Exercise testing in patients with ME/CFS vs. healthy controls:
   –    Triggers a characteristic gene expression “signature” involving 15 cytokines/adipokines/growth factors (Stanford
   –    When repeated 24 hours after a first exercise test leads to a significant decline in peak heart rate (“chronotropic incompetence”), which could contribute to post-exertional malaise (U of the Pacific)
   –    Leads to postural tachycardia after exercise (as contrasted to after tilt table testing) in a subset of ME/CFS patients and Gulf War Illness patients, due to increased sympathetic activity (Georgetown)
   –    Exercise testing in patients with ME/CFS vs. healthy control subject:
       –   Leads to lower oxygen consumption and earlier conversion to anaerobic metabolism (Nova and Wisconsin)
       –   Blood lactate levels in 2nd exercise test after 24 hours
       –   ME/CFS patients lactate levels are higher at all work loads
       –   Healthy controls: lactate leels are lower at all work loads.

Immunology:

Huge study: 192 cases, 392 healthy controls.
   –    Levels of 17/51 cytokines/adipokines/growth factors were significantly different in ME/CFS than healthy controls
   –    Most of the cytokines were pre-inflammatory, and their levels correlated significantly with the severity of symptoms (Stanford University)

Interesting because many clinicians and researchers in this field have long believed that the disease was caused by abnormal cytokines in the brain.

The errant B cell:
   –   The early rituximab studies, indicating therapeutic benefit in some patients (Bergen, Norway)
   –   Reduced diversity and increased clonality of B cells in ME/CFS (NCNP, Japan)

Microbiome;

How the Microbiome may affect the brain
   –   The human microbiome: 10 times as many bacterial cells as human cells, containing 5-8 million genes compared to our 20,000+ genes
   –    Microbes in our gut:
        –   Synthesize hormones and neurotransmitters (e.g. norepinephrine, serotonin, dopamine, Ach, GABA)

        –   Synthesize molecules of inflammation (cytokines, prostaglandins) and elicit the production of those molecules by the gut immune system
        –   Through inflammation, create a “leaky gut”: the tight junctions that bind gut epithelia cells together become loosened – allowing bacteria and bacterial toxins to enter the blood.

In addition to the recently-reported reduction in bacterial diversity in ME/CFS, the team reports finding an increased number of Caudovirales bacteriophage viruses in ME/CFS.

 All of these findings point to low-level inflammation in the gut. (Cornell)

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 Brain and Nervous System

   –   Impaired speed in processing information is shown to be a critical deficit in both ME/CFS and Gulf War Illness
   –   Compared to healthy children, pediatric patients with ME/CFS had impaired information processing speed and attention.  After exertion, these deficits worsened and ME/CFS kids also had poorer performance on tasks of working memory.
   –   Impairments in cerebral blood flow and cortical glutathione levels – not affected by comorbid psychiatric disease.
   –   A third of ME/CFS, but no healthy controls, had high white cell count or elevated protein in spinal fluid.
   –   Altered heart rate variability, due to reduced cardiac vagal activity, in ME/CFS v. healthy controls.  [There is some evidence that this can be a sign or contributory factor to heart disease later.]

Functional connectivity among different brain regions impaired:
   –   Followed a cognitive test in ME/CFS v. healthy controls, determined by PET
   –   As determined by diffusion MRI in GWI patients
   –   As determined by EEG (eLORETTA) in ME/CFS patients at rest

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Epigenetic studies
   –   Disease is caused not just by mutated genes
   –   It also is caused by perfectly normal, non-mutated genes, when those genes are not “expressed” (turned on or off) appropriately
   –   Gene expression is controlled by many different “epigenetic” forces
   –   Epigenetic studies are increasingly being done in ME/CFS v. healthy control
   –   ME/CFS: genes involved in signal transduction are hypomethylated more often, whereas genes involved in cell differentiation/cell death are hypermethylated more often
   –   ME/CFS: significantly different gene expression patterns for genes, involved in immune regulation (JAK-STAT pathway), hormone regulation and mitochondrial dysfunction.
   –   Gulf War Illness: 19 related groups of genes (“functional modules”) were found to have significantly altered gene expression.  Specific immunosuppressant and hormonal therapies were identified that might target these dysregulated genes, and possibly improve symptoms.
   –   ME/CFS patients, compared to healthy controls, have 13 different gene lci, all involving glucocorticoid sensitivity that are differentially methylated.  The different methylation patterns correlated with clinical symptoms
   –   Characteristic expression of two particular microRNAs in plasma leads to elevated homocysteine levels identified in ME/CFS
   –   Three SNPs distinguished ME/CFS [atients from healthy controls.  All involve a gene that codes for a subunit of NADH dehydrogenase – an important energy molecule.
   –   MicroRNAs in spinal luid predict orthostatic tachycardia after exercise.
   –   No clear gene expression differences in ME/CFS v. healthy controls, at rest.

