J Neurol Neurosurg Psychiatry 2016;87:1127-1132 doi:10.1136/jnnp-2016-313458
Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention
Received 2 March 2016 ,Revised 5 April 2016 ,Accepted 21 April 2016 ,Published Online First 10 May 2016
Abstract
Introduction Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.
Methods A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups.
Results Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users.
Conclusions Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Use of Plant-Based Therapies and Menopausal Symptoms - A Systematic Review and Meta-analysisOscar H. Franco, MD, PhD1; Rajiv Chowdhury, MD, PhD2; Jenna Troup, MSc1; et al Trudy Voortman, PhD1,3; Setor Kunutsor, MD, PhD2; Maryam Kavousi, MD, PhD1; Clare Oliver-Williams, PhD2; Taulant Muka, MD, PhD1,3
Article Information1Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
JAMA. 2016;315(23):2554-2563. doi:10.1001/jama.2016.8012 editorial comment icon
Editorial
Comment
Abstract
Importance Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms.
Objective To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness.
Data Sources The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies.
Study Selection Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness.
Data Extraction Data were extracted by 2 independent reviewers using a predesigned data collection form.
Main Outcomes and Measures Hot flashes, night sweats, and vaginal dryness.
Results In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, −1.31 [95% CI, −2.02 to −0.61]) and vaginal dryness score (pooled mean difference of changes, −0.31 [95% CI, −0.52 to −0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, −2.14 [95% CI, −5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, −0.79 [−1.35 to −0.23]) and vaginal dryness score (pooled mean difference of changes, −0.26 [−0.48 to −0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality.
Conclusions and Relevance This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.
Nature Genetics | Letter
Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number
Nature Genetics:Year published:(2016) DOI:
doi:10.1038/ng.3696
Received 26 July 2016 Accepted 16 September 2016 Published online 17 October 2016
Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown1, 2. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.
Mortality In Patients With Myalgic Encephalomyelitis And Chronic Fatigue Syndrome.
Stephanie L. McManimen, Andrew R. Devendorf, Abigail A. Brown, Billie C. Moore, James H. Moore, & Leonard A. Jason
Center for Community Research, DePaul University
Abstract Background: There is a dearth of research examining mortality in individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Some studies suggest there is an elevated risk of suicide and earlier mortality compared to national norms. However, findings are inconsistent as other researchers have not found significant increases in all-cause mortality for patients.
Objective: This study sought to determine if patients with ME or CFS are reportedly dying earlier than the overall population from the same cause.
Methods: Family, friends, and caregivers of deceased individuals with ME or CFS were recruited through social media, patient newsletters, emails, and advocate websites. This study analyzed data including cause and age of death for 56 individuals that had ME or CFS.
Results: The findings suggest patients in this sample are at a significantly increased risk of earlier all-cause (M = 55.9 years) and cardiovascular-related (M = 58.8 years) mortality, and they had a directionally lower mean age of death for suicide (M = 41.3 years) and cancer (M =66.3 years) compared to the overall U.S. population [M = 73.5 (all-cause), 77.7 (cardiovascular), 47.4 (suicide), and 71.1 (cancer) years of age].
Conclusions: The results suggest there is an increase in risk for earlier mortality in patients with ME and CFS. Due to the small sample size, the findings should be replicated to determine if the directional differences for suicide and cancer mortality are significantly different from the overall U.S. population.
Source: http://bit.ly/2dYeqi1
Randomized, Double-blind, Placebo-controlled Phase III Trial of Duloxetine Monotherapy in Japanese Patients With Chronic Low Back Pain
Shinichi Konno, MD, PhD; Natsuko Oda, MS; Toshimitsu Ochiai, MS; Levent Alev, MD
Disclosures
Spine. 2016;41(22):1709-1717.
Abstract
Study Design. A 14-week, randomized, double-blind, multicenter, placebo-controlled study of Japanese patients with chronic low back pain (CLBP) who were randomized to either duloxetine 60 mg once daily or placebo.
Objective. This study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP.
Summary of Background Data. In Japan, duloxetine is approved for the treatment of depression, diabetic neuropathic pain, and pain associated with fibromyalgia; however, no clinical study of duloxetine has been conducted for CLBP.
Methods. The primary efficacy measure was the change in the Brief Pain Inventory (BPI) average pain score from baseline to Week 14. Secondary efficacy measures included BPI pain (worst pain, least pain, pain right now), Patient's Global Impression of Improvement, Clinical Global Impressions of Severity, and Roland-Morris Disability Questionnaire, among other measures, and safety and tolerability.
Results. In total, 458 patients were randomized to receive either duloxetine (n = 232) or placebo (n = 226). The BPI average pain score improved significantly in the duloxetine group compared with that in the placebo group at Week 14 [-2.43 ± 0.11 vs. −1.96 ± 0.11, respectively; between-group difference (95% confidence interval), − 0.46 [-0.77 to-0.16]; P = 0.0026]. The duloxetine group showed significant improvement in many secondary measures compared with the placebo group, including BPI pain (least pain, pain right now) (between-group difference: −1.69 ± 0.10, P = 0.0009; −2.42 ± 0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ± 0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ± 0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ± 0.22, P = 0.0439). Adverse events occurring at a significantly higher incidence in the duloxetine group were somnolence, constipation, nausea, dizziness, and dry mouth, most of which were mild or moderate in severity and were resolved or improved.
Conclusion. Duloxetine 60 mg was effective and well tolerated in Japanese CLBP patients.
Most patients who reach disease remission following anti-TNF therapy continue to report fatigue: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis
Katie L. Druce -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Yagnaseni Bhattacharya -
Gareth T. Jones -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Gary J. Macfarlane -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Neil Basu
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Rheumatology (Oxford) (2016) 55 (10): 1786-1790.
https://doi.org/10.1093/rheumatology/kew241
Published: 21 June 2016Navbar
Methods. Data from the British Society for Rheumatology Biologics Register for RA were used. In participants with severe baseline fatigue [36-item Short Form Health Survey (SF-36) vitality score ⩽12.5], we identified those in disease remission [28-joint DAS (DAS28) <2.6] by 6 months. Fatigue response was evaluated according to partial (SF-36 vitality score >12.5) and complete remission (SF-36 vitality score >50) at follow-up. Demographic (e.g. sex, age), clinical (e.g. inflammation, joint erosion and co-morbidities) and psychosocial (e.g. SF-36 domains and HAQ) characteristics were compared between responder and non-responder groups.
