Are ME/CFS and FM immune exhaustion disorders?

Posted on 04/07/2016 by wames

Are Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Immune Exhaustion Disorders?, by Cort Johnson 21 March 2016

When we think of immune problems we often think of the immune system going berserk and attacking healthy cells but another kind of immune issue called can be present. Recent studies suggest immune exhaustion may be more of a problem for many chronic fatigue syndrome (ME/CFS) and/or fibromyalgia patients than an immune system run amok.

“I think what we’re seeing is an immune system exhaustion over time” Dr. Mady Hornig

Chronic fatigue syndrome (ME/CFS) has generally been thought of as an immune activation disorder. Although much of the interest in the Lipkin/Hornig 2015 study focused on the immune activation found early in the disease, the study found 13 downregulated immune factors in the plasma of longer duration patients relative to the healthy controls.  Remarkably the same cytokines that were upregulated early in the disease were downregulated later in the disease.

Are ME/CFS and fibromyalgia immune exhaustion disorders?

That pattern smacked of something called “immune exhaustion”. Immune exhaustion is a well-known pattern of immune depletion seen in people with chronic infections or autoinflammatory diseases.  Immune exhaustion may be the main reason why some people just can’t knock an infection.

The patterns seen in the big 2015 Lipkin/Hornig Chronic Fatigue Initiative immune blood study were intriguing but not conclusive. Studies published since then, though, suggest that immune exhaustion – not immune activation – could be the main culprit in people with longer duration chronic fatigue syndrome (ME/CFS) and fibromyalgia.

It should be noted, again, how important it was to differentiate shorter from longer duration patients. No immune abnormalities when the two subsets were mixed; only when they were differentiated by disease duration did the immune issues pop up.

The Simmaron Research/Lipkin/Hornig Spinal Fluid Study
Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome by Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI.Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31.PMID: 25824300

Next came the Lipkin/Hornig/Simmaron Research Foundation study examining immune factors in the spinal fluid of ME/CFS and multiple sclerosis patients and healthy controls. Not only was a broad pattern of immune inhibition found in the longer duration patients but for the first time match between blood and spinal fluid study was found: the same issues appeared to be occurring in both the central nervous system and the body.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

The number of downregulated immune factors – twenty-one in all (vs 13 in the blood study) in the spinal fluid of longer duration ME/CFS patients relative to healthy controls was notable and suggested that the closer one moves to the brain the more evidence of immune exhaustion one may find.

Both ME/CFS and MS patients exhibited immune exhaustion compared to healthy controls but the degree of immune exhaustion seen in ME/CFS was greater than that seen in MS. Demonstrating how complex the immune system is, the two diseases differed more from each other than from the healthy controls

An upregulated chemokine suggests that a viral infection could have triggered central nervous system changes in ME/CFS and MS

In one perhaps important way, though, they were quite alike. A chemokine called CXCL10 that clears the way for the entry of natural killer cells and T lymphocytes into the brain in response to a viral infection was increased in both disorders.  Increased levels of that chemokine in conjunction with the different kinds of immune exhaustion found in both disorders suggests that either different viruses could be present or a different response to the same virus has occurred.

The fact that infectious mononucleosis or glandular fever increases the risk of coming down with either ME/CFS or multiple sclerosis is intriguing in this regard. Could ME/CFS and MS simply reflect differing responses to the same virus?

Jarred Younger recently suggested that MS may be a more damaging form of ME/CFS. Neuroinflammation is present in both, but in one (MS) the neurons are damaged and in the other (ME/CFS) they are not.

Very high levels of CXCL10, such as appear to be present in MS, are associated with nerve damage. More moderately raised levels, such as seen in ME/CFS, are not. CXCL10 levels may also be able to tell us which patients respond better to antivirals. Hepatitis C and HIV patients with higher CXCL10 levels responded less well to antivirals than patients with lower levels.

The Lipkin spinal fluid study is looking more and more like it could end up being a seminal study.  It highlighted a new subset – “the Peterson subset” and validated and expanded on the dramatic immune downregulation seen in the earlier blood study.

A follow-up Simmaron Research/Lipkin/Hornig spinal fluid study is in the works.

