Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome.

Background: Fatigue of unknown origin is a hallmark symptom in chronic fatigue syndrome (CFS) and is also found in 20% of hypothyroidism patients despite appropriate levothyroxine treatment. Here, we suggest that in these disorders, peripheral serotonin levels are low, and elevating them to normal range with L-carnitine is accompanied with reduced fatigue. Methods: We conducted a retrospective analysis of follow-up clinical data (CFS N=12; hypothyroidism with fatigue N=40) where serum serotonin and fatigue levels were compared before vs. after 7 weeks of oral L-carnitine supplementation. Results: After L-carnitine, serotonin increased (8-fold in CFS, Sig. = 0.002, 6-fold in hypothyroidism, Sig. < 0.001) whereas fatigue decreased (2-fold in both CFS and hypothyroidism, Sig. = 0.002 for CFS, Sig. < 0.001 for hypothyroidism). There was a negative correlation between serotonin level and fatigue (for CFS, rho = -0.49 before and -0.67 after L-carnitine; for hypothyroidism, rho = -0.24 before and -0.83 after L-carnitine). Conclusions: These findings suggest a new link between low peripheral serotonin, L-carnitine, and fatigue.

Chinese herbal medicine for post-viral fatigue: A systematic review of randomized controlled trials.

BACKGROUND: Fatigue is a common symptom after viral infection. Chinese herbal medicine (CHM) is thought to be a potential effective intervention in relieving fatigue. PURPOSE: To assess the effectiveness and safety of CHM for the treatment of post-viral fatigue. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: The protocol of this systematic review was registered on PROSPERO (CRD42022380356). Trials reported changes of fatigue symptom, which compared CHM to no treatment, placebo or drugs, were included. Six electronic databases and three clinical trial registration platforms were searched from inception to November 2023. Literature screening, data extraction, and risk bias assessment were independently carried out by two reviewers. Quality of the included trials was evaluated using Cochrane risk of bias tool, and the certainty of the evidence was evaluated using GRADE. The meta-analysis was performed using Review Manager 5.4, mean difference (MD) and its 95% confidence interval (CI) was used for estimate effect of continuous data. Heterogeneity among trials was assessed through I2 value. RESULTS: Overall, nineteen studies with 1921 patients were included. Results of individual trial or meta-analysis showed that CHM was better than no treatment (MD = -0.80 scores, 95%CI -1.43 to -0.17 scores, P = 0.01, 60 participants, 1 trial), placebo (MD = -1.90 scores, 95%CI -2.38 to -1.42 scores, P<0.00001, 184 participants, 1 trial), placebo on basis of rehabilitation therapy (MD = -14.90 scores, 95%CI -24.53 to -5.27 scores, P = 0.02, 118 participants, 1 trial) or drugs (MD = -0.38 scores, 95%CI -0.48 to -0.27 scores, I2 = 0%, P<0.00001, 498 participants, 4 trials) on relieving fatigue symptoms assessing by Traditional Chinese Medicine fatigue scores. Trials compared CHM plus drugs to drugs alone also showed better effect of combination therapy (average MD = -0.56 scores). In addition, CHM may improve the percentage of CD4 T lymphocytes and reduce the level of serum IL-6 (MD = -14.64 scores, 95%CI 18.36 to -10.91 scores, I2 = 0%, P<0.00001, 146 participants, 2 trials). CONCLUSION: Current systematic review found that the participation of CHM can improve the symptoms of post-viral fatigue and some immune indicators. However, the safety of CHM remains unknown and large sample, high quality multicenter RCTs are still needed in the future.

Low-dose Naltrexone Improves post-COVID-19 condition Symptoms.

PURPOSE: Treatments for myalgic encephalomyelitis and chronic fatigue syndrome can be adapted for post-COVID-19 condition. Our aim was to compare treatments in patients from our post-COVID-19 clinic. METHODS: We conducted a retrospective cohort study and included consecutive patients enrolled in our post-COVID-19 clinic. We included patients who received low-dose naltrexone, amitriptyline, duloxetine, and physical therapy, and evaluated improvements in fatigue, pain, dyspnea, and brain fog recorded in the electronic health record. We calculated the adjusted relative hazard of improvement using Cox proportional models. We adjusted for demographic characteristics, comorbidities, and prior COVID-19 hospitalization. FINDINGS: We included the first 108 patients with post-COVID-19 enrolled in the clinic. Most of the patients received amitriptyline. The relative hazard of improvement for those taking low-dose naltrexone was 5.04 (95% CI, 1.22-20.77; P = 0.02) compared with physical therapy alone. Both fatigue and pain were improved in patients taking low-dose naltrexone; only fatigue was improved in patients taking amitriptyline. IMPLICATIONS: Post-COVID-19 condition symptoms may improve in patients taking medications adapted from myalgic encephalomyelitis and chronic fatigue syndrome. Randomized controlled trials should evaluate these medications and translational studies should further evaluate their mechanisms of action.

Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.

Yeast Beta-Glucan Supplementation with Multivitamins Attenuates Cognitive Impairments in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.

This research aimed to examine the potential alleviative effects of beta-glucan administration on fatigue, unrefreshing sleep, anxiety/depression symptoms and health-related quality of life in ME/CFS. A 36-week unicenter, randomized, double-blind, placebo-controlled trial was conducted in 65 ME/CFS patients, who were randomly allocated to one of two arms to receive four capsules each one of 250 mg beta-glucan, 3.75 µg vitamin D3, 1.05 mg vitamin B6, and 7.5 mg zinc (n = 35), or matching placebo including only microcrystalline cellulose as an excipient (n = 30) once daily. The findings showed that the beta-glucan supplementation significantly improved cognitive fatigue (assessed with FIS-40 scores) after the 36-week treatment compared to the baseline (p = 0.0338). Taken together, this study presents the novel finding that yeast-derived beta-glucan may alleviate cognitive fatigue symptoms in ME/CFS. Thus, it offers valuable scientific insights into the potential use of yeast beta-glucan as a nutritional supplement and/or functional food to prevent or reduce cognitive dysfunction in patients with ME/CFS. Further interventions are warranted to validate these findings and also to delve deeper into the possible immunometabolic pathomechanisms of beta-glucans in ME/CFS.

A prospective randomized, double-blind placebo-controlled study to evaluate the effectiveness of neuroprotective therapy using functional brain MRI in patients with post-covid chronic fatigue syndrome.

BACKGROUND AND PURPOSE: to assess executive network using resting-state fMRI and patterns of brain activation using task fMRI with a cognitive paradigm, against the background of taking the drug in comparison with placebo in patients with post-COVID asthenic syndrome. METHODS: The study employed a prospective, randomized, double-blind, placebo-controlled trial approach to assess the efficacy of utilizing functional MRI of the brain as a neuroprotective therapy for treating patients with chronic fatigue syndrome following COVID-19. The study included 30 patients matched by sex and age with post-COVID asthenic syndrome. All patients were examined with MFI-20, MoCA, FAS-10 scales, MRI using a Siemens MAGNETOM Prisma 3 T scanner before and after a course of therapy with coordination complex with succinate acid anion (CCSA) or placebo (15 patients each) using resting state fMRI and with cognitive paradigm. RESULTS: The changes obtained as a result of the treatment of post-Covid asthenic syndrome demonstrated clinical superiority in the reduction of asthenic symptoms for the group of patients treated with CCSA (MFI-20 scores: -20·0 points in the CCSA group compared to -12 points in the placebo group, p = 0·043). The data obtained also correlate with the analysis of task fMRI and resting state fMRI may indicate an increase in the functional cognitive status after a course of therapy with CCSA. Clinically, this correlates with a statistically significant improvement in the MoCA score (2 points in the CCSA group compared to 1 point in the placebo group, p < 0·05). CONCLUSIONS: the study demonstrates the potential effectiveness of CCSA therapy in relation to a wide range of symptoms (chronic fatigue syndrome/ asthenic syndrome and cognitive impairment) in patients with post-COVID syndrome. The first time demonstrated the effectiveness of neuroprotective therapy after post-COVID asthenic syndrome with the use of high-tech neuroimaging techniques.

Experimental drugs in randomized controlled trials for long-COVID: what's in the pipeline? A systematic and critical review.

INTRODUCTION: Over three years have passed since the emergence of coronavirus disease 2019 (COVID-19), and yet the treatment for long-COVID, a post-COVID-19 syndrome, remains long overdue. Currently, there is no standardized treatment available for long-COVID, primarily due to the lack of funding for post-acute infection syndromes (PAIS). Nevertheless, the past few years have seen a renewed interest in long-COVID research, with billions of dollars allocated for this purpose. As a result, multiple randomized controlled trials (RCTs) have been funded in the quest to find an effective treatment for long-COVID. AREAS COVERED: This systematic review identified and evaluated the potential of current drug treatments for long-COVID, examining both completed and ongoing RCTs. EXPERT OPINION: We identified four completed and 22 ongoing RCTs, investigating 22 unique drugs. However, most drugs were deemed to not have high potential for treating long-COVID, according to three pre-specified domains, a testament to the ordeal of treating long-COVID. Given that long-COVID is highly multifaceted with several proposed subtypes, treatments likely need to be tailored accordingly. Currently, rintatolimod appears to have modest to high potential for treating the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) subtype, LTY-100 and Treamid for pulmonary fibrosis subtype, and metformin for general long-COVID prevention.