Results. Severe baseline fatigue was reported by 2652 participants, of whom 271 (10%) achieved a DAS28 <2.6 by 6 months. In total, 225 participants (83%) reported partial remission and were distinguished from those who did not by better health status on all psychosocial domains. Far fewer [n = 101 (37.3%)] reported full fatigue remission. In addition to reporting clinically poorer health status, they were distinguished on the basis of a history of hypertension, depression and stroke as well as baseline treatment use of steroids and antidepressants.
Conclusion. Despite achieving clinical remission, many RA patients do not achieve complete remission of their fatigue. Therefore, despite being important in overall disease control, reductions in disease activity are not always sufficient to ameliorate fatigue, so other symptom-specific management approaches must be considered for those for whom fatigue does not resolve.
fatigue, disease activity, remission
Clinical Science
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Øystein Fluge,1 Olav Mella,1,2 Ove Bruland,1,3 Kristin Risa,1 Sissel E. Dyrstad,4 Kine Alme,1 Ingrid G. Rekeland,1 Dipak Sapkota,1 Gro V. Røsland,4 Alexander Fosså,5 Irini Ktoridou-Valen,1 Sigrid Lunde,1 Kari Sørland,1 Katarina Lien,6 Ingrid Herder,6 Hanne Thürmer,7 Merete E. Gotaas,8 Katarzyna A. Baranowska,8 Louis M.L.J. Bohnen,9Christoph Schäfer,9 Adrian McCann,10 Kristian Sommerfelt,11 Lars Helgeland,12 Per M. Ueland,2,10 Olav Dahl,1,2 and Karl J. Tronstad4
First published December 22, 2016 -
Metabolism
Abstract
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.
ORIGINAL RESEARCH |Ann Intern Med. Published online March 7, 2017.
Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial
Megan E. Roerink, MD; Sebastian J.H. Bredie, MD, PhD; Michael Heijnen; Charles A. Dinarello, MD; Hans Knoop, PhD; Jos W.M. Van der Meer, MD, PhD
Abstract
Background:
Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS).
Objective:
To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS.
Design:
Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210) Setting:University hospital in the Netherlands.
Patients:
50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment.
Intervention:
Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50).
Measurements:
The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks. Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 nd 24 weeks.
Results:
At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).
Limitation:
Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms.
Conclusion:
Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.
Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of MorphineH.H. Doyle, L.N. Eidson, D.M. Sinkiewicz and A.Z. Murphy
Journal of Neuroscience 20 February 2017, 2906-16; DOI: https://doi.org/10.1523/JNEUROSCI.2906-16.2017
AbstractAlthough morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require 2-3 times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ opioid receptor (MOR), morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that while no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more “activated” phenotype in females at baseline, with the degree of activation a significant predictor of morphine ED50 values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males that was accompanied by increased transcription levels of IL-1ß and a significant rightward shift in the morphine dose response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone significantly potentiated morphine antinociception in females such that no sex differences in ED50 were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation, and contribute to the sexually dimorphic effects of morphine in the rat.
SIGNIFICANCE STATEMENT
We demonstrate that PAG microglia contribute to the sexually dimorphic effects of morphine. Specifically, we report that increased activation of microglia in the PAG contributes to the attenuated response to morphine observed in females. Our data further implicate the innate immune receptor TLR4 as an underlying mechanism mediating these effects, and establish that TLR4 inhibition in the PAG of females reverses the sex differences in morphine responsiveness. These data suggest novel methods to improve current opioid-based pain management via inhibition of glial TLR4, and illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women.
Footnotes
Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Received: 20 December 2016 Accepted: 18 February 2017 Pub: 23 February 2017
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
Methods
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
Results
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
Conclusions
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population
Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine
Scott W. Powers, Ph.D., Christopher S. Coffey, Ph.D., Leigh A. Chamberlin, R.D., M.Ed., Dixie J. Ecklund, R.N., M.S.N., Elizabeth A. Klingner, M.S., Jon W. Yankey, M.S., Leslie L. Korbee, B.S., Linda L. Porter, Ph.D., and Andrew D. Hershey, M.D., Ph.D., for the CHAMP Investigators*
N Engl J Med 2017; 376:115-124 January 12, 2017DOI: 10.1056/NEJMoa1610384
Share:
Background
Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established.
Methods
We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.
Results
A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.
Conclusions
There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281).
Vitamin D and Statin-Related Myalgia
Philip J. Gregory, PharmD
Disclosures | March 10, 2017
· Statin-Associated Side Effects
Do low vitamin D levels increase the risk for myalgia in patients who are taking statins?
Response from Philip J. Gregory, PharmD
Associate Professor, Pharmacy Practice, Center for Drug Information & Evidence-Based Practice, Creighton University, Omaha, Nebraska
About 1%-2% of patients who take hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins for hyperlipidemia develop muscle pain. This myalgia can feel like the aches and pains experienced with the flu. Muscles may feel sore or stiff and be sensitive to touch.[1] In some cases, statin-related myalgia can lead to poor adherence or discontinuation of the drug.[2]
The mechanism for statin-related myalgia is not fully understood, but vitamin D has been speculated to play a role.
Vitamin D deficiency itself is associated with symptoms of myalgia that resemble those caused by statins.[1,3] There has been speculation that statins themselves might affect vitamin D levels. Because low-density lipoprotein (LDL)-cholesterol is a vitamin D carrier and statins reduce LDL cholesterol, it has been proposed that statins could decrease vitamin D levels. On the other hand, both vitamin D and some statins are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Owing to competitive inhibition at CYP3A4, it has been proposed that statins could increase levels of vitamin D.
Clinical trials and observational studies have produced mixed resuotlts in terms of the actual effect of statins on vitamin D levels. Overall, a meta-analysis of clinical trials found increased vitamin D levels in statin users.[4]
Several retrospective studies have shown that low vitamin D levels (measured as 25-hydroxyvitamin D) are associated with a higher risk for statin-induced myalgia. In a study by Shantha and colleagues,[5]patients with vitamin D levels in the lowest quartile had a 1.21 times increased risk for statin-induced myalgia compared with those in the highest quartile. Levels of 15 ng/mL or lower positively predicted the development of myalgia in statin users.
