2019 – Page 14 – American ME and CFS Society

Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding. The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets. We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients. We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients. Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique. In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin. Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.

METHODS: Whole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.

RESULTS: We confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls. The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients. In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.

CONCLUSIONS: Impaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research. This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.

Source: Cabanas H, Muraki K, Balinas C, Eaton-Fitch N, Staines D, Marshall-Gradisnik S. Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients. Mol Med. 2019 Apr 23;25(1):14. doi: 10.1186/s10020-019-0083-4. https://www.ncbi.nlm.nih.gov/pubmed/31014226

Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study

Abstract:

OBJECTIVE: Acute Epstein-Barr virus (EBV) infection is a known trigger of both acute and chronic fatigue. The aim of this study was to investigate associations to fatigue in adolescents with EBV infection during the initial stage and six months after, as well as in healthy controls.

METHODS: 200 adolescents (12-20 years old) with EBV infection were assessed as soon as possible after the onset of symptoms (EBVbaseline) and six months later (EBVsix months, 5 drop-outs). Also, 70 healthy controls (HC) were included. Associations between current fatigue and 148 different variables (including symptoms, functional abilities and biomarkers) were investigated separately for EBVbaseline, EBVsix months and HC using linear regression modelling.

RESULTS: Fatigue was associated with symptoms of sleeping difficulties, negative emotions, and quality of life under all circumstances. Fatigue was independently associated with markers of immune response at EBVsix months and in HC, not at EBVbaseline. An association between fatigue and markers of autonomic cardiovascular control was only present at EBVsix months. Cognitive functioning shifted from a positive association to fatigue at EBVbaseline to a negative trend at EBVsix months. Markers of infection were not associated with fatigue at EBVbaseline, EBVsix months nor in HC.

CONCLUSION: Irrespective of the cause, fatigue is important for quality of life and is highly associated with negative emotions. Markers of infection and immune response had respectively none and barely any association to fatigue. Autonomic alterations and cognitive dysfunction were exclusively associated with fatigue long after infection, corroborating findings from studies of the Chronic Fatigue Syndrome.

Source: Pedersen M, Asprusten TT, Godang K, Leegaard TM, Osnes LT, Skovlund E, Tjade T, Øie MG, Wyller VBB. Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study. J Psychosom Res. 2019 Apr 10. pii: S0022-3999(18)30946-2. doi: 10.1016/j.jpsychores.2019.04.008. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31003854

Meeting the Educational Needs of Young, ME/CFS Patients: Role of the Treating Physician

Introduction:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling, chronic disease characterized by the body’s inability to produce sufficient energy for normal everyday activities. Children with ME/CFS experience debilitating fatigue referred to as post-exertional malaise (PEM) after minimal mental or physical exertion which is not relieved by sleep. It can significantly reduce the ability of the child to take part in personal, educational, or social activities and can compromise executive function, and can result in a moderate to severe disability. As many as 1% of school-age children suffer from this disease in varying degrees of severity, and ME/CFS has been shown to negatively impact school attendance, participation, connectedness, and academic performance (1). Some studies suggest that ME/CFS may be the major cause of extended school absences (2).

Whereas, the literature supplying practice-based guidance for other chronic conditions affecting children in school, such as Autism and Attention Deficit Hyperactivity Disorder (ADHD) will be found in educational journals, very little guidance for students with ME/CFS appears in the clinical medicine literature. Although school nurses are beginning to play a larger role in supporting these children, physicians or healthcare providers retain primary responsibility of informing the school system of the needed adjustments for the young ME/CFS patient to succeed in the school environment.

This article argues that the physician has a much broader responsibility to provide diagnostic, symptomatic, and treatment information about ME/CFS than they would with other conditions such as Autism or ADHD that qualify students for special services. For students with ME/CFS, the physician’s letter required in the school’s evaluation process is a critical resource to advise and guide education professionals regarding appropriate student placement, classroom support, and instructional accommodations or modifications. The specifics of what should be included in a model physician’s letter are included.

Source: Newton, Faith R. “Meeting the Educational Needs of Young, ME/CFS Patients: Role of the Treating Physician.” Frontiers in pediatrics vol. 7 104. 2 Apr. 2019, doi:10.3389/fped.2019.00104 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455006/ (Full article)

Medically Unexplained Symptoms (MUS): Faults and Implications

Abstract:

The classification of medically unexplained symptoms (MUS) could have negative consequences for patients with functional somatic syndromes (FSS). By grouping related but distinct syndromes into one label, the MUS classification fails to inform clinicians about their patients’ health condition. In research settings, the MUS classification makes patient samples more heterogeneous, obstructing research into the underlying pathology of FSS. Long-term studies have shown that MUS are often appraised as medically explained symptoms at follow-up and vice versa, raising doubts about the reliability of this distinction.

