Search

Light AR, Bateman L, Jo D, Hughen RW, VanHaitsma TA, White AT, Light KC (University of Utah, Salt Lake City, UT, USA). Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med 2012; 271: 64–81. Objectives. To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. Design. Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. Results. No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor’s transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. Conclusions. At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

ADCC (antibody-dependent cell-mediated cytotoxicity) requires the cytotoxic subset of NK cells that can also recognize antibody. In vivo function may depend on the number of these ADCC NK cells. We report on ADCC activity and the number of IgG FcR-positive NK cells/ul blood as risk factors for chronic fatigue syndrome (CFS). ADCC capacity was measured as CX1:1 (PMID 29113954), the % Daudi B tumor cells killed at a 1:1 ratio of CD16A FcR-pos CD56pos NK effector cells to Daudi targets with obinutuzumab anti-CD20. CFS patients met the 1994 Fukuda diagnostic guidelines. We examined 5 families with 2 or more patients per family, comparing patients with their non-CFS family members and with unrelated healthy controls. ADCC activity and effector cell counts were similar between CFS patients and their family members. Surprisingly, the CX1:1 of both the CFS patients and their non-CFS family members was low, 77% of the controls (P=0.03). The ADCC effector cell counts/ul blood were also lower for both (two-tailed P=0.09, insignificant). The potential for synergistic interaction of low CX1:1 and low effector cell counts was 24-fold greater for CFS family members than for unrelated healthy controls (P

Postexertional malaise (PEM) is a defining characteristic of chronic fatigue syndrome (CFS) that remains a source of some controversy. The purpose of this study was to explore the effects of an exercise challenge on CFS symptoms from a patient perspective.This study included 25 female CFS patients and 23 age-matched sedentary controls. All participants underwent a maximal cardiopulmonary exercise test. Subjects completed a health and well-being survey (SF-36) 7 days postexercise. Subjects also provided, approximately 7 days after testing, written answers to open-ended questions pertaining to physical and cognitive responses to the test and length of recovery. SF-36 data were compared using multivariate analyses. Written questionnaire responses were used to determine recovery time as well as number and type of symptoms experienced.Written questionnaires revealed that within 24 hours of the test, 85% of controls indicated full recovery, in contrast to 0 CFS patients. The remaining 15% of controls recovered within 48 hours of the test. In contrast, only 1 CFS patient recovered within 48 hours. Symptoms reported after the exercise test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands. A significant multivariate effect for the SF-36 responses (p0.001) indicated lower functioning among the CFS patients, which was most pronounced for items measuring physiological function.The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls.

To assess the burden of fibromyalgia (FM) in patients with FM taking antidepressant medication for comorbid depression.Symptom burden, impact on work and activity, and healthcare resource utilisation (HCRU) was examined at randomisation in patients enrolled in a clinical trial. Symptom burden was estimated based on self-reported health status measures. The Work Productivity and Activity Impairment: Specific Health Problem scale adapted to FM and a separate HCRU questionnaire were completed. The relationship between FM severity and burden was evaluated.The total population analysed comprised 193 patients; 71 (36.8%) had moderate FM and 119 (61.7%) severe FM. Patients had moderate pain, severe impairment in functioning due to FM, sleep disruption, mild anxiety, and mild depression. In the 7 days preceding randomisation, an average of 58.0% overall work impairment was reported, with 15.2% of working hours missed and 54.0% productivity while at work. In the 3 months preceding randomisation, on average, 5.0 visits per patient were made to healthcare professionals. Physical treatments were used by 34.7% and supplements by 31.6% of patients. Prescription and non-prescription medications, as well as professional services providing help with activities of daily living (ADL) that are impacted by FM, were used by75% of patients. In addition, 50.4 hours of unpaid help was provided for ADL assistance. Total out-of-pocket expenditures were US$307.1, €410.4, or C$211.3, depending on location. FM burden worsened with increasing FM severity.This study demonstrates the significant burden of FM in patients with comorbid depression treated with an antidepressant.

Background There are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM. Methods Patients, ages 13–17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with ≥50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double-blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. Results The milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM. Conclusions The open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment. Trial registration NCT01328002; NCT01331109 Electronic supplementary material The online version of this article (doi:10.1186/s12969-015-0025-9) contains supplementary material, which is available to authorized users.