The spinal fluid study wasn’t the end of the trend towards immune downregulation, though; right on its heels came the large Landi-Houghton blood study.

The Simmaron Research Foundation Australian Spinal Fluid Study

Mediators Inflamm. 2015;2015:929720. doi: 10.1155/2015/929720. Epub 2015 Mar 5.Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Peterson D1, Brenu EW2, Gottschalk G1, Ramos S2, Nguyen T2, Staines D2, Marshall-Gradisnik S2.

The Simmaron Research Foundation also participated with Sonya Marshall-Gradisnik at Griffith University in a small pre-pilot spinal fluid study. In this smaller study only one immune factor, IL-10, significantly differed between the ME/CFS patients and the healthy controls but the trend was the same; IL-10 was significantly reduced in the ME/CFS patients.

This study may tell us how immune depletion in one area can lead to immune activation in another. Because IL-10 is an anti-inflammatory, reduced IL-10 levels in the cerebral spinal fluid could reflect a brain with inflammation.

The Houghton-Landi Blood Study

Cytokine. 2016 Feb;78:27-36. doi: 10.1016/j.cyto.2015.11.018. Epub 2015 Nov 28. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Landi A1, Broadhurst D2, Vernon SD3, Tyrrell DL4, Houghton M5.

Michael Houghton isn’t just any researcher. A Lasker award winner, he got bit by the ME/CFS bug during the XMRV saga. (He got bit so hard that the Solve ME/CFS Initiative even got him onto the federal advisory panel for ME/CFS ( CFSAC) for a while.)  Researchers of his ilk are a real asset to our community and it’s good to see him remaining engaged. In this study he worked with Bateman-Horne Center’s “Research Czarista” Suzanne Vernon.

The Landi-Houghton study examined 34 immune and growth factors in no less than 100 longer duration ME/CFS patients.  This study also found little evidence of overt immune activation. Instead,  a cluster of down-regulated immune factors ( IL-16, IL-7 and VEGF-A) popped up which suggested ME/CFS –  at least in its later stages – was more characterized by immune depletion. They also suggested that ME/CFS patients might be a aging a bit more rapidly than normal.

Early Aging?

Immune depletion showed up in longer duration patients in the Houghton study

IL-7 plays a critical role in NK and T-cell proliferation and induction and IL-7 levels are associated with cognitive declines during aging. The authors suggested that the immune signature they found could mimic aging. It’s not the first result to suggest early aging may be present in either ME/CFS or FM.

One FM study found cognitive declines suggestive of people who were twenty years older.  Reduced telomere lengths (a sign of aging) were found in the white blood cells for FM patients and the CDC has reported finding reduced telomere length in chronic fatigue syndrome as well.

Two Factors Stand Out

VEGF-A – VEGF-A promotes the survival and stability of endothelial cells lining the blood vessels, stimulates muscle and blood vessels and has neuroprotective factors.  It also promotes neuron growth by stimulating epithelial cells to release BDNF – which appears to be low in ME/CFS.

VEGF-A is becoming a factor to look out for in ME/CFS. For one thing it affects the blood vessels. For another reduced VEGF-A levels also popped up in the Simmaron Foundation/Lipkin/Hornig spinal fluid study and in a Gulf War Syndrome study .

Eotaxin – Eotaxin has suddenly appeared on the ME/CFS scene. It was one of only two factors upregulated in the spinal fluid study. Remarkably, high eotaxin levels have been found in long duration patients in three recent studies.

Increased levels of eotaxin have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age.

These consistently increased eotaxin levels could signify either an allergic response a central nervous system infection.

FIBROMYALGIA

The results of immune studies in FM are mixed but three recent studies suggest a scenario of immune depletion may be occurring in FM as well.

A 2012 study found that immune cells from FM patients that were stimulated with an antigen failed to respond as readily as did those of healthy controls.  The dramatic reductions – from 1.5 fold to 10-fold of normal – were found across a wide range of immune factors (IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β, MCP-1 and MIP1-α).

