interacts with NK cells; stomach; skin; lung; muscle; testis lymphocyte adhesion NM_024882 Chromosome 6 open reading frame 155 C6orf155 AK026814 Sorting nexin 25 SNX25 Signal transduction; phosphoinositide Ubiquitous AF255647 Transmembrane protein 163 TMEM163 Ubiquitous NM_003610 RAE1 RNA export 1 homolog (S. pombe) RAE1 Interacts with NK cell lectins, nucleoporin; RNA Cytoskeleton; Ubiquitous binding and export; microtubule binding; nuclear mitotic spindle assembly membrane NM_005952 Metallothionein 1X MT1X Iron, zinc, copper, and cadmium ion binding; Ubiquitous electron transport AC010974 LY6/PLAUR domain containing 1 LYPD1 GPI-anchored protein binding Plasma membrane Ubiquitous AC063956 Casein alpha s2-like A CSN1S2A Transporter activity Extracellular Muscle AK002014 Chromosome 6 open reading frame 70 C6orf70 region Ubiquitous NM_014319 LEM domain containing 3 LEMD3 Nuclear endoplasmic reticulumassociated Nuclear inner Ubiquitous Buschke-Ollendorff syndrome; melorheostosis degradation pathway; glycosylation of membrane with osteopoikilosis mammalian N-linked oligosaccharides; nucleotide binding NM_019893 N-acylsphingosine amidohydrolase ASAH2 Ceramide, lipid, and sphingolipid metabolism Mitochondria; Skin; bladder (non-lysosomal ceramidase) 2 signal transduction; apoptosis plasma membrane AF020762 Acyl-Coenzyme A binding domain ACBD3 Maintenance of Golgi structure and function; Golgi membrane; Ubiquitous containing 3 hormonal regulation of steroid formation cytoplasm; mitochondrion BC029816 Ovostatin 2 OVOS2 Endopeptidase inhibitor activity Secreted protein Testis; lung; eye; brain; lymph node; mammary gland; pituitary gland; bone; kidney; cranial nerve AL356315 Zinc finger and BTB domain containing 41 ZBTB41 Nucleic acid, protein, and zinc ion binding Nucleus Ubiquitous NM_014473 Dimethyladenosine transferase HSA9761 rRNA modification and processing; transferase Nucleus Ubiquitous activity AF004813 Solute carrier family 4, sodium bicarbonate SLC4A4 Intracellular pH regulation; sodium ion binding Cell membrane Ubiquitous Proximal renal tubular acidosis with ocular cotransporter, member 4 and transport; anion exchange activity NM_004512 Interleukin 11 receptor, alpha IL11RA Hematopoietin/interferon-class (D200-domain) Plasma membrane Ubiquitous High expression in Hodgkin lymphoma; possible cytokine receptor activity; Jak-STAT signaling prostate cancer pathway NM_004980 Potassium voltage-gated channel, Sha KCND3 Regulation of neurotransmitter release, heart Plasma membrane; Brain; testis; prostate; lung; thyroid; l-related subfamily, member 3 rate, insulin secretion, neuronal excitability, voltage-gated mammary gland; colon; heart; epithelial electrolyte transport, smooth potassium adrenal gland muscle contraction, and cell volume; metal channel complex ion, potassium, and protein binding NM_016598 Zinc finger, DHHC-type containing 3 ZDHHC3 Acyltransferase activity; metal ion binding Vacuolar membrane Ubiquitous NM_017594 GIPC PDZ domain containing family, GIPC1 Interacts with integrins, b-adrenergic receptor Cytoplasm; plasma Ubiquitous member 1 signaling pathway; spliceosomal assembly membrane; nucleus NM_017594 Small nuclear ribonucleoprotein SNRPG RNA and protein binding; RNA splicing; Nucleus Ubiquitous polypeptide G spliceosome assembly NM_002922 Regulator of G-protein signaling 1 RGS1 (also G-protein signaling; adenylate cyclase inhibition Plasma membrane Ubiquitous BL34) pathway; GTPase activator activity; calmodulin binding ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Figure captions Figure 1. Schematic outline of the data analysis process Figure 2. Cluster analysis of the filtered gene list including data from the baseline time point (T1). The gene expression data from T1 for the 733 features included in the filtered list were used in an unsupervised hierarchical cluster analysis, to identify a gene expression signature early during the course of infectious mononucleosis that predicted postinfective fatigue syndrome (PIFS) or recovery. Individual genes are in rows, and subjects ("PIFS" indicates case subjects; "C" indicates control subjects) are in columns. Figure 3. Symptom factor scores over time for case subjects with postinfective fatigue syndrome (PIFS) and control subjects. Normalized symptom factor scores for all data points for each subject at each categorized time point (T1T4) were calculated . Subjects with PIFS are represented by black circles, and control subjects are represented by white circles. Figure 4. Expression of postinfective fatigue syndromeassociated genes over time in subjects with varied illness outcomes. Selected genes of interest of the 35 identified with temporal expression patterns consistent with the course of illness, associated with either fatigue (A) or musculoskeletal pain (B), are shown. The size of the symbols is proportional to the mean symptom factor score for the subgroup of subjects. References 1. Callan M, Steven N, Krausa P, et al. Large clonal expansions of CD8 T cells in acute infectious mononucleosis. Nat Med 1996; 2:906-11. 