Cytokine alterations are more strongly correlated with illness duration than with measures of illness severity., Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness. Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246). Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disease of unknown pathogenesis consisting of a variety of flu-like symptoms including severe fatigue. Initial analysis of the use of rintatolimod (Poly I: Poly C 12U), a selective TLR3 agonist, in a Phase III, double-blind, randomized, placebo-controlled trial of CFS/ME demonstrated statistical significance (p 9 minutes. Analysis of improvement in exercise performance at the ≥ 25% and ≥ 50% levels using ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using the pre-specified baseline exercise stratum (baseline ET duration >9 minutes). For this subset of patients (n=126), 33% (n=20), and 12% (n=8) of rintatolimod vs. placebo patients, respectively, improved ET duration by ≥ 25% (p=0.004) while 23% (n=14) compared to 4.5% (n=3) of rintatolimod vs. placebo patients, respectively improved ET duration by ≥ 50% (p=0.003). This corresponds to increases of ≥ 186 and ≥ 373 seconds for patients receiving rintatolimod, respectively, at ≥ 25% and ≥ 50% improvement responses. A frequency distribution analysis of ≥ 25% improvement, 9 minutes cohort showed net improvement to be 18.3% for the rintatolimod cohort vs. 4.6% deterioration for placebo (p=0.015). A continuous responder analysis using 5% increments from ≥ 25% to ≥ 50% provided a robust clinical enhancement in ET effect in the rintatolimod cohorts as compared to placebo. The KPS and Vitality (SF-36 subscale) quality of life secondary endpoints demonstrated similar clinically significant improvements for the rintatolimod cohort as a function of the same ET dichotomization. Rintatolimod was generally well-tolerated in this CFS/ME population. Conclusions: Using a modified Bruce ET protocol with reduced physical exertion allowed clear identification of patient responders to rintatolimod with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes in a modified Bruce ET test. Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod.

Antibody-dependent cell-mediated cytotoxicity (ADCC) supports anti-viral protection and monoclonal antibody anti-tumor therapies. We used two assays to compare ADCC of healthy donors: CX@1:1 (the percentage cells killed at a 1:1 ratio of CD16Apositive NK cells to ‘target’ cells that were pre-labeled with saturating antibody); and EC50 (the effective concentration of antibody that supports 50% of maximal ADCC). CX@1:1 measures lytic capacity while the EC50 measures cellular recognition; there was no correlation between the 2 assays though we observed 4.5-fold differences among donors in each assay. We correlated ADCC with 5 cytometric parameters (the median fluorescent intensities [MFIs] of the CD16A IgG Fc-receptor; the %NK cells positive & MFIs of the adhesion molecule CD2; the MFIs of perforin; and the %CD16Apositive of CD56positive NK cells) and with CD16A V&F genotypes that affect FcR affinity. For CX@1:1, the best donor killed 73% of targets while the worst killed 16% and perforin levels correlated weakly (P=0.11). Unexpectedly and inexplicably, the %CD16Apositive cells among NK cells correlated (P

Lucinda Bateman,1 Robert H Palmer,2 Joel M Trugman,2 Yuhua Lin2 1Fatigue Consultation Clinic, Salt Lake City, UT, 2Forest Research Institute, Jersey City, NJ, USA Background: The purpose of this study was to evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia patients experiencing inadequate clinical response to duloxetine after receiving treatment for 6 weeks or longer. Methods: This exploratory study included 107 patients with fibromyalgia who had been treated with duloxetine 60 mg/day for at least 4 weeks prior to enrollment. Following a 2-week open-label period on duloxetine, patients who had visual analog scale pain scores ≥ 40 and were dissatisfied with current treatment were randomized 4:1 to milnacipran 100 mg/day (n = 86) or placebo (n = 21) for 10 weeks of double-blind treatment. The small placebo group was included solely to blind the study and minimize expectation bias among patients and investigators, and there was no preplanned statistical comparison between treatment groups. The primary efficacy parameter was the percentage of patients rating themselves as “much improved” or “very much improved” on the Patient Global Impression of Change (PGIC) at the final visit. Other efficacy parameters included changes in one-week recall visual analog scale pain, Fibromyalgia Impact Questionnaire Revised (FIQR), and Multiple Ability Self-Report Questionnaire (MASQ). Results: Of patients switched to milnacipran, 32.9% were classified as PGIC responders, and they also demonstrated improvement in visual analog scale pain, FIQR total, and MASQ total scores (mean changes from baseline were −12.3, −7.77, and −2.39, respectively). Nausea and dizziness were the most common treatment-emergent adverse events in patients switched to milnacipran, reported in 21% and 15%, respectively, of patients in this group. Conclusion: Results from this exploratory study suggest that switching from duloxetine to milnacipran may be beneficial in some patients with fibromyalgia who have an inadequate response to duloxetine. Further research investigating the efficacy and safety of switching fibromyalgia therapies is warranted. Keywords: fibromyalgia, milnacipran, duloxetine, switch

Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions.Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors.PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p0.005 and r=-0.34, p0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001).PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection., IMPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen dediscovery that may be helpful to others working in this field.

Chronic fatigue syndrome (CFS) is a multisystem disorder characterized by prolonged and severe fatigue that is not relieved by rest. Attempts to treat CFS have been largely ineffective primarily because the etiology of the disorder is unknown. Recently, CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations. We collected blood samples from 100 CFS patients and 200 self-reported healthy volunteers from the same geographical area. We analyzed these in a blind manner using molecular, serological, and viral replication assays. We also analyzed samples from patients in the original study that reported XMRV in CFS patients. We did not find XMRV or related MLVs either as viral sequences or infectious viruses, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies. Our findings do not support an association between CFS and MLV-related viruses, including XMRV, and the off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.

For over a decade, investigators have examined whether patients with chronic fatigue syndrome (CFS) show altered serum cytokine profiles. Early studies (Gupta, Aggarwal, See, & Starr, 1997; Moss, Mercandetti, & Vojdani, 1999) suggested that CFS patients showed evidence of an enhanced pro-inflammatory state, reflected in higher levels of TNF-α and lower levels of IL-10 together with higher IL-6, which is often interpreted as having mixed pro- and anti-inflammatory effects. Other studies (Borish et al., 1998; Zhang et al., 1999) found elevated levels of both proinflammatory cytokines (including TNF-α, IL-2, and IFNγ) and anti-inflammatory cytokines (IL-10) but only in some of the CFS patients, specifically, those with active allergies, psychiatric symptoms, or with GulfWar syndrome. More recent studies have generally not supported the link between CFS and a greater proinflammatory cytokine profile. Instead, numerous studies have observed that their CFS samples showed IL-6 and pro-inflammatory cytokines that were lower or not different or even showed higher anti-inflammatory cytokines compared to controls (Amel, Kashipaz, Swinden, Todd, & Powell, 2003; Gaab et al., 2005; Patarca-Montero, Antoni, Fletcher & Klimas, 2001; Skowera et al., 2004; terWolbeek et al., 2007; Visser et al., 2001). Prospective studies of several infectious disorders known to lead to CFS in a small subgroup of those who are infected have also yielded mixed observations in regard to whether pro-inflammatory cytokines like IL-1β, TNF-α, IL-2, and IFNγ or IL-6 remain elevated in those patients who do develop CFS in the postinfectious state (Kerr & Tyrrell, 2003; Vollmer-Conna et al., 2007). Nevertheless, antiviral treatments and similar interventions have proven successful in some CFS patients (Kerr, Cunniffe, Kelleher, Bernstein, & Bruce, 2003; Lerner, Beqaj, Deeter, & Fitzgerald, 2007). Several studies have used exercise as a stimulus when they compared cytokine profiles in CFS patients and healthy individuals. Post-exercise exacerbation of the central symptoms of CFS lasting 24–48 h or longer (including worsening of physical fatigue, problems with memory and concentration, and both muscle and joint pain) is so common that it is part of the Centers for Disease Control (CDC) diagnostic profile for CFS (Fukuda et al., 1994). CFS patients often remark that if they try to follow an exercise regimen, after each bout of exercise there is a significant cost for the next several days in terms of greater symptoms