Another fibromyalgia study found a “stark decrease: in the levels of three Th2 cytokines (IL-4, IL-5, and IL-13). Because the cytokines with lowered levels had anti-inflammatory effects the authors speculated that inflammation might be increased in FM. Note that reductions of these anti-inflammatory cytokines (and IL-10 in ME/CFS) might be all that is needed for normal levels of pro-inflammatory cytokines to produce inflammatory effects.

Similar trends toward reduced levels of anti-inflammatory cytokines has also been found in  depression.

Exercise Study Reveals Immune Depletion

J Neuroimmunol. 2014 Dec 15;277(1-2):160-7. doi: 10.1016/j.jneuroim.2014.10.003. Epub 2014 Oct 18.Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia. Torgrimson-Ojerio B1, Ross RL2, Dieckmann NF3, Avery S4, Bennett RM5, Jones KD6, Guarino AJ7, Wood LJ8.

Another fibromyalgia study found a marked difference between the immune and hormonal responses of healthy controls during exercise and FM patients. Four anti-inflammatory factors (IL-6, IL-10, ACTH, and cortisol) increased and two pro-inflammatory factors (TNF-a, IL-8) decreased during exercise in the healthy controls.

The anti-inflammatory response, however, was blunted in FM patients (ACTH, cortisol, and IL-10)  during exercise.

Exercise was associated with immune depletion in one fibromyalgia study.

This study also found normal IL- 6 levels which was a surprise given the reductions in IL-10 (another anti-inflammatory cytokine) found.  (IL-6 production by the muscle cells during exercise is believed to trigger IL-10 production.)

That odd finding suggested another way to inhibit anti-inflammatory activity. The authors speculated that FM patients’ muscles may be pumping out normal levels of IL-6, but the signal IL-6 produces to create anti-inflammatory products is simply not getting through.

They suggested that a reduced anti-inflammatory response during exercise could very well play a role in the pain FM patients associate with exercise. Anti-inflammatory cytokines stop the pain receptors on nerves from being activated. Take away those cytokines and FM patients could experience increased pain during exercise.

The authors proposed that a quick immune hit during exercise could be responsible for lasting pain, stiffness and fatigue FM patients experience after exercise.
See Is the Immune System Causing the Post-exertional Malaise in Fibromyalgia?

Conclusion

While some studies differ, recent studies suggest a broad pattern of immune exhaustion may be taking place in both chronic fatigue syndrome and fibromyalgia. That exhaustion is most likely caused by what Lipkin and Hornig called an “exuberant stimulation” of the immune system due to an auto-inflammatory process or a chronic infection.

It’s possible that exhaustion in one part of our carefully balanced immune systems could lead to undue prominence of another part.  Lipkin and Hornig suggested the immune reductions in the spinal fluid found suggested that immune activation might be occurring in the central nervous system. Likewise the FM study suggested the depletion of Th2 factors suggested immune activation could be occurring even though levels of pro-inflammatory cytokines were not increased.

Immune exhaustion is a serious issue in several diseases and efforts are being made to battle it. How the medical profession is tackling immune exhaustion is a subject for another blog.

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MRI shows brainstem/midbrain nerve conduction deficit in CFS

Posted on 04/07/2016 by wames

Research highlights:

• For the first time in CFS, we performed MRI regressions with steady state BP and HR.
• Vasomotor centre, midbrain and hypothalamus correlations were abnormal in CFS.
• MRI group comparisons between CFS and controls detected no differences.
• Regulatory nuclei and peripheral effectors/sensors appear to function correctly.
• Signalling between brainstem/midbrain regulatory nuclei appears to be impaired.

Research abstract:

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking.

The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure  (BP) and heart rate (HR).

In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring.

We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D).

Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter.

Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations.

This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome by Leighton R. Barnden, Richard Kwiatek, Benjamin Crouch, Richard Burnet, Peter Del Fante in J. NeuroImage: Clinical [Available online 31 March 2016]

Dr Charles Shepherd comments on the significance of this research on the MEA website

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MicroRNAs as potential biomarkers in ME/CFS

Posted on 04/06/2016 by wames

ME Research UK comments on recent research:

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME), by RD Petty, NE McCarthy, R Le Dieu, J R Kerr in PLoS One. 2016 Mar 11;11(3):e0150904

Ribonucleic acid (RNA) is found in all living cells, and controls the manufacture of the proteins needed for all essential functions of life, from hormones to immunological responses. It comes in different forms, and the best known is messenger RNA which passes information from our DNA to the sites where proteins are actually made. In recent years, however, another fascinating form has been identified – microRNA or miRNA. While other types of RNA have a ‘positive’ role in the creation of proteins, miRNAs tend to prevent things happening – they ‘silence’ mRNA molecules by cleaving them, destabilising them, or interfering with their work.