In a cross-sectional study, statin-treated patients with vitamin D levels of less than 15 ng/mL had a 1.9 times increased odds of myalgia compared with non-statin users; however, statin users with higher vitamin D levels did not have an increased risk for myalgia compared with non-statin users.[6]
A retrospective chart review in veterans taking statins found that levels of vitamin D were approximately 10 ng/dL lower in those who experienced statin-induced myalgia compared with those who did not.[7]
A meta-analysis of seven observational studies found that vitamin D levels were significantly lower in statin-treated patients who had symptoms of myalgia compared with those who were asymptomatic. The mean difference in vitamin D levels between the groups was approximately 9.4 ng/mL.[2]
Not all studies have found an association between low vitamin D and myalgia, especially in studies evaluating patients with symptoms confirmed to be caused by statins.[8,9] The discrepancies in findings may be because of the nonspecific nature of muscle symptoms. Some evidence shows that up to 50% of self-reported symptoms of muscle pain in statin users may not be because of statins specifically. Therefore, low vitamin D levels may contribute to muscle pain symptoms more generally, including in patients with statin-induced myalgia or nonspecific myalgia.[9]
Assessing and treating low vitamin D levels may be worth considering before starting or restarting a statin in patients who develop muscle pain while taking a statin.
A retrospective chart review found that replenishing vitamin D before a statin rechallenge in previously intolerant patients increases statin tolerability and adherence.[10]
In uncontrolled studies, some authors have used vitamin D2 (ergocalciferol) supplements (from 50,000 units to 100,000 units per week) in statin-treated patients with muscle symptoms and low vitamin D levels and reported resolution of myalgia in about 90% of patients. In these studies, low vitamin D levels were considered to be less than 32 ng/mL.[11,12]
Open Access Copyright: © 2016
The PACE Trial Invalidates the Use of Cognitive Behavioral and Graded Exercise Therapy in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: A Review
Mark Vink* Family Physician, Soerabaja Research Center, Amsterdam, The Netherlands
Received date: 12 Jan 2016; Accepted date: 24 Mar 2016; Published date: 30 Mar 2016.
. J Neurol Neurobiol 2(3): doi http://dx.doi.org/10.16966/2379- 7150.124 Copyright: © 2016 Vink M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. * Corresponding author: Mark Vink, Family Physician, Soerabaja Research Center, Amsterdam, The Netherlands, E-mail: [email protected]
Introduction Following an extensive review of the literature, the American Institute of Medicine (IOM) concluded that “myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious, debilitating conditions that affect millions of people in the United States and around the world”; that it is a “medical - not a psychiatric or psychological - illness” without a “known cause or effective treatment” which “can cause significant impairment and disability” [1] rendering 25% of patients homebound or bedridden [2] yet “the term chronic fatigue syndrome can result in trivialization and stigmatization” of this “complex, multisystem, and often devastating disorder” [1] . Most doctors are unaware of the seriousness of ME or that it has been classified as a neurological disease by the World Health Organization (WHO) since 1969 [3]; therefore, patients often receive “hostility from their health care provider” and are “subjected to treatment strategies that exacerbate their symptoms” (i.e., CBT and GET) [1]. ISSN 2379-7150 Abstract The main findings reported in the PACE trial were that cognitive behavioral therapy (CBT) and graded exercise therapy (GET) were moderately effective treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and fear avoidance beliefs constituted the strongest mediator of both therapies. These findings have been challenged by patients and, more recently, a number of top scientists, after public health expert Tuller, highlighted methodological problems in the trial. As a doctor who has been bedridden with severe ME for a long period, I analyzed the PACE trial and its follow-up articles from the perspectives of a doctor and a patient. During the PACE trial the eligibility criteria, both subjective primary outcomes, and most of the recovery criteria were altered, creating an overlap of the eligibility and recovery criteria; consequently, 13% of patients were considered “recovered,” with respect to 1 or 2 primary outcomes, as soon as they entered the trial. In addition, 46% of patients reported an increase in ME/CFS symptoms, 31% reported musculoskeletal and 19% reported neurological adverse events. Therefore the proportion negatively affected by CBT and GET would be between 46% and 96%, most likely estimated at 74%, as shown in a large survey recently conducted by the ME Association. Medication with such high rates of adverse events would be withdrawn with immediate effect. There was no difference in long-term outcomes between adaptive pacing therapy, CBT, GET and specialist medical care, and none of them were effective, invalidating the biopsychosocial model and use of CBT and GET for ME/CFS. The discovery that an increase in exercise tolerance did not lead to an increase in fitness means that an underlying physical problem prevented this; validates that ME/CFS is a physical disease and that none of the treatments studied addressed this issue.
Dietary and nutrition interventions for the therapeutic
treatm ent of chronic fatigue syndrome/myalgic
encephalomyelitis: a systematic review
N. Campagnolo,1,2S. Johnston,1,2A. Collatz,1,2 D. Staines1.2 & S. Marshall-Gradisnik1,2
School of Medical Science, Griffith University, Gold Coast, QLD, Australia
National Centre for Neuroimmuno logy and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD,
Australia
J Hum Nutr Diet.
doi: 10.1111/jhn.12435
This is an open access article under the terms of
the Creative Commons Attribution-
NonCommercial-NoDerivs License, which permits
use and distribution in any medium, provided the
original work is properly cited, the use is non-
commercial and no modifications or adaptations
are made.
Abstract
Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/
ME) is characterised by unexplained fatigue for at least 6 months accompa-
nied by a diverse but consistent set of symptoms. Diet modification and
nutritional supplements could be used to improve patient outcomes, such
fatigue and quality of life. We reviewed and discussed the evidence for
nutritional interventions that may assist in alleviating symptoms of CFS/
ME.
Methods: Medline, Cinahl and Scopus were systematically searched from
1994 to May 2016. All studies on nutrition intervention were included
where CFS/ME patients modified their diet or supplemented their habitual
diet on patient-centred outcomes (fatigue, quality of life, physical activity
and/or psychological wellbeing).
Results: Seventeen studies were included that meet the inclusion criteria. Of
these, 14 different interventions were investigated on study outcomes. Many
studies did not show therapeutic benefit on CFS/ME. Improvements in fati-
gue were observed for nicotinamide adenine dinucleotide hydride (NADH),
probiotics, high cocoa polyphenol rich chocolate, and a combination of
NADH and coenzyme Q10.
Conclusions: This review identified insufficient evidence for the use of
nutritional supplements and elimination or modified diets to relieve CFS/
ME symptoms. Studies were limited by the number of studies investigating
the interventions, small sample sizes, study duration, variety of instruments
used, and studies not reporting dietary intake method. Further research is
warranted in homogeneous CFS/ME populations.
Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channelsAuthors· T. Nguyen,S. Johnston,L. Clarke,P. Smith,D. Staines,S. Marshall-Gradisnik
Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome
© The Author(s). 2017
Received: 11 January 2017 Accepted: 4 April 2017 Published: 26 April 2017
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.
ResultsTopological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.
ConclusionsIndependent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.
KeywordsMyalgic encephalomyelitis Chronic fatigue syndrome Microbiota-gut-brain axis Metagenomic Topological data analysis Irritable bowel syndrome Metabolic pathway
Modern Clinical Medicine Research, Vol. 1, No. 1, April 2017
Access to Medical Care for Individuals with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome:
A Call for Centers of Excellence
Madison Sunnquist1 , Laura Nicholson1 , Leonard A. Jason1*, and Kenneth J. Friedman2 1 Center for Community Research, DePaul University, Chicago, Illinois, United States 2 Green Mountain College, Poultney, Vermont, United States Email: [email protected]
Abstract. The current study sought to better understand the experience of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) in accessing care for their debilitating illness. Of 898 participants, less than half had ever seen an ME or CFS specialist, though 99% of participants were interested in specialist care. Participants cited geographic and financial barriers as most frequently precluding access to specialists. Furthermore, satisfaction with specialist care greatly exceeded satisfaction with non-specialist care. These findings suggested that individuals with ME and CFS represent a medically-underserved population, due to lack of available care. The CFS Advisory Committee and NIH Pathways to Prevention Working Group recommended the creation of ME and CFS Centers of Excellence to improve the healthcare access of patients with ME and CFS. The current study documents the need for these centers, as they would ameliorate geographic and financial barriers to quality care. Keywords: Myalgic encephalomyelitis, chronic fatigue syndrome, healthcare access, specialist care,
Baby thought to have been shaken has rare syndrome, family court finds
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2136 (Published 02 May 2017)Cite this as: BMJ 2017;357:j2136
Clare Dyer
A baby who was thought to have been shaken by one of her parents actually has a rare syndrome that affects her blood vessels, Ehlers-Danlos syndrome type IV, a family court has heard.
Effie Stillwell was taken from her parents and placed with foster carers last September, after she collapsed, at nearly 3 months old, and was taken to hospital unresponsive and with difficulty breathing. Retinal haemorrhages and bleeding on the brain were identified, and police began a criminal investigation. But the medical evidence that emerged during the family court hearing persuaded Buckinghamshire County Council to drop its application for a care order.
Gluten-free diet is not recommended for people without celiac disease
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2135 (Published 03 May 2017)Cite this as: BMJ 2017;357:j2135
Zosia Kmietowicz
Gluten is not associated with a risk of coronary heart disease in people without celiac disease—and restricting gluten may result in a low intake of whole grains, which are associated with cardiovascular benefits, a study in The BMJ has found.1
The researchers said that promoting gluten-free diets among people without celiac disease should not be encouraged.
The number of people without celiac disease who avoid gluten has increased in recent years
Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort studyBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1892 (Published 02 May 2017)Cite this as: BMJ 2017;357:j1892
Benjamin Lebwohl, assistant professor1 2, Yin Cao, instructor3 4 5, Geng Zong, postdoctoral fellow5,
Frank B Hu, professor5 6, Peter H R Green, professor1, Alfred I Neugut, Eric B Rimm, Laura Sampson, Lauren W Dougherty, Edward GiovannucciWalter, C Willett, professor5 6 7, Qi Sun, Andrew T Chan,
Correspondence to: A T Chan [email protected]
Accepted 4 April 2017
AbstractObjective To examine the association of long term intake of gluten with the development of incident coronary heart disease.
Design Prospective cohort study.
Setting and participants 64 714 women in the Nurses’ Health Study and 45 303 men in the Health Professionals Follow-up Study without a history of coronary heart disease who completed a 131 item semiquantitative food frequency questionnaire in 1986 that was updated every four years through 2010.
Exposure Consumption of gluten, estimated from food frequency questionnaires.
Main outcome measure Development of coronary heart disease (fatal or non-fatal myocardial infarction).
Results During 26 years of follow-up encompassing 2 273 931 person years, 2431 women and 4098 men developed coronary heart disease. Compared with participants in the lowest fifth of gluten intake, who had a coronary heart disease incidence rate of 352 per 100 000 person years, those in the highest fifth had a rate of 277 events per 100 000 person years, leading to an unadjusted rate difference of 75 (95% confidence interval 51 to 98) fewer cases of coronary heart disease per 100 000 person years. After adjustment for known risk factors, participants in the highest fifth of estimated gluten intake had a multivariable hazard ratio for coronary heart disease of 0.95 (95% confidence interval 0.88 to 1.02; P for trend=0.29). After additional adjustment for intake of whole grains (leaving the remaining variance of gluten corresponding to refined grains), the multivariate hazard ratio was 1.00 (0.92 to 1.09; P for trend=0.77). In contrast, after additional adjustment for intake of refined grains (leaving the variance of gluten intake correlating with whole grain intake), estimated gluten consumption was associated with a lower risk of coronary heart disease (multivariate hazard ratio 0.85, 0.77 to 0.93; P for trend=0.002).
Conclusion Long term dietary intake of gluten was not associated with risk of coronary heart disease. However, the avoidance of gluten may result in reduced consumption of beneficial whole grains, which may affect cardiovascular risk. The promotion of gluten-free diets among people without celiac disease should not be
Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention
- Andre Leite Gonçalves1,2, Adriana Martini Ferreira1, Reinaldo Teixeira Ribeiro2,3, Eliova Zukerman1, José Cipolla-Neto4, Mario Fernando Prieto Peres1
Received 2 March 2016 ,Revised 5 April 2016 ,Accepted 21 April 2016 ,Published Online First 10 May 2016
Abstract
Introduction Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.
Methods A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups.
Results Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users.
Conclusions Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Use of Plant-Based Therapies and Menopausal Symptoms - A Systematic Review and Meta-analysisOscar H. Franco, MD, PhD1; Rajiv Chowdhury, MD, PhD2; Jenna Troup, MSc1; et al Trudy Voortman, PhD1,3; Setor Kunutsor, MD, PhD2; Maryam Kavousi, MD, PhD1; Clare Oliver-Williams, PhD2; Taulant Muka, MD, PhD1,3
Article Information1Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
- 2Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- 3Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
JAMA. 2016;315(23):2554-2563. doi:10.1001/jama.2016.8012 editorial comment icon
Editorial
Comment
Abstract
Importance Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms.
Objective To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness.
