Tag: 2017

Daily Fluctuations of Progesterone and Testosterone are Associated with Fibromyalgia Pain Severity

Abstract:

The purpose of this longitudinal blood sampling study was to examine relationships between sex hormones and fibromyalgia pain. Eight women meeting case definition criteria for fibromyalgia provided venous blood samples and reported their fibromyalgia pain severity over 25 consecutive days. All women exhibited normal menstrual cycles and were not taking oral contraceptives. Cortisol, and the sex hormones estradiol, progesterone, and testosterone, were assayed from serum. A linear mixed model was used to determine if fluctuations of sex hormones were associated with changes in pain severity.

In the entire sample, day-to-day changes in both progesterone (p = 0.002) and testosterone (p = 0.015) were significantly and inversely correlated with pain severity. There was no relationship between estradiol and pain (p = 0.551) or cortisol and pain (p = 0.633). These results suggest that progesterone and testosterone play a protective role in fibromyalgia pain severity. Sex and other hormones may serve to both increase and decrease fibromyalgia pain severity.

Source: Meredith Schertzinger, Kate Wesson-Sides, BA, Luke Parkitny, PhD, Jarred Younger, PhD. Daily Fluctuations of Progesterone and Testosterone are Associated with Fibromyalgia Pain Severity. The Journal of Pain. DOI: http://dx.doi.org/10.1016/j.jpain.2017.11.013 (Full article)

Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study

Abstract:

Objectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS).

Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls.

Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP>400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning.

Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments.

Source: Cara Tomas, Andreas Finkelmeyer, Tim Hodgson, Laura MacLachlan, Guy A MacGowan, Andrew M Blamire, Julia L Newton. Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study. Open Heart 2017;4:e000697. doi:10.1136/ openhrt-2017-000697 http://openheart.bmj.com/content/openhrt/4/2/e000697.full.pdf (Full article)

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment

Abstract:

BACKGROUND: Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades.

METHODS: Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA.

RESULTS: In CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls.

CONCLUSIONS: In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra.

TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014.

Source: Roerink ME, Knoop H, Bronkhorst EM, Mouthaan HA, Hawinkels LJAC, Joosten LAB, van der Meer JWM. Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment. J Transl Med. 2017 Dec 29;15(1):267. doi: 10.1186/s12967-017-1371-9. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1371-9 (Full article)

Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patient

Abstract:

OBJECTIVE: Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome(CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients.

METHODS: In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF).

RESULTS: Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1-1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing.

CONCLUSIONS: In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS.

Copyright © 2017 Elsevier Inc. All rights reserved.

Source: Vangeel EB, Kempke S, Bakusic J, Godderis L, Luyten P, Van Heddegem L, Compernolle V, Persoons P, Lambrechts D, Izzi B, Freson K, Claes S. Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients. J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20. https://www.ncbi.nlm.nih.gov/pubmed/29275786

Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands

Abstract:

OBJECTIVE: We previously described symptom-based chronic fatigue syndrome (CFS/ME) phenotypes in clinical assessment data from 7041 UK and 1392 Dutch adult CFS/ME patients. Here we aim to replicate these phenotypes in a more recent UK patient cohort, and investigate whether phenotypes are associated with 1-year treatment outcome.

METHODS: 12 specialist CFS/ME services (11 UK, 1 NL) recorded the presence/absence of 5 symptoms (muscle pain, joint pain, headache, sore throat, and painful lymph nodes) which can occur in addition to the 3 symptoms (post-exertional malaise, cognitive dysfunction, and disturbed/unrefreshing sleep) that are present for almost all patients. Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes). Multinomial logistic regression models were fitted to quantify associations between phenotypes and overall change in health 1year after the start of treatment.