A lot of effort has gone into discovering whether miRNAs are involved in human disease, and a role in cancer was first reported in 2002 in chronic lymphocytic leukaemia. Since then, a large array of different miRNA molecules have been linked with different diseases and, in fact, there is a specific database containing information about these links. While it’s now clear that miRNAs are involved in regulating blood cell formation and moderating immune cascades, they probably have a role in constraining or subduing the workings of many, if not most, biochemical pathways in the body.

Dr Robert Petty and Dr Jonathan Kerr (Queen Mary University of London, and St George’s University of London & Universidad del Rosario, Colombia) have just published a paper in the journal PlosOne on the role of miRNAs in ME/CFS. The work was undertaken during Dr Petty’s PhD project, and the research group received funding from ME Research UK and the CFS Research Foundation among others over the years, producing a range of scientific reports. Read more

The team examined miRNA expression in mononuclear white blood cells (T-cells, B-cells, natural killer cells and monocytes involved in defence and immunity) in Fukuda and Canadian Consensus-defined ME/CFS patients and healthy controls. There were three stages to the experimental work. The first step was to determine whether miRNA expression (i.e. its activity) was different between one set of 15 ME/CFS patients and 30 healthy control individuals. Next, the researchers undertook a replication stage, attempting to repeat their findings in another independent group of 20 ME/CFS patients and 20 controls, and to identify the particular types of mononuclear cells involved. The final step involved a separate experiment to see if the ME/CFS-associated  miRNAs could be linked with particular genes by ‘transfecting’ them into primary natural killer cells and observing which genes were produced.

In essence, the analysis identified ‘differential expression’ or activation of 34 miRNAs, all of which were up-regulated. Using quantitative PCR to validate the findings, expression changes were confirmed in four of these miRNAs  – hsa-miR-99b, hsa-miR-330-3p, hsa-miR-30c and hsa-miR-126 – which, in addition, were found to be suitable for further investigation as potential biomarkers for ME/CFS as their specificities ranged from 0.71 to 0.78. The two miRNAs which showed the greatest degree of over expression were hsa-miR-99b and hsa-miR-330-3p, which are also know to be important in other illnesses. For instance, hsa-miR-99b has a distinctive pattern of microRNA expression in primary muscular disorders, while hsa-miR-330 signatures are associated with certain lymphomas.

At the replication analysis, changes in miRNA expression were found in the four types of white blood cells, with the most significant abnormalities occurring in natural killer cells. ‘Transfection’ of natural killer cells with hsa-miR-99b or has-miR-330-3p led to gene expression changes, including in genes involved in the activation of cellular processes and immunity. The researchers concluded that the natural killer cells were ‘activated’ but with reduced functioning, consistent with what we know already about the low activity of these cells in ME/CFS.

Overall, the researchers found that four miRNAs expressed in mononuclear white blood cells have potential as biomarkers  in ME/CFS, particularly hsa-miR-99b and hsa-miR-330-3p which may also be involved in the natural killer cell dysfunction characteristic of the illness. As the authors point out, the results are particularly interesting since the messenger RNAs regulated by hsa-miR-99b and hsa-miR-330-3p have a large degree of overlap with the messenger RNAs found to be upregulated in previous work by the Kerr group, strengthening the case for the role of abnormalities in the innate immune system in the pathogenesis of ME/CFS.

Because miRNAs are ‘protected’ and stable in various body fluids and tissues, there is now an enormous literature on their use as possible biomarkers, mainly in cancer but also in diseases like epilepsy, malarial infection and multiple sclerosis. In all these illnesses, there is a need for non-invasive, easily detected, sensitive biomarkers, and ME/CFS is no different. For that reason, these interesting findings deserve to be taken much further in large validation studies, as well as in investigations to elucidate the particular role played by immune system abnormalities in the pathogenesis of the disease.