and less ability to function (symptom flare [SF]). Exercise physiologists have documented that several cytokines are increased from 4 to 24 h after sustained or strenuous exercise even in very fit individuals, and these include both pro-inflammatory IL-1β and anti-inflammatory IL-10, as well as IL-6 and IL-8 (Nielsen & Pedersen, 2007; Patarca-Montero et al., 2001; Peake et al., 2005, 2008; Pedersen & Fischer, 2007). LaManca and colleagues (1999) used a maximal exercise task that did cause a worsening of fatigue and other symptoms in their CFS patients but produced no differences in cytokine responses between CFS and control groups. Although a maximal exercise task may help demonstrate physiological and performance limits in this disorder, this type of challenge is too extreme to generalize to real-life experiences; a mild to moderate exercise task is thus a more appropriate choice to mimic what CFS patients do naturally that can lead to such a SF. Gupta, Aggarwal, and Starr (1999) reported that when CFS patients were tested twice, once when feeling a typical level of fatigue for their condition and once during a natural SF, they showed significantly greater IL-6 levels during the SF. They also attempted to experimentally induce SF through exercise, but only examined cytokine responses immediately after exercise, before the SF was manifested, when CFS patients and controls did not differ. In contrast, Cannon et al. (1999) employed a mild leg exercise task (15 min of stair-step exercise) but examined post-exercise responses for 24 h after exercise, which did induce increases in both IL-6 and IL-1β. They found that although CFS and control groups did not differ in terms of IL-1β, CFS patients did have modestly higher lipopolysccharide-stimulated IL-6 levels if post-exercise levels were combined with pre-exercise levels (Cannon et al., 1999). However, this study was not definitive because their exercise task was so mild or involved such a restricted set of muscles that it failed to induce an increase in fatigue or other symptoms, nor did they examine a full profile of proinflammatory and anti-inflammatory cytokines. Because pro-inflammatory and anti-inflammatory cytokines are mutually inhibitory, changes in one type can secondarily lead to changes in the other, indicating the need to study both types (for reviews, see Elenkov & Chrousos, 2002; Elenkov, Wilder, Chrousos, & Vizi, 2000). The present study used a moderate exercise task to examine worsening of the central symptoms of fatigue and pain in CFS patients for 48 h after the exercise task while also monitoring pre- and post-exercise cytokine responses for this full period. Our protocol improves upon earlier research in the following ways: (a)We attempted to control for variables that might have caused SF at baseline by asking both CFS and control subjects to refrain from all exercise for 48 h prior to the study and by not testing patients who recently were diagnosed or needed additional medical intervention. (b) We employed a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients. (c) Physical fatigue, mental fatigue, and overall pain symptoms were obtained concurrently with blood samples for cytokines at five times: pre-exercise and at 0.5, 8, 24, and 48 h post-exercise. (d) Whereas prior studies in CFS typically assessed only one or two cytokines, our cytokine profile included six pro-inflammatory cytokines/ligands, four anti-inflammatory/regulatory cytokines, and two exercise-responsive cytokines that have mixed effects. We included one new pro-inflammatory marker, CD40 ligand (CD40L), that has not been previously examined in this population. Genetic alterations that reduce levels of CD40L have been shown to enhance vulnerability to opportunistic infections (Danielian, Oleastro, Rivas, Cantisano, & Zelazko, 2007), a pattern typical of a subgroup of CFS patients.