Data Sources The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies.
Study Selection Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness.
Data Extraction Data were extracted by 2 independent reviewers using a predesigned data collection form.
Main Outcomes and Measures Hot flashes, night sweats, and vaginal dryness.
Results In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, −1.31 [95% CI, −2.02 to −0.61]) and vaginal dryness score (pooled mean difference of changes, −0.31 [95% CI, −0.52 to −0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, −2.14 [95% CI, −5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, −0.79 [−1.35 to −0.23]) and vaginal dryness score (pooled mean difference of changes, −0.26 [−0.48 to −0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality.
Conclusions and Relevance This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.
Nature Genetics | Letter
Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number
- Jonathan J Lyons,1,Xiaomin Yu,1,Jason D Hughes,2,Quang T Le,3,Ali Jamil,1, Yun Bai,1, Nancy Ho,4, Ming Zhao,5, Yihui Liu,1, Michael P O'Connell,1, Neil N Trivedi,6, 7, ,1,
- Thomas DiMaggio,1, Nina Jones,8, Helen Matthews,9, Katie L Lewis,10, Andrew J Oler,11, Ryan J Carlson,1, Peter D Arkwright,12, Celine Hong,10, Sherene Agama,1, Todd M Wilson,1, Sofie Tucker,1, Yu Zhang,13,Joshua J McElwee,2, Maryland Pao,14,
- Sarah C Glover,15,Marc E Rothenberg,16,Robert J Hohman,5,Kelly D Stone,1,
- George H Caughey,6, 7,Theo Heller,4,Dean D Metcalfe,1,Leslie G Biesecker,10,
- Lawrence B Schwartz3,& Joshua D Milner1,et al.
Nature Genetics:Year published:(2016) DOI:
doi:10.1038/ng.3696
Received 26 July 2016 Accepted 16 September 2016 Published online 17 October 2016
Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown1, 2. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.
Mortality In Patients With Myalgic Encephalomyelitis And Chronic Fatigue Syndrome.
Stephanie L. McManimen, Andrew R. Devendorf, Abigail A. Brown, Billie C. Moore, James H. Moore, & Leonard A. Jason
Center for Community Research, DePaul University
Abstract Background: There is a dearth of research examining mortality in individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Some studies suggest there is an elevated risk of suicide and earlier mortality compared to national norms. However, findings are inconsistent as other researchers have not found significant increases in all-cause mortality for patients.
Objective: This study sought to determine if patients with ME or CFS are reportedly dying earlier than the overall population from the same cause.
Methods: Family, friends, and caregivers of deceased individuals with ME or CFS were recruited through social media, patient newsletters, emails, and advocate websites. This study analyzed data including cause and age of death for 56 individuals that had ME or CFS.
Results: The findings suggest patients in this sample are at a significantly increased risk of earlier all-cause (M = 55.9 years) and cardiovascular-related (M = 58.8 years) mortality, and they had a directionally lower mean age of death for suicide (M = 41.3 years) and cancer (M =66.3 years) compared to the overall U.S. population [M = 73.5 (all-cause), 77.7 (cardiovascular), 47.4 (suicide), and 71.1 (cancer) years of age].
Conclusions: The results suggest there is an increase in risk for earlier mortality in patients with ME and CFS. Due to the small sample size, the findings should be replicated to determine if the directional differences for suicide and cancer mortality are significantly different from the overall U.S. population.
Source: http://bit.ly/2dYeqi1
Randomized, Double-blind, Placebo-controlled Phase III Trial of Duloxetine Monotherapy in Japanese Patients With Chronic Low Back Pain
Shinichi Konno, MD, PhD; Natsuko Oda, MS; Toshimitsu Ochiai, MS; Levent Alev, MD
Disclosures
Spine. 2016;41(22):1709-1717.
Abstract
Study Design. A 14-week, randomized, double-blind, multicenter, placebo-controlled study of Japanese patients with chronic low back pain (CLBP) who were randomized to either duloxetine 60 mg once daily or placebo.
Objective. This study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP.
Summary of Background Data. In Japan, duloxetine is approved for the treatment of depression, diabetic neuropathic pain, and pain associated with fibromyalgia; however, no clinical study of duloxetine has been conducted for CLBP.
Methods. The primary efficacy measure was the change in the Brief Pain Inventory (BPI) average pain score from baseline to Week 14. Secondary efficacy measures included BPI pain (worst pain, least pain, pain right now), Patient's Global Impression of Improvement, Clinical Global Impressions of Severity, and Roland-Morris Disability Questionnaire, among other measures, and safety and tolerability.
Results. In total, 458 patients were randomized to receive either duloxetine (n = 232) or placebo (n = 226). The BPI average pain score improved significantly in the duloxetine group compared with that in the placebo group at Week 14 [-2.43 ± 0.11 vs. −1.96 ± 0.11, respectively; between-group difference (95% confidence interval), − 0.46 [-0.77 to-0.16]; P = 0.0026]. The duloxetine group showed significant improvement in many secondary measures compared with the placebo group, including BPI pain (least pain, pain right now) (between-group difference: −1.69 ± 0.10, P = 0.0009; −2.42 ± 0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ± 0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ± 0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ± 0.22, P = 0.0439). Adverse events occurring at a significantly higher incidence in the duloxetine group were somnolence, constipation, nausea, dizziness, and dry mouth, most of which were mild or moderate in severity and were resolved or improved.
Conclusion. Duloxetine 60 mg was effective and well tolerated in Japanese CLBP patients.
Most patients who reach disease remission following anti-TNF therapy continue to report fatigue: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis
Katie L. Druce -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Yagnaseni Bhattacharya -
Gareth T. Jones -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Gary J. Macfarlane -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Neil Basu
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Rheumatology (Oxford) (2016) 55 (10): 1786-1790.
https://doi.org/10.1093/rheumatology/kew241
Published: 21 June 2016Navbar
- Abstract
Methods. Data from the British Society for Rheumatology Biologics Register for RA were used. In participants with severe baseline fatigue [36-item Short Form Health Survey (SF-36) vitality score ⩽12.5], we identified those in disease remission [28-joint DAS (DAS28) <2.6] by 6 months. Fatigue response was evaluated according to partial (SF-36 vitality score >12.5) and complete remission (SF-36 vitality score >50) at follow-up. Demographic (e.g. sex, age), clinical (e.g. inflammation, joint erosion and co-morbidities) and psychosocial (e.g. SF-36 domains and HAQ) characteristics were compared between responder and non-responder groups.