Dr Neil Abbot
ME Research UK
Perth PH1 5PP, UK

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Natural killer cell & SNP dysfunction in ME/CFS

Posted on 04/05/2016 by wames

Research abstract:

Aim: The aim of this paper was to determine natural killer (NK) cytotoxic activity and if single nucleotide polymorphisms (SNPs) and genotypes in transient receptor potential (TRP) ion channels and acetylcholine receptors (AChRs) were present in isolated NK cells from previously identified myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients.

Subjects and methods: A total of 39 ME/CFS patients (51.69±2 years  old) and 30 unfatigued controls (47.60±2.39 years old) were included in this study. Patients were defined according to the 1994 Centers for Disease Control and Prevention criteria. Flow cytometry protocols were used to examine NK cytotoxic activity. A total of 678 SNPs from isolated NK cells were examined for 21 mammalian TRP ion channel genes and for nine mammalian AChR genes via the Agena Bioscience iPlex Gold assay. SNP association and genotype was determined using analysis of variance and Plink software.

Results: ME/CFS patients had a significant reduction in NK percentage lysis of target cells (17%±4.68%) compared with the unfatigued control group (31%±6.78%). Of the 678 SNPs examined, eleven SNPs for TRP ion channel genes (TRPC4, TRPC2, TRPM3, and TRPM8) were identified in the ME/CFS group. Five of these SNPs were associated with TRPM3, while the remainder were associated with TRPM8, TRPC2, and TRPC4 (P<0.05).

Fourteen SNPs were associated with nicotinic and muscarinic AChR genes: six with CHRNA3, while the remainder were associated with CHRNA2, CHRNB4, CHRNA5, and CHRNE (P<0.05). There were sixteen genotypes identified from SNPs in TRP ion channels and AChRs for TRPM3 (n=5), TRPM8 (n=2), TRPC4 (n=3), TRPC2 (n=1), CHRNE (n=1), CHRNA2 (n=2), CHRNA3 (n=1), and CHRNB4 (n=1) (P<0.05).

Conclusion: We identified a number of SNPs and genotypes for TRP ion channels and AChRs from isolated NK cells in patients with ME/CFS, suggesting these SNPs and genotypes may be involved in changes in NK cell function and the development of ME/CFS pathology. These anomalies suggest a role for dysregulation of Ca2+ in AChR and TRP ion channel signaling in the pathomechanism of ME/CFS.

Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome, by Sonya Marshall-Gradisnik, Teilah Huth, Anu Chacko, Samantha Johnston, Pete Smith, Donald Staines in The Application of Clinical Genetics, 31 March 2016 Volume 2016:9 Pages 39—47

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Can psychological treatments be harmful?

Posted on 04/05/2016 by wames

Guardian article, by Dr Luisa Dillner, 4 April 2016: Can psychological treatments be harmful?

The mind is a delicate thing, so can therapies actually have a negative effect? The evidence points to some cause for concern

The side effects of antidepressants are well known – nausea, dry mouth, constipation and loss of interest in sex. But what if your depression is being treated by a psychological therapy? Are there any risks in that? Research in the British Journal of Psychiatry suggests there might be – out of 14,587 people who responded to a survey asking about a range of psychological therapies, one in 20 said they had “lasting bad effects” from treatment.

In a separate, in-depth study, researchers found that some people complained of becoming more angry, anxious or losing self-esteem, though they did not follow up to see if these symptoms were resolved. People were more likely to feel harmed if they did not know which psychological therapy they were being given, or if they were not white and heterosexual. So should you worry about being harmed by a dose of psychological therapy?

The solution

Psychological therapies are generally safe. Scott O Lilienfeld, professor of psychology at Emory University in the US and author of a review on the harms of psychological therapies, says it is hard to know if people would have got worse anyway, without therapy. Symptoms such as anger, anxiety and depression can fluctuate over time.

But some psychological therapies do have evidence of harm. Critical incident stress debriefing, often offered after violent events (such as witnessing terrorism), can paradoxically increase the risk of post-traumatic stress disorder.

