Investigations of B cell phenotype & metabolic function in patients with ME/CFS

Investigations of B cell phenotype and metabolic function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Fane Kojo Fosu Mensah. PhD thesis University College London, Division of Medicine, Sep 2019

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition characterized by multiple systemic symptoms including fatigue, postexertional malaise and cognitive impairment, lasting for at least 6 months.

Immune system dysfunction triggered by infection or other insult is generally assumed to be a major causal factor that contributes to changes in energy metabolism leading to the pathophysiology of ME/CFS.

B cells became of interest after reported clinical improvement following B cell depletion-therapy with rituximab (anti-CD20). A possible but undefined role for B cells was, therefore, proposed.

The initial aim of this thesis was to explore subtle alterations in B cell sBlausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. ubsets in ME/CFS patients which could be used as a diagnostic and prognostic marker for the disease. Further, the dynamic nature of B cells was utilised as a model to observe changes in energy demand and for performing comprehensive metabolomic profiling of activated and maturating B cells under culture conditions.

Results for HC and ME/CFS patients could, therefore, be compared under similar conditions of stress. Flow-cytometric analysis of CD19+B cells revealed increased frequencies and expression of the heat-stable antigen CD24 in ME/CFS patients, as well as an increased memory B cell subset (CD21+CD38-). Retention of CD24 was linked to unresponsiveness to proliferative and pro-apoptotic signals and phosphorylation of AMPK (pAMPK). PAMPK was found to be largely confined to IgD+IgM+ memory B cells.

Metabolic analysis of cell culture supernatant using 1H-NMR spectroscopy revealed significant correlations between CD24+B cell frequencies and the usage of glucose and the production of lactate.

Novel findings described in this thesis, therefore, established a link between CD24 positivity of B cells and energy metabolism. Immunophenotype and metabolite profiles of cultured B cells from HC and ME/CFS patients were also revealed to respond with different dynamics to interventions, thereby providing a potential platform for more focused research and diagnosis.

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Evidence of altered cardiac autonomic regulation in ME/CFS

Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis, by Maximillian J Nelson, Jasvir S Bahl, Jonathan D Buckley, Rebecca L Thomson, Kade Davison in Medicine October 2019 , Vol 98, Issue 43 [doi: 10.1097/MD.0000000000017600]

 

Review abstract:

Background:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.

Methods:

A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.

Results: 

Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD ± 95% CI = 4.14 ± 1.38, P < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = –13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = –0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (–0.34 ± 0.22, P = .002) were lower in ME/CFS patients.

Conclusions: 

The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.

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The DePaul Symptom Questionnaire-2: a validation study

The DePaul Symptom Questionnaire-2: a validation study, by Helen Bedree, Madison Sunnquist & Leonard A Jason in Journal Fatigue: Biomedicine, Health & Behavior Vol 7, 2019 – Issue 3, pp 166-179 [https://doi.org/10.1080/21641846.2019.1653471]

 

Research abstract:

Background:

The DePaul Symptom Questionnaire (DSQ) was developed to assess the symptomatology and case definition fulfillment of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). The questionnaire was recently revised to improve its psychometric properties, increase its diagnostic reliability, and assess symptoms required by case definitions. The resulting instrument was named the DSQ-2.

Purpose:

The current study sought to evaluate the utility and reliability of the new and revised items in the DSQ-2.

Method:

A cross-sectional sample of 399 adults with ME or CFS was recruited to complete the DSQ-2.

Results:

Descriptive analyses of the DSQ-2 suggest that the new and revised items enhance the instrument’s ability to assess certain symptom domains and evaluate recent case definitions. Additionally, an exploratory factor analysis resulted in an eight-factor solution: post-exertional malaise, cognitive impairment, fever and flu, pain, sleep disruption, orthostatic intolerance, genitourinary issues, and temperature intolerance. The items within each factor demonstrated strong internal consistency reliability (Cronbach’s alphas = .73 – .91).

Conclusion:

These analyses indicate that the DSQ-2 offers a more thorough and precise understanding ME and CFS symptomology and case definition fulfillment.