Results. Severe baseline fatigue was reported by 2652 participants, of whom 271 (10%) achieved a DAS28 <2.6 by 6 months. In total, 225 participants (83%) reported partial remission and were distinguished from those who did not by better health status on all psychosocial domains. Far fewer [n = 101 (37.3%)] reported full fatigue remission. In addition to reporting clinically poorer health status, they were distinguished on the basis of a history of hypertension, depression and stroke as well as baseline treatment use of steroids and antidepressants.
Conclusion. Despite achieving clinical remission, many RA patients do not achieve complete remission of their fatigue. Therefore, despite being important in overall disease control, reductions in disease activity are not always sufficient to ameliorate fatigue, so other symptom-specific management approaches must be considered for those for whom fatigue does not resolve.
fatigue, disease activity, remission
Clinical Science
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Øystein Fluge,1 Olav Mella,1,2 Ove Bruland,1,3 Kristin Risa,1 Sissel E. Dyrstad,4 Kine Alme,1 Ingrid G. Rekeland,1 Dipak Sapkota,1 Gro V. Røsland,4 Alexander Fosså,5 Irini Ktoridou-Valen,1 Sigrid Lunde,1 Kari Sørland,1 Katarina Lien,6 Ingrid Herder,6 Hanne Thürmer,7 Merete E. Gotaas,8 Katarzyna A. Baranowska,8 Louis M.L.J. Bohnen,9Christoph Schäfer,9 Adrian McCann,10 Kristian Sommerfelt,11 Lars Helgeland,12 Per M. Ueland,2,10 Olav Dahl,1,2 and Karl J. Tronstad4
First published December 22, 2016 -
Metabolism
Abstract
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.
ORIGINAL RESEARCH |Ann Intern Med. Published online March 7, 2017.
Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial
Megan E. Roerink, MD; Sebastian J.H. Bredie, MD, PhD; Michael Heijnen; Charles A. Dinarello, MD; Hans Knoop, PhD; Jos W.M. Van der Meer, MD, PhD
Abstract
Background:
Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS).
Objective:
To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS.
Design:
Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210) Setting:University hospital in the Netherlands.
Patients:
50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment.
Intervention:
Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50).
Measurements:
The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks. Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 nd 24 weeks.
Results:
At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).
Limitation:
Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms.
Conclusion:
Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.
Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of MorphineH.H. Doyle, L.N. Eidson, D.M. Sinkiewicz and A.Z. Murphy
Journal of Neuroscience 20 February 2017, 2906-16; DOI: https://doi.org/10.1523/JNEUROSCI.2906-16.2017
AbstractAlthough morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require 2-3 times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ opioid receptor (MOR), morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that while no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more “activated” phenotype in females at baseline, with the degree of activation a significant predictor of morphine ED50 values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males that was accompanied by increased transcription levels of IL-1ß and a significant rightward shift in the morphine dose response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone significantly potentiated morphine antinociception in females such that no sex differences in ED50 were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation, and contribute to the sexually dimorphic effects of morphine in the rat.
SIGNIFICANCE STATEMENT
We demonstrate that PAG microglia contribute to the sexually dimorphic effects of morphine. Specifically, we report that increased activation of microglia in the PAG contributes to the attenuated response to morphine observed in females. Our data further implicate the innate immune receptor TLR4 as an underlying mechanism mediating these effects, and establish that TLR4 inhibition in the PAG of females reverses the sex differences in morphine responsiveness. These data suggest novel methods to improve current opioid-based pain management via inhibition of glial TLR4, and illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women.
Footnotes
- The authors report no conflict of interest
- National Institutes of Health Grant DA16272 awarded to A.Z.M. supported this work. (-)-Morphine sulfate and (+)-naloxone were kindly provided by the National Institute on Drug Abuse drug supply program. The authors thank Lauren Hanus and Alyssa Bartlett for their technical assistance.
Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
- Wilfred C. de Vega,Santiago Herrera,Suzanne D. Vernon and Patrick O. McGowanBMC Medical GenomicsBMC series – open, inclusive and trusted201710:11
Received: 20 December 2016 Accepted: 18 February 2017 Pub: 23 February 2017
Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
Methods
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
Results
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
Conclusions
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population
Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine
Scott W. Powers, Ph.D., Christopher S. Coffey, Ph.D., Leigh A. Chamberlin, R.D., M.Ed., Dixie J. Ecklund, R.N., M.S.N., Elizabeth A. Klingner, M.S., Jon W. Yankey, M.S., Leslie L. Korbee, B.S., Linda L. Porter, Ph.D., and Andrew D. Hershey, M.D., Ph.D., for the CHAMP Investigators*
N Engl J Med 2017; 376:115-124 January 12, 2017DOI: 10.1056/NEJMoa1610384
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Background
Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established.
Methods
We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.
Results
A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.
Conclusions
There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281).
Vitamin D and Statin-Related Myalgia
Philip J. Gregory, PharmD
Disclosures | March 10, 2017
· Statin-Associated Side Effects
Do low vitamin D levels increase the risk for myalgia in patients who are taking statins?
Response from Philip J. Gregory, PharmD
Associate Professor, Pharmacy Practice, Center for Drug Information & Evidence-Based Practice, Creighton University, Omaha, Nebraska
About 1%-2% of patients who take hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins for hyperlipidemia develop muscle pain. This myalgia can feel like the aches and pains experienced with the flu. Muscles may feel sore or stiff and be sensitive to touch.[1] In some cases, statin-related myalgia can lead to poor adherence or discontinuation of the drug.[2]
The mechanism for statin-related myalgia is not fully understood, but vitamin D has been speculated to play a role.
Vitamin D deficiency itself is associated with symptoms of myalgia that resemble those caused by statins.[1,3] There has been speculation that statins themselves might affect vitamin D levels. Because low-density lipoprotein (LDL)-cholesterol is a vitamin D carrier and statins reduce LDL cholesterol, it has been proposed that statins could decrease vitamin D levels. On the other hand, both vitamin D and some statins are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Owing to competitive inhibition at CYP3A4, it has been proposed that statins could increase levels of vitamin D.
Clinical trials and observational studies have produced mixed resuotlts in terms of the actual effect of statins on vitamin D levels. Overall, a meta-analysis of clinical trials found increased vitamin D levels in statin users.[4]
Several retrospective studies have shown that low vitamin D levels (measured as 25-hydroxyvitamin D) are associated with a higher risk for statin-induced myalgia. In a study by Shantha and colleagues,[5]patients with vitamin D levels in the lowest quartile had a 1.21 times increased risk for statin-induced myalgia compared with those in the highest quartile. Levels of 15 ng/mL or lower positively predicted the development of myalgia in statin users.