Source: Tack M. Medically Unexplained Symptoms (MUS): Faults and Implications. Int J Environ Res Public Health. 2019 Apr 8;16(7). pii: E1247. doi: 10.3390/ijerph16071247. https://www.mdpi.com/1660-4601/16/7/1247 (Full article)

Therapeutic Effect and Metabolic Mechanism of A Selenium-Polysaccharide from Ziyang Green Tea on Chronic Fatigue Syndrome

Abstract:

Ziyang green tea was considered a medicine food homology plant to improve chronic fatigue Ssyndrome (CFS) in China. The aim of this research was to study the therapeutic effect of selenium-polysaccharides (Se-TP) from Ziyang green tea on CFS and explore its metabolic mechanism.

A CFS-rats model was established in the present research and Se-TP was administrated to evaluate the therapeutic effect on CFS. Some serum metabolites including blood urea nitrogen (BUN), blood lactate acid (BLA), corticosterone (CORT), and aldosterone (ALD) were checked. Urine metabolites were analyzed via gas chromatography-mass spectrometry (GC-MS). Multivariate statistical analysis was also used to check the data. The results selected biomarkers that were entered into the MetPA database to analyze their corresponding metabolic pathways.

The results demonstrated that Se-TP markedly improved the level of BUN and CORT in CFS rats. A total of eight differential metabolites were detected in GC-MS analysis, which were benzoic acid, itaconic acid, glutaric acid, 4-acetamidobutyric acid, creatine, 2-hydroxy-3-isopropylbutanedioic acid, l-dopa, and 21-hydroxypregnenolone. These differential metabolites were entered into the MetPA database to search for the corresponding metabolic pathways and three related metabolic pathways were screened out. The first pathway was steroid hormone biosynthesis. The second was tyrosine metabolism, and the third was arginine-proline metabolism. The 21-hydroxypregnenolone level of rats in the CFS group markedly increased after the Se-TP administration.

In conclusion, Se-TP treatments on CFS rats improved their condition. Its metabolic mechanism was closely related to that which regulates the steroid hormone biosynthesis.

Source: Shao C, Song J, Zhao S, Jiang H, Wang B, Chi A. Therapeutic Effect and Metabolic Mechanism of A Selenium-Polysaccharide from Ziyang Green Tea on Chronic Fatigue Syndrome. Polymers (Basel). 2018 Nov 15;10(11). pii: E1269. doi: 10.3390/polym10111269. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401680/ (Full article)

EBV-requisitioning physicians’ guess on fatigue state 6 months after acute EBV infection

Abstract:

We assessed referring medical practitioner’s ability to predict chronic fatigue development in adolescents presenting with acute infectious mononucleosis. Compared with ‘not fatigued’ being predicted as ‘unsurely fatigued’ and ‘likely fatigued’ were both strongly associated with developing fatigue 6 months later (OR 2.5, 95% CI 1.16% to 5.47% and 3.2, 95% CI 1.19% to 8.61%, respectively, P=0.012). The positive and negative predictive values were 66% and 62%, respectively. Disentangling the physician’s intuition may be of interest in further investigations of risk factors and prophylactic factors for fatigue development.

Source: Asprusten TT, Pedersen M, Skovlund E, Wyller VB. EBV-requisitioning physicians’ guess on fatigue state 6 months after acute EBV infection. BMJ Paediatr Open. 2019 Mar 1;3(1):e000390. doi: 10.1136/bmjpo-2018-000390. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422241/ (Full article)

Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity.

We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L).

The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02–0.15) compared to controls, and OR = 0.16 (95% CI = 0.07–0.40), compared to mild cases). This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.

Source: Nacul, L.; de Barros, B.; Kingdon, C.C.; Cliff, J.M.; Clark, T.G.; Mudie, K.; Dockrell, H.M.; Lacerda, E.M. Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study. Diagnostics 2019, 9, 41. https://www.mdpi.com/2075-4418/9/2/41 (Full article available as PDF file)

Varied Presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Needs for Classification and Clinician Education: A Case Series

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, heterogeneous and serious disease. In this article, we analyze the cases of 3 patients with ME/CFS. Due to the disbeliefs, misconceptions, and stigmas that are attached to ME/CFS, patient diagnosis is made after years of disease progression. Over this period, physicians tried to determine the etiology of the disease, taking into account its onset and symptoms. The suspected conditions correlated with possible subgroups that researchers speculate may exist in ME/CFS. Therefore, a registry of well-selected data on clinical history could help to cluster patients into more homogenous groups, and could be beneficial for research.

Source: Martín-Martínez E, Martín-Martínez M. Varied Presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Needs for Classification and Clinician Education: A Case Series. Clin Ther. 2019 Apr 1. pii: S0149-2918(19)30114-6. doi: 10.1016/j.clinthera.2019.02.014. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30948154

Clinical research of auricular gold-needle therapy in treatment of chronic fatigue syndrome of qi deficiency constitution

Abstract:

OBJECTIVE: To observe the clinical therapeutic effects of auricular gold-needle therapy on chronic fatigue syndrome of qi deficiency constitution and explore its potential mechanism.