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Naltrexone restores impaired Transient Receptor Potential Melastatin 3 ion channel function in Natural Killer Cells from ME/CFS

Naltrexone restores impaired Transient Receptor Potential Melastatin 3 ion channel function in Natural Killer Cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients, by Helene Cabanas,  Katsuhiko Muraki,  Donald Staines and Sonya Marshall-Gradisnik in Front. Immunol., 31 October 2019 [https://doi.org/10.3389/fimmu.2019.02545]

 

Research abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation.

ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions.

Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role.

Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS.

Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin.

We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating.

The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

More information about the safety and use of naltrexone in medicine

Low-dose Naltrexone Explored as Option for Chronic Pain (in FM & ME/CFS)

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The effect of comorbid medical & psychiatric diagnoses on CFS

The effect of comorbid medical and psychiatric diagnoses on Chronic Fatigue Syndrome, by Benjamin H Natelson, Jin-Mann S Lin, Gudrun Lange, Sarah Khan, Aaron Stegner & Elizabeth R Unger in Annals of Medicine, published online: 23 Oct 2019 [https://doi.org/10.1080/07853890.2019.1683601]

 

Research abstract:

Objective:

To determine if presence of co-existing medically unexplained syndromes or psychiatric diagnoses affect symptom frequency, severity or activity impairment in Chronic Fatigue Syndrome.

Patients:

Sequential Chronic Fatigue Syndrome patients presenting in one clinical practice.

Design:

Participants underwent a psychiatric diagnostic interview and were evaluated for fibromyalgia, irritable bowel syndrome and/or multiple chemical sensitivity.

Results:

Current and lifetime psychiatric diagnosis was common (68%) increasing mental fatigue/health but not other illness variables and not with diagnosis of other medically unexplained syndromes. 81% of patients had at least one of these conditions with about a third having all three co-existing syndromes. Psychiatric diagnosis was not associated with their diagnosis. Increasing the number of these unexplained conditions was associated with increasing impairment in physical function, pain and rates of being unable to work.

Conclusions:

Patients with Chronic Fatigue Syndrome should be evaluated for current psychiatric conditions because of their impact on patient quality of life, but they do not act as a symptom multiplier for the illness. Other co-existing medically unexplained syndromes are more common than psychiatric co-morbidities in patients presenting for evaluation of medically unexplained fatigue and are also more associated with increased disability and the number and severity of symptoms.

Key Messages

  • When physicians see patients with medically unexplained fatigue, they often infer that this illness is due to an underlying psychiatric problem.
  • This paper shows that the presence of co-existing psychiatric diagnoses does not impact on any aspect of the phenomenology of medically unexplained fatigue also known as chronic fatigue syndrome. Therefore, psychiatric status is not an important causal contributor to CFS.
  • In contrast, the presence of other medically unexplained syndromes [irritable bowel syndrome; fibromyalgia and/or multiple chemical sensitivity] do impact on the illness such that the more of these that co-exist the more health-related burdens the patient has.

Read full paper

 

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Intra brainstem connectivity is impaired in CFS

Intra brainstem connectivity is impaired in chronic fatigue syndrome, by Leighton R Barnden, Zack Y Shan, Donald R Staines, Sonya Marshall-Gradisnik, Kevin Finegan, Timothy Ireland, Sandeep Bhuta, in NeuroImage: Clinical Vol 24, 2019, [https://doi.org/10.1016/j.nicl.2019.102045]

 

Research highlights:

  • RAS connectivity was detected in HC and CFS groups both during rest and task.
  • Strong connections were active for CFS from hippocampus to midbrain and medulla.
  • RAS connectivity was diminished in CFS in the brainstem and to the hippocampus.
  • RAS nuclei generate oscillatory signals which facilitate thalamocortical signal coherence.
  • Impaired RAS affects cortical coherence necessary for attention, memory and problem solving.

Research abstract:

Brain stem highlighted

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem.

Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC).

We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections.

When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. Strong hippocampal connections with midbrain and medulla nuclei were detected for ME/CFS. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task.