Health-related quality of life, depressive symptoms, and chronic fatigue in long-term survivors of Hodgkin lymphoma.

High-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) is the preferred treatment option in relapsed or refractory Hodgkin lymphoma (HL). We analyzed the association between treatment intensity and health-related quality of life (HRQoL), depressive symptoms, and chronic fatigue (CF) in long-term survivors of HL (HLS), identified in two population-based national cross-sectional studies on late adverse effects. We included 375 HLS treated between 1987 and 2006, 264 with conventional therapy only, and 111 with HDT-ASCT. Despite similar differences to the matched general population, when controlling for other imbalances between the groups, use of HDT-ASCT was not associated with poorer outcome in multivariable analysis. However, work participation, family income, comorbidities, and lifestyle factors had stronger associations with aspects of HRQoL, depressive symptoms, and CF. Our data suggest that better rehabilitation to work participation and adequate income as well as follow-up for comorbidities may reduce differences in long-term outcome after treatment for HL.

Astragalus polysaccharide ameliorated complex factor-induced chronic fatigue syndrome by modulating the gut microbiota and metabolites in mice.

Chronic fatigue syndrome (CFS) is a debilitating disease with no symptomatic treatment. Astragalus polysaccharide (APS), a component derived from the traditional Chinese medicine A. membranaceus, has significant anti-fatigue activity. However, the mechanisms underlying the potential beneficial effects of APS on CFS remain poorly understood. A CFS model of 6-week-old C57BL/6 male mice was established using the multiple-factor method. These mice underwent examinations for behavior, oxidative stress and inflammatory indicators in brain and intestinal tissues, and ileum histomorphology. 16 S rDNA sequencing analysis indicated that APS regulated the abundance of gut microbiota and increased production of short chain fatty acids (SCFAs) and anti-inflammatory bacteria. In addition, APS reversed the abnormal expression of Nrf2, NF-κB, and their downstream factors in the brain-gut axis and alleviated the reduction in SCFAs in the cecal content caused by CFS. Further, APS modulated the changes in serum metabolic pathways induced by CFS. Finally, it was verified that butyrate exerted antioxidant and anti-inflammatory effects in neuronal cells. In conclusion, APS could increase the SCFAs content by regulating the gut microbiota, and SCFAs (especially butyrate) can further regulate the oxidative stress and inflammation in the brain, thus alleviating CFS. This study explored the efficacy and mechanism of APS for CFS from the perspective of gut-brain axis and provides a reference to further explore the efficacy of APS and the role of SCFAs in the central nervous system.

Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan.

OBJECTIVE: An increased prevalence of psychiatric comorbidities (including depression and anxiety disorder) has been observed among patients with chronic fatigue syndrome (CFS). However, few studies have examined the presence of depression and anxiety disorder before the diagnosis of CFS. This study aimed to clarify the preexisting comorbidities and treatments associated with patients with subsequent CFS diagnosis in a population-based cohort in Taiwan. METHODS: An analysis utilizing the National Health Insurance Research Database of Taiwan was conducted. Participants included were 6303 patients with CFS newly diagnosed between 2000 and 2010 and 6303 age-/sex-matched controls. RESULTS: Compared with the control group, the CFS group had a higher prevalence of depression and anxiety disorder before the diagnosis of CFS. Sampled patients who took specific types of antidepressants, namely, selective serotonin reuptake inhibitors (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] 1.04-1.39), serotonin antagonists and reuptake inhibitors (SARI; aOR = 1.87, 95% CI 1.59-2.19), and tricyclic antidepressants (aOR = 1.46, 95% CI 1.09-1.95), had an increased risk of CFS. CFS risk was also higher among participants taking benzodiazepine, muscle relaxants, and analgesic drugs. A sub-group analysis revealed that SARI use was related to an increased risk of CFS in the depression, anxiety disorder, male, and female groups. In the depression and anxiety disorder groups, analgesic drug use was associated with an increased CFS risk. Nonpharmacological treatment administration differed between men and women. CONCLUSION: This population-based retrospective cohort study revealed an increased risk of CFS among populations with preexisting depression and anxiety disorder, especially those taking SARI and analgesic drugs.