“Pop psychology says it is best to get everything out of your system, but that may not be everyone’s coping style,” says Lilienfeld. “In crisis debriefing, because it is done in group sessions, you can’t titrate the amount of exposure to the individual, so some may get more upset. The intervention is short, so there may be lack of resolution.”

Recovered memory techniques, meanwhile, have shown a five-fold increase in admissions to mental health institutions and a seven-fold rise in suicidal thoughts. In New Jersey, a programme called Scared Straight that exposed at-risk adolescents to the realities of prison life, actually led to an increase in offending.

Lilienfield thinks it is more important to identify harmful therapists than treatments. Therapists who are confrontational, lack empathy and don’t disclose which treatment they are using should be avoided. There is a list of evidence-based treatments*, so you can check the one you are being given works for your condition. Most should work regardless of ethnic group or sexual orientation. Lilienfeld says that if you are no better after a month of therapy, then you should ask your therapist why this is. Some therapies, for example for obsessive-compulsive disorders, should show improvement after a couple of sessions​ (even if it is from feeling terrible to horrible). Your therapist should always ask if your symptoms have got worse. And Lilienfield says you don’t have to feel worse in therapy before you get better.

*NB  This American list doesn’t mention ME or CFS

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Aloe vera juice with L-arginine has promising positive effect on CFS symptoms

Posted on 04/04/2016 by wames

Research abstract:

L-Arginine is one of the most metabolically versatile amino acids. Several in vitro/in vivo experiments have indicated that exogenous L-arginine intake has multiple beneficial pharmacological and pharmaco-kinetic effects. Such effects include reduction in the risk of vascular and heart diseases and chronic fatigue syndrome.

The effects of a dietary supplementation of aloe vera juice with L-arginine to chronic fatigue syndrome were demonstrated and a questionnaire was given to adult subjects. The questionnaire included 10 points regarding their mental, circulatory and muscle functions. Table 1 and 2 summarize the most noteworthy information on supplementation of aloe vera juice with L-arginine.

The demonstrated benefits of aloe vera juice with L-arginine show promises to chronic fatigue syndrome in adult subjects.

Putative Prophylaxes of Aloe Vera Juice with L-arginine to Chronic Fatigue Syndrome, by Akira Yagi, Suzuka Ataka in Journal of Gastroenterology and Hepatology Research, 5(2): 1950-1956, 22 March 2016

 

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Research protocol for Mental training for CFS/ME in adolescents

Posted on 04/02/2016 by wames

Norwegian research studies: Protocol for intervention «Mental training for chronic fatigue syndrome (CFS/ME) following EBV infection in adolescents: a randomised controlled trial»  26 March 2016

This blogpost will provide you with the research protocol for the mental/biopsychological/ adjusting behavorial  intervention and RTC «Mental training for chronic fatigue syndrome (CFS/ME) following EBV infection in adolescents: a randomised controlled trial» (after only six mnd. with PI-EBV). This part two study (CEBA) started 1 oct 2015 and  ends 31 dec 2018. The principal investigator of this study; MD PhD Vegard Bruun Wyller at Akershus University Hospital (AHUS), Norway.

continues

 

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Mortality in ME/CFS

Posted on 04/01/2016 by wames

Review article by ME Research UK, 19 February 2016: Mortality in ME/CFS

Whether or not people with ME/CFS die earlier, for whatever reason, than the general population is an important question, and there are few good clues to the answer in the scientific literature.

One analysis of information on 166 deceased patients in a memorial list kept by the National CFIDS Foundation in the USA found three of the most prevalent causes of death to be heart failure, suicide and cancer – valuable findings, but impossible to generalise to the overall population of patients with ME/CFS, as the authors made clear (read more).

Another study, from the National Cancer Institute, of people aged 66 years and older, interrogated cancer data from registries across the USA and found that the overall risk of cancer was not increased in those with a diagnosis of CFS. There was, however, a small increased risk of non-Hodgkin lymphoma which was “likely too small to affect the clinical management of patients” (read more).

Other studies have examined prognosis and outcomes in ME/CFS (Joyce 1997; Cairns 2005; Jason 2011; and Smith 2006), but none have uncovered convincing evidence that mortality is increased compared with the general population.