In a cross-sectional study, statin-treated patients with vitamin D levels of less than 15 ng/mL had a 1.9 times increased odds of myalgia compared with non-statin users; however, statin users with higher vitamin D levels did not have an increased risk for myalgia compared with non-statin users.[6]
A retrospective chart review in veterans taking statins found that levels of vitamin D were approximately 10 ng/dL lower in those who experienced statin-induced myalgia compared with those who did not.[7]
A meta-analysis of seven observational studies found that vitamin D levels were significantly lower in statin-treated patients who had symptoms of myalgia compared with those who were asymptomatic. The mean difference in vitamin D levels between the groups was approximately 9.4 ng/mL.[2]
Not all studies have found an association between low vitamin D and myalgia, especially in studies evaluating patients with symptoms confirmed to be caused by statins.[8,9] The discrepancies in findings may be because of the nonspecific nature of muscle symptoms. Some evidence shows that up to 50% of self-reported symptoms of muscle pain in statin users may not be because of statins specifically. Therefore, low vitamin D levels may contribute to muscle pain symptoms more generally, including in patients with statin-induced myalgia or nonspecific myalgia.[9]
Assessing and treating low vitamin D levels may be worth considering before starting or restarting a statin in patients who develop muscle pain while taking a statin.
A retrospective chart review found that replenishing vitamin D before a statin rechallenge in previously intolerant patients increases statin tolerability and adherence.[10]
In uncontrolled studies, some authors have used vitamin D2 (ergocalciferol) supplements (from 50,000 units to 100,000 units per week) in statin-treated patients with muscle symptoms and low vitamin D levels and reported resolution of myalgia in about 90% of patients. In these studies, low vitamin D levels were considered to be less than 32 ng/mL.[11,12]
Open Access Copyright: © 2016
The PACE Trial Invalidates the Use of Cognitive Behavioral and Graded Exercise Therapy in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: A Review
Mark Vink* Family Physician, Soerabaja Research Center, Amsterdam, The Netherlands
Received date: 12 Jan 2016; Accepted date: 24 Mar 2016; Published date: 30 Mar 2016.
. J Neurol Neurobiol 2(3): doi http://dx.doi.org/10.16966/2379- 7150.124 Copyright: © 2016 Vink M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. * Corresponding author: Mark Vink, Family Physician, Soerabaja Research Center, Amsterdam, The Netherlands, E-mail: [email protected]
Introduction Following an extensive review of the literature, the American Institute of Medicine (IOM) concluded that “myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious, debilitating conditions that affect millions of people in the United States and around the world”; that it is a “medical - not a psychiatric or psychological - illness” without a “known cause or effective treatment” which “can cause significant impairment and disability” [1] rendering 25% of patients homebound or bedridden [2] yet “the term chronic fatigue syndrome can result in trivialization and stigmatization” of this “complex, multisystem, and often devastating disorder” [1] . Most doctors are unaware of the seriousness of ME or that it has been classified as a neurological disease by the World Health Organization (WHO) since 1969 [3]; therefore, patients often receive “hostility from their health care provider” and are “subjected to treatment strategies that exacerbate their symptoms” (i.e., CBT and GET) [1]. ISSN 2379-7150 Abstract The main findings reported in the PACE trial were that cognitive behavioral therapy (CBT) and graded exercise therapy (GET) were moderately effective treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and fear avoidance beliefs constituted the strongest mediator of both therapies. These findings have been challenged by patients and, more recently, a number of top scientists, after public health expert Tuller, highlighted methodological problems in the trial. As a doctor who has been bedridden with severe ME for a long period, I analyzed the PACE trial and its follow-up articles from the perspectives of a doctor and a patient. During the PACE trial the eligibility criteria, both subjective primary outcomes, and most of the recovery criteria were altered, creating an overlap of the eligibility and recovery criteria; consequently, 13% of patients were considered “recovered,” with respect to 1 or 2 primary outcomes, as soon as they entered the trial. In addition, 46% of patients reported an increase in ME/CFS symptoms, 31% reported musculoskeletal and 19% reported neurological adverse events. Therefore the proportion negatively affected by CBT and GET would be between 46% and 96%, most likely estimated at 74%, as shown in a large survey recently conducted by the ME Association. Medication with such high rates of adverse events would be withdrawn with immediate effect. There was no difference in long-term outcomes between adaptive pacing therapy, CBT, GET and specialist medical care, and none of them were effective, invalidating the biopsychosocial model and use of CBT and GET for ME/CFS. The discovery that an increase in exercise tolerance did not lead to an increase in fitness means that an underlying physical problem prevented this; validates that ME/CFS is a physical disease and that none of the treatments studied addressed this issue.
Dietary and nutrition interventions for the therapeutic
treatm ent of chronic fatigue syndrome/myalgic
encephalomyelitis: a systematic review
N. Campagnolo,1,2S. Johnston,1,2A. Collatz,1,2 D. Staines1.2 & S. Marshall-Gradisnik1,2
School of Medical Science, Griffith University, Gold Coast, QLD, Australia
National Centre for Neuroimmuno logy and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD,
Australia
J Hum Nutr Diet.
doi: 10.1111/jhn.12435
This is an open access article under the terms of
the Creative Commons Attribution-
NonCommercial-NoDerivs License, which permits
use and distribution in any medium, provided the
original work is properly cited, the use is non-
commercial and no modifications or adaptations
are made.
Abstract
Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/
ME) is characterised by unexplained fatigue for at least 6 months accompa-
nied by a diverse but consistent set of symptoms. Diet modification and
nutritional supplements could be used to improve patient outcomes, such
fatigue and quality of life. We reviewed and discussed the evidence for
nutritional interventions that may assist in alleviating symptoms of CFS/
ME.
Methods: Medline, Cinahl and Scopus were systematically searched from
1994 to May 2016. All studies on nutrition intervention were included
where CFS/ME patients modified their diet or supplemented their habitual
diet on patient-centred outcomes (fatigue, quality of life, physical activity
and/or psychological wellbeing).
Results: Seventeen studies were included that meet the inclusion criteria. Of
these, 14 different interventions were investigated on study outcomes. Many
studies did not show therapeutic benefit on CFS/ME. Improvements in fati-
gue were observed for nicotinamide adenine dinucleotide hydride (NADH),
probiotics, high cocoa polyphenol rich chocolate, and a combination of
NADH and coenzyme Q10.