In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations.

Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

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How psychiatric referrals influence stigmatization in patients with ME & CFS

How psychiatric referrals influence stigmatization in patients with myalgic encephalomyelitis and chronic fatigue syndrome: an examination of American and British models, by Julia Terman, Joseph Cotler, Leonard A Jason in Community Psychology in Global Perspective Vol 5, #2, pp 19–29 , Oct 2019 [DOI: 10.1285/i24212113v5i2p19]

 

Research abstract:

Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are controversial chronic illnesses with a myriad of debilitating symptoms. This study aimed to explore physician referrals to psychiatrists or psychologists, perceived stigma, and estrangement for patients with ME and CFS.

Findings indicate that patients who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness.  These relationships are moderated by the country of residence, the United States and the United Kingdom. The implications of physician referrals for people with ME and CFS are discussed.

Discussion:

The present findings indicate that patients with ME and CFS who have been referred to psychiatrists are likely to perceive illness stigma and feel estranged from others due to their illness. As previous studies have shown a high propensity of patients with ME and CFS to be misdiagnosed with a psychiatric condition (Deale & Wessely, 2000), these referrals are likely a cause of anxiety and stigma for the patient receiving them. The relationship between psychiatric referral and estrangement was mediated by perceived stigma, yet the impact was stronger for the British sample than the American sample.

Despite the different mediation model outcomes due to the moderation effect of country, all three variables correlate with one another for individuals from both countries. These findings corroborate the qualitative accounts that have been reported in previous literature (Åsbring & Närvänen, 2002; Dickson et al., 2007; Jason, Taylor, Plioplys, Stepanek, & Shlaes, 2002), which suggest that physician attitudes related to stigma and estrangement of individuals with ME and CFS.

Findings indicated that patients are at risk for estrangement and high stigma. Stigma can impair help-seeking and predict mental health challenges (Clement et al., 2015; McManimen et al., 2018). Estrangement is also a risk factor for patients because socially isolated individuals may experience loneliness, and loneliness predicts subsequent depression (Cacioppo, Hawkley, & Thisted, 2010; Matthews et al., 2016). Thus, individuals with chronic illness who feel estranged may be at risk for depression (Cacioppo et al., 2010), as well as early mortality (Smith, Jackson, Kobayashi, & Steptoe, 2018).

The differences between the American and British models may, in part, be explained by different illness profiles and cultural differences. British individuals experience more severe symptomology than Americans across several indicators (Zdunek et al., 2015), which may impact their experiences with healthcare providers and peers. It is possible that a patient with more severe symptoms may be treated more negatively by physicians than someone with less severe symptoms, especially if the physician upholds a stigmatizing view of the illness.

Another possibility may be due to differences in diagnostic and treatment guidelines between the two countries. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) guidelines for ME and CFS stipulate the cognitive behavioural therapy (CBT) and graded exercise treatment (GET) should be part of the treatment program for patients with ME and CFS (https://www.nice.org.uk/guidance/cg53/chapter/1-Guidance#diagnosis)…

While this has positive outcomes for patients with depression, patients report that GET often exacerbate symptoms and leaves them feeling more fatigued and more ill than before (Wilshire et al., 2018; Maes & Twisk, 2010). CBT has had more mixed findings, but it has been demonstrated that CBT’s effectiveness is directly tied to patient comorbid diagnosis of depression (Sunnquist & Jason, 2018).

While these guidelines are in place for U.K. practitioners, the Institute of Medicine in the U.S. does not have specific guidelines for treating ME or CFS. Attitudes toward the illness and treatment likely differ in Britain compared to America due to these nuanced sets of differences, as has been demonstrated with attitudes toward the cause of ME and CFS (Zdunek et al., 2015). These outcomes highlight the importance of co-production in patient healthcare, as stigmatization in patient healthcare can be reduced through the involvement of patients in planning and implementing their treatment and outcome options (Turakhia & Combs, 2017).

Community psychologists can use these findings to identify patients who may be at risk for further social and family estrangement due to false positive referrals, and to help administer proper therapies aimed at reintegration into social settings that negate perceived stigma.