RESULTS: Baseline data were available for N=918 UK and N=1392 Dutch patients, of whom 416 (45.3%) and 912 (65.5%) had 1-year follow-up data, respectively. 3- and 4-class phenotypes identified in the previous UK patient cohort were replicated in the new UK cohort. UK patients who presented with ‘polysymptomatic’ and ‘pain-only’ phenotypes were 57% and 67% less likely (multinomial odds ratio (MOR) 0.43 (95% CI 0.19-0.94) and 0.33 (95% CI 0.13-0.84)) to report that their health was “very much better” or “much better” than patients who presented with an ‘oligosymptomatic’ phenotype. For Dutch patients, polysymptomatic and pain-only phenotypes were associated with 72% and 55% lower odds of improvement (MOR 0.28 (95% CI 0.11, 0.69) and 0.45 (95% CI 0.21, 0.99)) compared with oligosymptomatic patients.

CONCLUSIONS: Adult CFS/ME patients with multiple symptoms or pain symptoms who present for specialist treatment are much less likely to report favourable treatment outcomes than patients who present with few symptoms.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Source: Collin SM, Heron J, Nikolaus S, Knoop H, Crawley E. Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands. J Psychosom Res. 2018 Jan;104:29-34. doi: 10.1016/j.jpsychores.2017.11.007. Epub 2017 Nov 8. https://www.ncbi.nlm.nih.gov/pubmed/29275782

Discovery Forum 2017: An Interview with Dr. Maureen Hanson

Solve ME/CFS Initiative’s 2nd Annual Discovery Forum, held on October 14th in Washington DC, brought together leaders from across industry, academia, federal agencies, and biotech companies to tackle the most pressing issues confronting ME/CFS. In this interview, Dr. Zaher Nahle discusses ME/CFS science and policy with Dr. Maureen Hanson, founder and director of the Center for Enervating Neuroimmune Disease at Cornell University and member of the Solve ME/CFS Initiative’s Research Advisory Council.

Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an example of a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as with specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, the association between DNA methylation and genetic background in relation to the ME/CFS is currently unknown.

In this study we explored this association by characterizing the genomic (~4.3 million SNPs) and epigenomic (~480 thousand CpG loci) variability between populations of ME/CFS patients and healthy controls. We found significant associations of methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism.

Finally, we found significant correlations of genotypes with methylation phenotypes associated with ME/CFS. The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS.

Source: Santiago Herrera, Wilfred C. de Vega, David Ashbrook, Suzanne D. Vernon, Patrick O. McGowan. Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. bioRxiv preprint first posted online Dec. 22, 2017; doi: http://dx.doi.org/10.1101/237958. (Full article)

Hemispherx Successfully Completes Commercial Scale Demonstration Batch of Ampligen® at Contract Manufacturer

NEW BRUNSWICK, N.J., Dec. 20, 2017 (GLOBE NEWSWIRE) — Hemispherx Biopharma (NYSE American:HEB) said, its Contract Manufacturing Organization (CMO) for Ampligen® has  completed a commercial scale demonstration/engineering manufacturing run,  along with the re-qualifications of analytical methods that were agreed upon during a previous successful Pre-Approval Inspection (PAI) as necessary prior to the production of commercial lots of Ampligen®.

This accomplishment, in addition to completing all qualification operations to address new equipment and new container closure/vial components, allows the manufacture of current Good Manufacturing Practice (cGMP) clinical product in March 2018 following a scheduled shut down of the CMO for its bi-annual maintenance program.  Completion of the demonstration/engineering manufacturing run provides confidence that the clinical product will meet the stringent quality control release and stability testing prior to release and should be available to patients by the end of the second quarter 2018.  The manufacture of a second clinical lot of Ampligen® is being scheduled to assure maintenance of the clinical supply inventory.

  • Ampligen® has been approved in Argentina for severely debilitated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. Hemispherx recently reported that discussions are underway with the U.S. FDA on the next steps regarding a New Drug Application (NDA) for Ampligen® in ME/CFS, which afflicts more than one million people in this country, according to the Centers for Disease Control (CDC). Ampligen® is the only drug to have completed a Phase 3 clinical trial in the U.S. in ME/CFS.
  • Earlier this year Hemispherx began supplying Ampligen® for pancreatic cancer patients in an Early Access Program (EAP) in the Netherlands.  In addition, work is underway at two leading U.S. cancer centers to define Ampligen®’s potential role in enhancing the effectiveness of PD-1 and PD-L1 checkpoint inhibitors in the fast-growing field of immuno-oncology.