Conclusions: This review identified insufficient evidence for the use of
nutritional supplements and elimination or modified diets to relieve CFS/
ME symptoms. Studies were limited by the number of studies investigating
the interventions, small sample sizes, study duration, variety of instruments
used, and studies not reporting dietary intake method. Further research is
warranted in homogeneous CFS/ME populations.
Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channelsAuthors· T. Nguyen,S. Johnston,L. Clarke,P. Smith,D. Staines,S. Marshall-Gradisnik
- First published: 23 November 2016Full publication history
- DOI: 10.1111/cei.12882View/save citation
- Cited by: 0 articles
Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome
- Dorottya Nagy-Szakal†,Brent L. Williams†,Nischay Mishra,Xiaoyu Che,Bohyun Lee,
- Lucinda Bateman,Nancy G. Klimas,Anthony L. Komaroff,Susan Levine,Jose G. Montoya,
- Daniel L. Peterson,Devi Ramanan,Komal Jain,Meredith L. Eddy,Mady Hornig and
- W. Ian LipkinEmail authorView ORCID ID profile
- Microbiome20175:44
© The Author(s). 2017
Received: 11 January 2017 Accepted: 4 April 2017 Published: 26 April 2017
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.
ResultsTopological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.
ConclusionsIndependent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.
KeywordsMyalgic encephalomyelitis Chronic fatigue syndrome Microbiota-gut-brain axis Metagenomic Topological data analysis Irritable bowel syndrome Metabolic pathway
Modern Clinical Medicine Research, Vol. 1, No. 1, April 2017
Access to Medical Care for Individuals with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome:
A Call for Centers of Excellence
Madison Sunnquist1 , Laura Nicholson1 , Leonard A. Jason1*, and Kenneth J. Friedman2 1 Center for Community Research, DePaul University, Chicago, Illinois, United States 2 Green Mountain College, Poultney, Vermont, United States Email: [email protected]
Abstract. The current study sought to better understand the experience of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) in accessing care for their debilitating illness. Of 898 participants, less than half had ever seen an ME or CFS specialist, though 99% of participants were interested in specialist care. Participants cited geographic and financial barriers as most frequently precluding access to specialists. Furthermore, satisfaction with specialist care greatly exceeded satisfaction with non-specialist care. These findings suggested that individuals with ME and CFS represent a medically-underserved population, due to lack of available care. The CFS Advisory Committee and NIH Pathways to Prevention Working Group recommended the creation of ME and CFS Centers of Excellence to improve the healthcare access of patients with ME and CFS. The current study documents the need for these centers, as they would ameliorate geographic and financial barriers to quality care. Keywords: Myalgic encephalomyelitis, chronic fatigue syndrome, healthcare access, specialist care,
Baby thought to have been shaken has rare syndrome, family court finds
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2136 (Published 02 May 2017)Cite this as: BMJ 2017;357:j2136
Clare Dyer
A baby who was thought to have been shaken by one of her parents actually has a rare syndrome that affects her blood vessels, Ehlers-Danlos syndrome type IV, a family court has heard.
Effie Stillwell was taken from her parents and placed with foster carers last September, after she collapsed, at nearly 3 months old, and was taken to hospital unresponsive and with difficulty breathing. Retinal haemorrhages and bleeding on the brain were identified, and police began a criminal investigation. But the medical evidence that emerged during the family court hearing persuaded Buckinghamshire County Council to drop its application for a care order.
Gluten-free diet is not recommended for people without celiac disease
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2135 (Published 03 May 2017)Cite this as: BMJ 2017;357:j2135
Zosia Kmietowicz
Gluten is not associated with a risk of coronary heart disease in people without celiac disease—and restricting gluten may result in a low intake of whole grains, which are associated with cardiovascular benefits, a study in The BMJ has found.1
The researchers said that promoting gluten-free diets among people without celiac disease should not be encouraged.
The number of people without celiac disease who avoid gluten has increased in recent years
Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort studyBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1892 (Published 02 May 2017)Cite this as: BMJ 2017;357:j1892
Benjamin Lebwohl, assistant professor1 2, Yin Cao, instructor3 4 5, Geng Zong, postdoctoral fellow5,
Frank B Hu, professor5 6, Peter H R Green, professor1, Alfred I Neugut, Eric B Rimm, Laura Sampson, Lauren W Dougherty, Edward GiovannucciWalter, C Willett, professor5 6 7, Qi Sun, Andrew T Chan,
Correspondence to: A T Chan [email protected]
Accepted 4 April 2017
AbstractObjective To examine the association of long term intake of gluten with the development of incident coronary heart disease.
Design Prospective cohort study.
Setting and participants 64 714 women in the Nurses’ Health Study and 45 303 men in the Health Professionals Follow-up Study without a history of coronary heart disease who completed a 131 item semiquantitative food frequency questionnaire in 1986 that was updated every four years through 2010.
Exposure Consumption of gluten, estimated from food frequency questionnaires.
Main outcome measure Development of coronary heart disease (fatal or non-fatal myocardial infarction).
Results During 26 years of follow-up encompassing 2 273 931 person years, 2431 women and 4098 men developed coronary heart disease. Compared with participants in the lowest fifth of gluten intake, who had a coronary heart disease incidence rate of 352 per 100 000 person years, those in the highest fifth had a rate of 277 events per 100 000 person years, leading to an unadjusted rate difference of 75 (95% confidence interval 51 to 98) fewer cases of coronary heart disease per 100 000 person years. After adjustment for known risk factors, participants in the highest fifth of estimated gluten intake had a multivariable hazard ratio for coronary heart disease of 0.95 (95% confidence interval 0.88 to 1.02; P for trend=0.29). After additional adjustment for intake of whole grains (leaving the remaining variance of gluten corresponding to refined grains), the multivariate hazard ratio was 1.00 (0.92 to 1.09; P for trend=0.77). In contrast, after additional adjustment for intake of refined grains (leaving the variance of gluten intake correlating with whole grain intake), estimated gluten consumption was associated with a lower risk of coronary heart disease (multivariate hazard ratio 0.85, 0.77 to 0.93; P for trend=0.002).
Conclusion Long term dietary intake of gluten was not associated with risk of coronary heart disease. However, the avoidance of gluten may result in reduced consumption of beneficial whole grains, which may affect cardiovascular risk. The promotion of gluten-free diets among people without celiac disease should not be
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