In summation, physician treatment, societal stigma, and the social estrangement of individuals with ME and CFS are interconnected in our two samples of patients. Findings indicate that referral to psychiatric treatment can be damaging when prescribed to someone as a means of dismissing physical complaints. Physicians can utilize a shared decision making treatment model to treat patients with ME and CFS (Bieber et al., 2008). This method involves mutual exchange of information between the doctor and patient, as the doctor holds medical knowledge and the patient holds knowledge about individual health experiences. This model has been effective for those with chronic invisible illnesses and may better allow physicians to aid patients who feel their symptoms are physical and not psychological (Bieber et al., 2008). By remaining sensitive, physicians, friends, and family can aim to improve the lives of those with ME and CFS.

 

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Shared microglial mechanisms underpinning depression & CFS & their comorbidities

Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities, by Adriano José Maia Chaves-Filho, Danielle S Macedo, David Freitas de Lucena, Michael Maes in Behavioural Brain Research Vol 372, 17 October 2019, 111975 [https://doi.org/10.1016/j.bbr.2019.111975]

 

Research abstract:

In 2011, it was reviewed that

a) there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS; and

b) the comorbidity between both disorders may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1.

Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity.

A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies, which are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors.

Recent evidence from preclinical studies indicates that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue.

In conclusion, based on our review we may posit that shared immune-inflammatory pathways and especially activated microglia underpin comorbid depression and CFS. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

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Neuroimmunology: what role for autoimmunity, neuroinflammation, & small fiber neuropathy in FM, CFS, & adverse events after HPV?

Neuroimmunology: what role for autoimmunity, neuroinflammation, and small fiber neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and adverse events after Human Papillomavirus Vaccination?, by Varvara A Ryabkova, Leonid P Churilov and Yehuda Shoenfeld in Int. J. Mol. Sci. 2019, 20(20), 5164; [https://doi.org/10.3390/ijms20205164]

 

Review abstract:

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate.

We highlight the role of three mechanisms—autoimmunity, neuroinflammation, and small fiber neuropathy—in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options.

Hypothalamus in brain

We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis.

Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.

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Open trial of Vitamin B12 nasal drops in adults with ME/CFS

Open trial of Vitamin B12 nasal drops in adults with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: comparison of responders and non-responders, by C (Linda) MC van Campen, Klaas Riepma and Frans C Visser in Frontiers in Pharmacology,  20 September 2019 [ https://doi.org/10.3389/fphar.2019.01102]

Research abstract:

Introduction:

A recent study reported a favorable effect of vitamin B12 injections/oral folic acid support in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Recently, vitamin B12 nasal drops were developed as an alternative to the vitamin B12 injections. As no data are available on efficacy of this formulation, we studied vitamin B12 serum levels, the physical activity scale of the RAND-36, the number of steps on an activity meter, and the fatigue and concentration scales of the CIS20r questionnaires, before and after 3 months of treatment in ME/CFS patients.

Methods and Results:

Fifty-one patients completed all measurements. Forty-four were female. Mean age was 42 years, and mean disease duration was 16 years. Median vitamin B12 levels before treatment were 328 (244–429) pmol/l, and 973 (476–1,476) pmol/l after treatment. Thirty-four patients reported a favorable response to treatment. In the non-responders, only a small but significant increase in vitamin B12 levels was observed. In contrast, in responders, the number of steps, the physical activity scale of the RAND-36, and the vitamin B12 serum levels increased significantly. The CIS20r fatigue scale decreased significantly, and the CIS20r concentration scale was unchanged.

Conclusions:

Nasal drop vitamin B12 administration resulted in a significant increase in vitamin B12 serum levels and therefore may be effective. This pilot study suggest that the nasal drops may be used as an alternative to injections because two thirds of ME/CFS patients reported a positive effect, accompanied by an increased number of steps, improvement of the RAND-36 physical functioning scale and the CIS20r fatigue scale, and a significant increase in serum vitamin B12 levels.

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