METHODS: A total of 120 patients were randomized into an auricular gold-needle therapy group, an auricular point pressure therapy group and a Chinese herb group, 40 cases in each one. Additionally, a health control group (40 cases) was set up, without any intervention. In the auricular gold-needle therapy group, the gold needle was used to stimulate the auricular points on one side and the cowherb seed pressure therapy on the other side. In the auricular point pressure therapy group, the cowherb seed pressure therapy was adopted only on one side. The auricular points were shen (CO10), xin (CO15), fei (CO14), pizhixia (AT4), etc. in the two groups. The auricular points on both sides were used alternatively. The treatment was given once a week, 4 treatments as one course and the consecutive 3 courses of treatment were required. In the Chinese herb group, buzhong yiqi wan was prescribed for oral administration, 6 g, twice a day, the medication for 1 month was as one session and the consecutive 3 sessions of medication were required. Before and after treatment, separately, the clinical symptom score, the levels of the serum immunoglobulins, i.e. IgA, IgG and IgM were observed in the patients of the three groups. The therapeutic effects were evaluated in the three groups.

RESULTS: The total effective rate was 90.0% (36/40) in the auricular gold-needle therapy group, better than 80.0% (32/40) in the auricular point pressure therapy group and 82.5% (33/40) in the Chinese herb group (both P<0.05). Before treatment, the clinical symptom scores of the patients in the three groups were obviously higher than the health control group (all P<0.001). After treatment, the symptom scores were all reduced as compared the scores before treatment in the three groups (all P<0.001) and the symptom scores in the auricular gold-needle therapy group were better than the auricular point pressure therapy group and the Chinese herb group (both P<0.01). Before treatment, the levels of serum IgA, IgG and IgM of the patients in the three groups were lower than the health control group (all P<0.001). The levels were all improved after treatment in the three groups (all P<0.01), and the levels in the auricular gold-needle therapy group was better than the auricular point pressure therapy group and the Chinese herb group (all P<0.05).

CONCLUSION: The auricular gold-needle therapy achieves the significant therapeutic effects on chronic fatigue syndrome of qi deficiency constitution and its mechanism is probably related to the regulation of immune function.

Source: Xu YY, Liu JH, Ding H, Tang H, Song SY, Zhong WQ, Pan ZB. Clinical research of auricular gold-needle therapy in treatment of chronic fatigue syndrome of qi deficiency constitution. Zhongguo Zhen Jiu. 2019 Feb 12;39(2):128-32. doi: 10.13703/j.0255-2930.2019.02.004.[Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/30942029

Acupuncture in the treatment of chronic fatigue syndrome based on “interaction of brain and kidney” in TCM: a randomized controlled trial

Abstract:

OBJECTIVE: To observe the effects of acupuncture on the fatigue symptoms of chronic fatigue syndrome, the potential symptoms and cytokines on the base of the theory as “interaction of brain and kidney” and explore its clinical therapeutic effects and the potential mechanism.

METHODS: A total of 68 patients were randomized into an observation group and a control group, 34 cases in each one. In the control group, oryzanol and vitamin B1 were prescribed for oral administration and the patients were required to have a proper rest and physical exercise. In the observation group, on the base of the theory as “interaction of brain and kidney”, acupuncture was added to Baihui (BL 20), Fengchi (GB 20), Pishu (BL 20), Shenshu (BL 23), Sanyinjiao (SP 6) and Taixi (KI 3). The treatment was given once a day, 5 treatments a week, with 2 days break. The consecutive treatment for 4 weeks was required. Before and after treatment, the score of the fatigue scale-14 (FS-14), the score of the somatic and psychological health report (SPHERE) and the score of the Pittsburgh sleep quality index (PSQI) were observed in the patients of the two groups separately. The enzyme-linked immunosorbent assay (ELISA) was adopted to determine the levels of serum interleukin-6 (IL-6) and interferon-γ (INF-γ) before and after treatment.

RESULTS: After treatment, FS-14 scores, SPHERE scores and PSQI scores were all reduced as compared with the scores before treatment in the two groups (P<0.05, P<0.01). After treatment, the levels of IL-6 and INF-γ in the serum in the observation group were reduced as compared with the levels before treatment (both P<0.01). After treatment, the scores of FS-14, SPHERE and PSQI as well as the levels of serum IL-6 and INF-γ in the observation group were all lower than the results in the control group (P<0.05, P<0.01).

CONCLUSION: On the base of the theory as “interaction of brain and kidney”, acupuncture therapy relieves the fatigue symptoms and the potential symptoms and improves the sleep quality in the patients of chronic fatigue syndrome. The effect mechanism is probably related to the decrease of the levels of IL-6 and INF-γ in serum.

Source: Xu YX, Luo HS, Sun D, Wang R, Cai J. Acupuncture in the treatment of chronic fatigue syndrome based on “interaction of brain and kidney” in TCM: a randomized controlled trial. Zhongguo Zhen Jiu. 2019 Feb 12;39(2):123-7. doi: 10.13703/j.0255-2930.2019.02.003. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/30942028