A new study just published in the Lancet (Kapur et al 2016), the largest examination to date of outcomes in patients from the UK, tends to confirm these findings for overall mortality (read more). In the study, researchers at King’s College London used data-mining techniques to examine the medical records of 2147 people with ME/CFS who had been referred by their GPs to the CFS service in London.

Over a 7-year period (2007-2013), only 17 of the patients had died: 8 from cancer, 5 from suicide, and 4 from other causes. When these mortality rates were compared with matched population data from the Office of National Statistics, the overall rate of deaths from all causes was no higher in ME/CFS patients than in the general population, and there was no difference in the rate of deaths from cancer. These findings will come as a relief to many patients and their families, particularly those who have been ill for many years.

The aspect of the data that has caught the attention of the media, however, concerns suicide. The 5 suicides in the ME/CFS group were more than would have been expected in the general population (<1 in a study population of 2147). In statistical terms, this means that the rate of deaths by suicide was increased by around 6.85-fold, allowing media headlines to chirrup that suicide was six times more likely in ME/CFS patients than in the general population. The authors themselves are more cautious, however, pointing out that the absolute number of deaths by suicide was small, and that the rate was far lower than in some other disorders.

An expert commentary (Roberts, 2016) accompanying this Lancet study highlighted the difficulty of interpreting this finding – “The increased suicide mortality…was based on just a few deaths and the confidence intervals were wide. Two fewer suicide deaths [i.e. 3 instead of 5] would have meant that the findings were no longer significant.” – and stressed the need for caution given the small numbers involved and the number of confounding factors that could be influencing the result. In essence, the increased suicides rate may be a true finding (as the authors say, “it is highly unlikely that the result is due to chance”), but far larger numbers of patients would be needed for cast-iron certainty.

Assuming that the small but significant increase in suicide is real, would it really be a surprise? ME/CFS patients make up a distinct group of chronically ill people, and chronic illnesses (such as multiple sclerosis, chronic pain, epilepsy, the heart diseases, etc.) are well known to be risk factors for suicide, particular in older adults (read more).

Importantly, suicide in the chronically ill is also linked with co-existing depressive illness – and in this Lancet study too, the risk of death by suicide was independently associated with a lifetime diagnosis of depression. For these reasons, chronicity as well as the appearance of signs of major depression should be red flags for clinicians and healthcare professionals in all long-term illnesses with potentially severe consequences, including ME/CFS.

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End ME/CFS Severe Patient Study Turns to the Mitochondria

Posted on 03/24/2016 by wames

Health rising article, by Cort Johnson 18 March 2016: End ME/CFS Severe Patient Study Turns to the Mitochondria

The mantra at the Severely Ill/Big Data study at the Open Medicine Foundation is to follow the evidence where it leads. We don’t know exactly what Davis has found or if will be ultimately validated. We do know that something eyebrow raising involving the mitochondria has shown up in the early stages of the Open Medicine Foundation’s End ME/CFS Severely Ill study. Something eyebrow raising enough for a mitochondrial expert to join the fold.

Davis has found abnormalities before but this is the first one, he told me, that has really leapt off the charts. It was orders of magnitude different from normal.

Whatever the finding is it has apparently lead to a mitochondrial expert, Robert Naviaux, MD, PhD being added to the Open Medicine Foundation’s Scientific Advisory Board.

We’ve had mitochondrial findings before but not from researchers of his ilk. Naviaux is not a doctor and sometime researcher. He’s a full-time mitochondrial researcher. His first paper on the subject occurred about 15 years ago. Since then he’s co-authored more than 80 studies on the mitochondria, genetics, metabolism and metabolomics. The metabolomics study that highlighted the possible mitochondrial issue in ME/CFS has been submitted to the Journal of the American Medical Association (JAMA). Publication, if it comes, is hoped for in early spring/summer.

He runs the Robert Naviaux Laboratory at UC San Diego, and is the founder and co-director of the Mitochondrial and Metabolic Disease Center at UCSD.. He’s also the co-founder and a former president of the Mitochondrial Medicine Society, and a founding associate editor of the journal Mitochondrion. This man is steeped in the mitochondria – but he also has an interesting immune side.