Possible Application of Melatonin in Long COVID.

Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, "long COVID". Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or "brain fog"), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration ("brain fog") and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.

[Effect of herbal cake-separated moxibustion on behavioral stress reactions and blood lactic acid level and muscular AMPK/PGC-1α signaling in rats with chronic fatigue syndrome].

OBJECTIVE: To observe the effect of herbal cake-separated moxibustion (HCSM) on serum lactic acid (BLA) level and AMPK/PGC-1α signaling pathway in the quadriceps femoris in chronic fatigue syndrome (CFS) rats, so as to explore its mechanisms underlying improvement of CFS. METHODS: According to the random number table, 50 SD rats were divided into blank control, model, HCSM, sham HCSM and medication (herbal medicine gavage) groups, with 10 rats in each group. The CFS model was established by using chronic restraint and exhaustive swimming, alternately, once daily for 21 days. The herbal cake was made of Xiaoyao Powder (Mental Ease Powder, composed of [Danggui (Radix Angelicae Sinensis), Baishao (Radix Paeoniae Alba), Chaihu (Radix Bupleuri), Fuling (Poria), Baizhu (Rhizoma Atractylodis, Macrocephalae), etc.]. The HCSM was applied to "Shenque" (CV8), "Guanyuan "(CV4), bilateral "Zusanli" (ST36) and "Qimen" (LR14), 5 moxa-cones for each acupoint, once daily for 10 days. For sham HCSM, the excipient was instead of herbal cake, and the same 5 moxa-cones was given as the HCSM group. Rats of the medication group received gavage of Xiaoyao Powder suspension (60 mg·kg-1), once daily for 10 days. The open field test and tail suspension test were conducted for determining the animals' locomotor activity. The blood sample was taken from the abdominal aorta under anesthesia for assaying the levels of serum BLA, chemokine ligand CXCL9 and ß-endorphin (EP) by ELISA. Bilateral quadriceps femoris were sampled for observing histopathological changes after staining with conventional H.E. technique, and for detecting the expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by using immunohistochemistry. RESULTS: Compared with the blank control group, the number of rearing and horizontal grid-crossing times, struggling times of tail suspension test were significantly decreased (P<0.05), and the immobility time was obviously prolonged (P<0.05) in the model group. Compared with the model group, both HCSM and medication groups had a significant increase of rearing, horizontal grid-crossing times and struggling times (P<0.05), and the immobility time had a significant decrease (P<0.05). But there were no significant differences in the total movement distance among the 5 groups (P>0.05), and in the 5 indexes of behavioral measurements between the HCSM and medication groups (P>0.05). The sham HCSM could also evidently increase the struggling times and reduce the immobility time (P<0.05). The contents of serum BLA, CXCL9 and ß-EP were obviously higher in the model group than in the blank control group (P<0.05), as well as remarkably lower in the HCSM and medication groups than in the model group (P<0.05). Whereas the expression levels of muscular p-AMPK and PGC-1α were considerably lower in the model group than in the blank control group (P<0.05), and significantly increased in both HCSM and medication groups relevant to the model group (P<0.05). Compared with the sham HCSM group, the contents of BLA, CXCL9 and ß-EP in serum of the HCSM group and contents of CXCL9, ß-EP in medication group were significantly decreased (P<0.05), and the protein expressions of p-AMPK and PGC-1α in quadriceps femoris in both HCSM and medication groups were significantly increased (P<0.05). H.E. staining showed smaller intercellular space, uneven cytoplasmic staining in some muscle fibers, nucleus pyknosis and condensation, and inflammatory cell infiltration in the model group, which was milder in both HCSM and medication groups. CONCLUSION: HCSM can mitigate the stress behavioral state in CFS rats, which may be related with its functions in lowering the levels of serum BLA, CXCL9 and ß-EP, and activating AMPK/PGC-1α signaling pathway (balancing energy metabolism) in the quadriceps femoris.

Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial.

BACKGROUND: There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue. METHODS: ME/CFS and Long-COVID patients were enrolled in an open label dose escalating "Proof of Concept" non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection. RESULTS: 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the "Chalder Fatigue Questionnaire" of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients' fatigue was significantly reduced by up to 46.8% in 6-weeks. CONCLUSIONS: Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. Trial Registration https://clinicaltrials.gov/ct2/show/NCT04592354 Registered October 19, 2020. 1,000 mg BID Normalized Fatigue Data for Baseline, 2-weeks and 6-weeks evaluated by 3 Validated Fatigue Scoring Questionnaires.

Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study.

BACKGROUND: This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database. METHODS: 6306 patients identified as having CFS during the 2000-2012 period and 6306 controls (with similar distributions of age and sex) were analyzed. RESULT: The patients with CFS were predominantly female and aged 35-64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn's disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group. CONCLUSION: This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.

Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, postexertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS. RESEARCH QUESTION: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS, and can its treatment improve exercise capacity? STUDY DESIGN AND METHODS: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60-mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 min later. The primary end point was the difference in peak exercise oxygen uptake (Vo2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange. RESULTS: Twenty-three subjects were assigned to receive pyridostigmine and 22 to receive placebo. The peak Vo2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs -40.2 ± 21.3 mL/min; P < .05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak vs rest Vo2 (25.9 ± 15.3 mL/min vs -60.8 ± 25.6 mL/min; P < .01), cardiac output (-0.2 ± 0.6 L/min vs -1.9 ± 0.6 L/min; P < .05), and right atrial pressure (1.0 ± 0.5 mm Hg vs -0.6 ± 0.5 mm Hg; P < .05) were greater in the pyridostigmine group compared with placebo. INTERPRETATION: Pyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03674541; URL: www. CLINICALTRIALS: gov.

Metabolomics study of the effect of Danggui Buxue Tang on rats with chronic fatigue syndrome.

Danggui Buxue Tang (DBT), a traditional Chinese medicine (TCM) formula for 'invigorating qi and enriching blood', has been reported to produce a good effect on chronic fatigue syndrome (CFS). However, the related mechanism remains largely undetermined. This study devised a metabolomics approach with GC-MS combined with pattern recognition to estimate the extent to which DBT alleviated CFS induced by food restriction and force swimming in rats. After 4 weeks of treatment, the endurance capability of rats was significantly better, and the motionless time was significantly shorter in the DBT group than in the CFS model group. Moreover, the activities of superoxide dismutase and glutathione peroxidase increased, whereas the levels of malondialdehyde, interleukin 6, and tumor necrosis factor alpha decreased in the DBT treatment group. Fifteen significantly changed metabolites were observed in the serum of rats with CFS, which was reversed markedly by DBT treatment. Metabolic pathway analysis showed that DBT could possibly alleviate CFS in rats by regulating the biosynthesis of phenylalanine, tyrosine, and tryptophan and the metabolism of glycine, serine, threonine, glycerolipid, glyoxylate, dicarboxylate, and tyrosine. It was observed that the metabolism of glycine, serine, and threonine was most closely related to the improvement in CFS by DBT treatment. This study showed that DBT could improve CFS effectively, and metabolomics was a powerful means to gain insights into the TCM formulas against CFS.

Does Coenzyme Q10 Plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a neuroinflammatory, multifaceted chronic disorder of unknown cause. Accumulating data indicate a link between a redox imbalance, mitochondrial dysfunction, and inflammation status in ME/CFS. Coenzyme Q10 (CoQ10) and selenium as effective antioxidant and anti-inflammatory agents have shown potential clinical implications in chronic diseases; however, their therapeutic benefits in ME/CFS remain elusive. This open-label exploratory study aimed to evaluate the effectiveness of combined CoQ10 plus selenium supplementation on clinical features and circulating biomarkers in ME/CFS. Twenty-seven ME/CFS patients received an oral combination of 400 mg of CoQ10 and 200 µg of selenium daily for 8 weeks. The primary endpoint was patient-reported changes in outcome measures from baseline to 8 weeks' postintervention. Secondary endpoint included changes in circulating biomarkers from baseline to each participant. After an 8-week intervention, a significant improvement was found for overall fatigue severity (p = 0.021) and global quality of life (p = 0.002), while there was no significant effect on the sleep disturbances (p = 0.480) among participants. After 8 week's intervention, there was significantly increased total antioxidant capacity, and there were reduced lipoperoxide levels from the participants (p < 0.0001 for both). Circulating cytokine levels decreased significantly (p < 0.01 for all), but with no significant changes in the C-reactive protein, FGF21, and NT-proBNP biomarkers after supplementation. Based on these findings, we hypothesized that long-term supplementation of combined CoQ10 and selenium may indicate a potentially beneficial synergistic effect in ME/CFS. Antioxid. Redox Signal. 36, 729-739.

Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of plasma from either ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence and presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data showed that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma. In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.