2. Kieff E, Rickinson A. EBV and its replication. In: Knipe D, Howley P, eds. Fields virology. Vol. 2. 4th ed. Philadelphia: Lippincott Wilkins & Williams, 2001:2511-74. 3. White P, Thomas J, Kangro H, et al. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 2001; 358:1946-54. 4. Buchwald D, Rea T, Katon W, Russo J, Ashley R. 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Biotechniques 2003; 35:968-73. 27. Whistler T, Unger E, Nisenbaum R, Vernon S. Integration of gene expression, clinical, and epidemiologic data to characterize chronic fatigue syndrome. J Transl Med 2003; 1:10. 28. Garrett-Mayer E. Overview of standard clustering approaches for gene microarray data analysis. In: Allison D, Page G, Beasley T, Edwards J, eds. DNA microarrays and related genomics techniques. Boca Raton, FL: Chapman & Hall CRC, 2006:131-58. 29. Zhang B, Kirov S, Snoddy J. Webgestalt: an integrated system for ex- ploring gene sets in various biological contexts. Nucleic Acids Res 2005; 33:W741-8. 30. Whitney A, Diehn M, Popper SJ, et al. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci USA 2003; 100:1896-901. 31. MAQC Consortium. The Microarray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression mea- surements. Nat Biotechnol 2006; 24:1151-61. 32. Hickie I, Lloyd A, Hadzi-Pavlovic D, Parker G, Bird K, Wakefield D. Can the chronic fatigue syndrome be defined by distinct clinical fea- tures? Psychol Med 1995; 25:925-35. 33. Lloyd AR. Chronic fatigue and chronic fatigue syndrome: shifting boundaries and attributions. Am J Med 1998; 105:7S-10S. 34. Powell R, Ren J, Lewith G, Barclay W, Holgate S, Almond J. Identi- fication of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients. Clin Exp Allergy 2003; 33:1450-6. 35. Vernon SD, Unger ER, Dimulescu IM, Rajeevan M, Reeves WC. Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome. Dis Markers 2002; 18:193-9. 36. Steinau M, Unger ER, Vernon SD, Jones JF, Rajeevan MS. Differential- display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. J Mol Med 2004; 82:750-5. 37. Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiol 2005; 5:5. 38. Kaushik N, Fear D, Richards SCM, et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol 2005; 58:826-32. 39. Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS. Gene expression profile of empirically delineated classes of un- explained chronic fatigue. Pharmacogenomics 2006; 7:375-86. 40. White PD. What causes chronic fatigue syndrome? BMJ 2004; 329: 928-9. 41. Rossi EL. Psychosocial genomics: gene expression, neurogenesis, and human experience in mind-body medicine. Adv Mind Body Med 2002; 18:22-30. -------- (c) 2007 Infectious Diseases Society of America. [Return to top] ------------------------------ Date: Mon, 9 Jul 2007 12:59:57 -0400 From: "Bernice A. Melsky" Subject: RES: Fibromyalgia patients show an abnormal dopamine response to pain Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci. 2007 Jun;25(12):3576-82. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA. McGill University Centre for Research on Pain, Faculty of Dentistry, 3640 University Street, Strathcona Building, Montreal, QC, Canada, H3A 2B2. PMID: 17610577 Fibromyalgia is characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances. Accumulating evidence indicates that fibromyalgia may involve a dysfunction of modulatory systems in the brain. While brain dopamine is best known for its role in pleasure, motivation and motor control, recent evidence suggests that it is also involved in pain modulation. Because dopamine is implicated in both pain modulation and affective processing, we hypothesized that fibromyalgia may involve a disturbance of dopaminergic neurotransmission. Fibromyalgia patients and matched healthy control subjects were subjected to deep muscle pain produced by injection of hypertonic saline into the anterior tibialis muscle. In order to determine the endogenous release of dopamine in response to painful stimulation, we used positron emission tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the brain during injection of painful hypertonic saline and nonpainful normal saline. Fibromyalgia patients experienced the hypertonic saline as more painful than healthy control subjects. Control subjects released dopamine in the basal ganglia during the painful stimulation, whereas fibromyalgia patients did not. In control subjects, the amount of dopamine release correlated with the amount of perceived pain but in fibromyalgia patients no such correlation was observed. These findings provide the first direct evidence that fibromyalgia patients have an abnormal dopamine response to pain. The disrupted dopaminergic reactivity in fibromyalgia patients could be a critical factor underlying the widespread [Return to top] ------------------------------
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