Naviaux trained at the NIH in tumor immunology and natural killer cell biology, and at the Salk Institute in virology and gene therapy. With all that experience he seems perfectly placed to understand the role infection/inflammation may play on mitochondrial issues, should they continue to show up, in ME/CFS. In conversation Ron Davis has suggested that mitochondrial problems with the immune cells could conceivably be driving the immune dysfunction in ME/CFS.

A busy researcher in a hot field, his joining of the OMF Scientific Advisory board speaks volumes about the possible significance of Davis’s recent finding. Naviaux wouldn’t sign on if something very intriguing hadn’t sparked his interest. One patient reported Naviaux replied to her email.

“I have only been working in the CFS world for a year, but we have already made several discoveries that have a chance to offer real hope for people who have suffered for so long. We have a paper in review at JAMA. If it is published, we will have a real start on seeing CFS in a new light, and having real tools for new ways to treat patients as individuals, and not just as a patient with CFS.”

Davis has stated that Dr. Nath of the NIH’s Clinical Center study has been informed of what they’ve found.

The Chronic Fatigue Initiative’s Mitochondrial Emphasis

J Transl Med. 2016 Jan 20;14(1):19. doi: 10.1186/s12967-016-0771-6.Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. Billing-Ross P1, Germain A2, Ye K3, Keinan A4, Gu Z5, Hanson MR6.

 The Chronic Fatigue Initiative’s move to the mitochondria recently resulted in a paper published by Maureen Hanson of Cornell University. The study involved sequencing the entire mitochondrial genome of almost 400 ME/CFS patients from five sites across the U.S. It determined whether single or groups of variations in mitochondrial genes or something called heteroplasmy were more common in ME/CFS.

The study found no evidence of inherited genetic disease or heteroplasmy in ME/CFS but one finding suggested that people whose genome gives them an increased tolerance of oxidative stress may be at reduced risk of coming down with ME/CFS. (The mitochondria produce large numbers of free radicals). ME/CFS patients with a group of variations in some mitochondrial genes also tended to display more joint pain, bloating, chemical or light sensitivity, disrupted sleep and experience more dead/heavy feelings after exercise.

This study did not suggest that variations in the mitochondrial genome caused ME/CFS but it did suggest that once you have ME/CFS some mitochondrial variations might make it worse. That could suggest that something affecting mitochondrial functioning could be present in ME/CFS.

One study that found evidence of mitochondrial genetic issues in ME/CFS and other “functional disorders” concluded that the “pathophysiology likely involves broad effects on the autonomic nervous system.”

There’s the genetics of mitochondrial disease and then there’s mitochondrial functioning. If an autoimmune or some other process is affecting the mitochondria then genetic problems need not be present for a disease to have a mitochondrial basis. The next step for Maureen Hanson and the CFI is to determine if mitochondrial problems caused by an autoimmune or another process are impairing the functioning of immune cells in ME/CFS.

Conclusion

The mitochondria are finally getting some serious attention in ME/CFS. Mitochondrial problems have been found before in the disease and interest is growing in the subject. Newton recently showed for the first time that mitochondrial disorders can cause fatigue as severe as that found in ME/CFS. She found comparable levels of fatigue in about a third of people with mitochondrial disorders. She suggested that future treatments developed to assist mitochondrial patients may be able to help people with ME/CFS. With results like that and researchers like Naviaux and Hanson in the mix, mitochondrial issues should be getting more attention in ME/CFS.

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How to recognise POTS

Posted on 03/23/2016 by wames

Article abstract:

This article describes the pathophysiology, clinical presentation, differential diagnosis, diagnosis, and management of postural orthostatic tachycardia syndrome (POTS), a potentially debilitating autonomic disorder that can have many causes and presentations. POTS can be mistaken for panic disorder, inappropriate sinus tachycardia, and chronic fatigue syndrome. Clinician suspicion for the syndrome is key to prompt patient diagnosis and treatment.

Recognizing postural orthostatic tachycardia syndrome, by D Pavlik, D Agnew, L Stiles, R Ditoro in JAAPA 2016 Mar 10. [Epub ahead of print]

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