Objective: To evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia (FM) patients with inadequate response to duloxetine. Background Milnacipran and duloxetine are approved for the management of FM. As individual patient responses to analgesic medications differ, switching therapies to achieve greater benefit or avoid certain side effects is common. Design/Methods: Patients receiving duloxetine 60 mg/day for ≥4 weeks at screening were eligible. After 2 weeks of open-label duloxetine 60 mg/day, patients with VAS pain scores ≥40 (range, 0-100 mm) and dissatisfied with duloxetine were randomized 4:1 to milnacipran 100 mg/day (n=86) or placebo (n=21) for 10 weeks. The primary efficacy parameter was responder status based on Patient Global Impression of Change (PGIC), with responders defined as patients rating themselves “much improved” or “very much improved”. The secondary efficacy parameter was change from baseline in 1-week recall VAS pain score. Statistical analyses were descriptive and used LOCF to impute missing data. Results: In patients switched from duloxetine to milnacipran, 32.9% were PGIC responders and the mean decrease from baseline in VAS pain was 12.3 mm at the Week 10 visit (23.8% of placebo-treated patients were PGIC responders and the mean decrease in VAS pain was 1.3 mm). In a post hoc analysis, 34.2%, 29.1%, and 25.3% of patients switched to milnacipran had ≥30%, ≥40%, and ≥50% improvement in VAS pain scores, respectively. The most common (TEAEs) in patients switched to milnacipran were nausea (21%) and dizziness (15%); nausea and dizziness occurred in 29% and 5% of patients switched to placebo, respectively. Conclusions: These results suggest that FM patients with an inadequate response to duloxetine treatment may benefit from a switch to milnacipran for management of their symptoms. Additionally, a direct switch from duloxetine to milnacipran was safe and well tolerated in this study. Supported by: Forest Laboratories, Inc. Disclosure: Dr. Bateman has received personal compensation for activities with Forest Laboratories consultations and The Speakers Bureau as a consultant and/or speaker. Dr. Spera has received personal compensation for activities with Forest Research Institute as an employee. Dr. Palmer has received personal compensation for activities with Forest Laboratories, Inc. as an employee. Dr. Trugman has received personal compensation for activities with Forest Laboratories as an employee. Dr. Thacker has received personal compensation for activities with Forest Laboratories, Inc. as and employee. Dr. Lin has received personal compensation for activities with Forest Research Institute as an employee.

Background Chronic Fatigue Syndrome (CFS) came to attention in the 1980s, but initial investigations did not find organic causes. Now decades later, the etiology of CFS has yet to be understood, and the role of genetic predisposition in CFS remains controversial. Recent reports of CFS association with the retrovirus xenotropic murine leukemic virus-related virus (XMRV) or other murine leukemia related retroviruses (MLV) might also suggest underlying genetic implications within the host immune system. Methods We present analyses of familial clustering of CFS in a computerized genealogical resource linking multiple generations of genealogy data with medical diagnosis data of a large Utah health care system. We compare pair-wise relatedness among cases to expected relatedness in the Utah population, and we estimate risk for CFS for first, second, and third degree relatives of CFS cases. Results We observed significant excess relatedness of CFS cases compared to that expected in this population. Significant excess relatedness was observed for both close (p Conclusions These analyses provide strong support for a heritable contribution to predisposition to Chronic Fatigue Syndrome. A population of high-risk CFS pedigrees has been identified, the study of which may provide additional understanding.

Background In 2009, a retrospective study reported the detection of xenotropic murine leukemia virus-related virus (XMRV) in clinical isolates derived from individuals with chronic fatigue syndrome or myalgic encephalomyelitis (CFS). While many efforts to confirm this observation failed, one report detected polytropic murine leukemia virus (pMLV), instead of XMRV. In both studies, Polymerase Chain Reaction (PCR)-based methods were employed which could provide the basis for the development of a practical diagnostic tool. To confirm these studies, we hypothesized that the ability to detect these viruses will not only depend upon the technical details of the methods employed but also on the criteria used to diagnose CFS and the availability of well characterized clinical isolates. Methods A repository of clinical isolates from geographically distinct sites was generated by the collection of fresh blood samples from well characterized CFS and healthy subjects. Molecular techniques were used to generate assay positive controls and to determine the lower limit of detection (LLOD) for murine retroviral and Intracisternal A particle (Cell 12(4):963-72, 1977) detection methods. Results We report the establishment of a repository of well-defined, clinical isolates from five, geographically distinct regions of the US, the comparative determination of the LLODs and validation efforts for the previously reported detection methods and the results of an effort to confirm the association of these retroviral signatures in isolates from individuals with CFS in a blinded, multi-site, prospective study. We detected various, murine retroviral DNA signatures but were unable to resolve a difference in the incidence of their detection between isolates from CFS (5/72; 6.7%) and healthy (2/37; 5.4%) subjects (Fisher’s Exact Test, p-value = 1). The observed sequences appeared to reflect the detection of endogenous murine retroviral DNA, which was not identical to either XMRV or pMLV. Conclusions We were unable to confirm a previously reported association between the detection of XMRV or pMLV sequences and CFS in a prospective, multi-site study. Murine retroviral sequences were detected at a low frequency that did not differ between CFS and control subjects. The nature of these sequences appeared to reflect the detection of pre-existing, endogenous, murine retroviral DNA in the PCR reagents employed.