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Energy Metabolism Studies
   –   Studies on patients in the rituximab trial have an energy metabolism deficit, and the key molecule is the enzyme pyruvate dehydrogenase (PDH).  Speculate that autoantibodies may be the cause of this deficit.  Upreulation of PDH inhibitors in white blood cells (Norway group – study will finish late 2017)
   –   Peripheral white blood cells from ME/CFS produce energy less well than WBCs from healthy subjects, particularly when the cells are exposed to stressors.
   –   Citric acid cycle metabolites are depleted.  Glucose as an energy source is being replaced by fatty acids and amino acids
   –   “Unbiased” metabolomics study finds that the metabolites that are most different between ME/CFS and healthy controls involve pathways harvesting energy from glucose, fatty acids and amino acids.
   –   Also finds a general hypometabolic state, as did the recent paper from Naviau (PNAS), though different metabolites were examined.

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Miscellaneous
   –   ME/CFS patients, but not healthy controls, experience a worsening of symptoms following true (but not sham) strain: neuromuscular strain (even sitting/driving for prolonged time) may contribute to symptoms of ME/CFS.  Physical therapy likely to help
   –   Five specific findings on physical examination were quite accurate in diagnosing ME/CFS.  This is of interest, since ME/CFS is defined exclusively by symptoms.
   –   Of over 200 single-nucleotide polymorphisms examined, three – all located in the gene for NADH dehydrogenases – were significantly different in ME/CFS patients than in healthy controls.
   –   ME/CFS patients have significantly higher anti-citrullinated protein antibodies than matched healthy controls, as is seen in the autoimmune whatever.
   –   Particular mutations in two nucleosome transport genes distinguish ME/CFS patients from healthy controls.
   –   A second case of ME/CFS caused by an enteroviral infection of the brain.
   –   Impressive hypothesis: dysregulation in the production/release of Hydrogen Sulfide could explain many of the symptoms and objective abnormalities seen in ME/CFS
   –   A subset of ME/CFS patients with sinusitis and/or hives has more pain and other symptoms

Possible Diagnostic Tests for ME/CFS?

 Four biomarkers – IL-8, sCD14, PGE2 and CD3/CD57+ count – correctly predicted ME?CFS in 97% of female cases (UNR)

 An ideal diagnostic test would:
   ·  Have very low false positive and false negative rates, compared to healthy controls and other fatiguing disease, when retested on a large number of new people
   ·  Be easy for perform reliably by many labs
   ·   Be inexpensive

Treatment Studies

   ·  MRI spectroscopy reealed 15% lower levels of the natural antioxidant, glutathione, in the brain in ME/CFS patients compared to controls.  N-acetyl-cysteine (NAC) treatment improved both brain glutathione levels and symptoms, and reduced oxidative stress, in the ME/CFS patients

   ·  Randomized trial of low-dose methylphenidate plus a nutritional regimen designed to improve mitochondrial function.  At 12 weeks, a trend toward reduced symptom that was not statistically significant; more severely ill patients seemed to benefit
   ·  A careful study of 990 ME/CFS patients found that patient beliefs about the cause of their illness did not explain their level of activity, a result that does not support the theoretical benefit of cognitive behavioral therapy.
   ·  Multimodel physical therapy improves symptoms in adolescents and young adults with ME/CFS and impaired range of motion.
   ·  Quantitative modeling identifies drug that are already FDA-approved and tat might target TNA-alpha, IL-2 and the glucocorticoid receptor – targets that may be important in causing the symptoms of GWI

Multisite consortia to standardize and pool clinical and biosample data
   ·  CDC: Multi-Site Clinic Assessment (MCAM), with 7 collaborating centers.  Biospeci and other things.

Questions addressed by many presentations:
   ·  In an illness defined exclusively by subjective symptoms, is there evidence of underlying biological abnormalities?
   ·  Could those biological abnormalities theoretically explain the symptoms?
   ·  Do the abnormalities in fact correlate with the symptoms?

 In Summary:

Case-control studies comparing patients with CFS to both disease comparison groups and healthy control subjects find robust evidence of 
   ·  the brain and autonomic nervous system
   ·  immune system
   ·  energy metabolism
   ·  oxidative and nitrosative stress

 The illness is not simply the expression of physical symptoms by people with a primary psychological disorder.

 [Komaroff believes that new methods are getting us closer, quicker,   Also the exercise evidence is changing the way people do research.]

Mary Schweitzer