Continue reading “Hemispherx Successfully Completes Commercial Scale Demonstration Batch of Ampligen® at Contract Manufacturer” →

Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency

Abstract:

AIM: To assess the efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency.

MATERIAL AND METHODS: Fifty-three patients with cerebrovascular disease, who complain about persistent fatigue, were randomized into two groups. Patients of the main group (n=33) received standard therapy and noophen, patients of the control group (n=20) received only standard therapy. Treatment efficacy was assessed using MFI-20, HADS-A, LSEQ. In addition, cognitive functioning was evaluated using Schulte test.

RESULTS AND CONCLUSION: Treatment with noophen resulted in the marked decrease in the total intensity of fatigue measured with MFI-20. The decrease in fatigue intensity by 30-50% was observed in 3/4 of patients of the main group. Noophen reduced all components of fatigue syndrome, including a mental component, and improved motivation. The reduction of the mental fatigue component was combined with the improvement of cognitive functioning assessed with Schulte test. Therefore, the effect of noophen on motivation and mental fatigue component can promote cognitive training in patients with cerebrovascular insufficiency.

Source: Vorob’eva OV, Rusaya VV. Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. [Article in Russian; Abstract available in Russian from the publisher] Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(11):31-36. doi: 10.17116/jnevro201711711131-36. https://www.ncbi.nlm.nih.gov/pubmed/29265084

Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome

Excerpt:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by unexplained and persistent or recurrent incapacitating fatigue accompanied by a variety of symptoms and substantial reductions in previous levels of occupational, educational, social and/or personal activity [1, 2]. Given the absence of biomarkers for diagnosis, ME/CFS is defined by a combination of symptoms, most of which are non-specific and common to a number of diseases and conditions.

Over 20 case definitions have been proposed, leading to large variations in sensitivity and specificity of diagnosis. These diverse sets of diagnostic criteria and distinct ways in which they have been applied pose significant problems, as research results may vary considerably according to which definition is used. A particular problem occurs when overly inclusive criteria are used, since their lack of specificity may lead to considerable selection bias [3, 4]. Unfortunately, many studies, clinical trials in particular, have used broad case definitions such as the Oxford criteria [5], which requires little more than the presence of persistent significant fatigue for over 6 months and the exclusion of conditions that could explain symptoms, for a diagnosis to be made.

This problem has been highlighted by the Agency for Healthcare Research and Quality (AHRQ) review of evidence for the NIH Pathways to Prevention Workshop [4], which showed significant changes to the interpretation of evidence for treatment, when studies using broad case definitions, such as the Oxford criteria, are excluded from the analysis. The implications for clinical practice suggest that fit-for-all management approaches to ME/CFS, although more applicable to those who fit such broadly inclusive criteria, may be inadequate for patients who fulfil better targeted case definitions.

For patients selected using more restrictive definitions, cognitive behavioural therapy (CBT), graded exercise therapy (GET) and other forms of non-drug management approaches to ME/CFS, are most appropriate as adjunct therapies rather than restorative treatments, when provided by therapists with a good understanding of ME/CFS. These forms of behavioural intervention have been shown to support the well-being and rehabilitation of those suffering from many chronic and disabling conditions [6]. However, it is very important that the use of behaviourally based management strategies does not deter researchers, physicians, and other health professionals from the overarching goal of investigating the causes and pathophysiology of ME/CFS in various sub-groups and the development of specific treatments.

Source: Luis Nacul, PhD, Caroline C. Kingdon, MS, Erinna W Bowman, MSc, Hayley Curran, MS, and Eliana M Lacerda, PhD. Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome.Fatigue. Author manuscript; available in PMC 2017 Dec 14. Published in final edited form as: Fatigue. 2017; 5(1): 1–4. Published online 2017 Jan 8. doi: 10.1080/21641846.2017.1273863 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730342/ (Full article)