[1] http://naviauxlab.ucsd.edu/wp-content/uploads/2016/09/cell_d... [2] http://naviauxlab.ucsd.edu/wp-content/uploads/2016/08/PNAS-2...
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.
[1] http://time.com/4327645/folic-acid-autism-pregnancy-b12-fola...
[2] Effect of High Folic Acid Diet on Mitochondrial DNA Content in Young Adult and Aged Mice - http://www.fasebj.org/content/30/1_Supplement/1171.4
However, the PACE trial was a complete bodge; the protocol and criteria for classifying "recovery" were changed during the trial (to the point that a patient that got worse could nevertheless be classified as having "recovered), the outcome measures were subjective and self-reported (which are liable to be affected by CBT or other forms of social pressure), and conflicts of interest were not reported to participants.
Re-analyses of the data were thwarted by the fact that the researchers did not publish anonymised trial data, which violated the requirements of one of their funding sources and the requirements of one of the journals in which they published. There were plenty of methodological criticisms of the trial (http://www.virology.ws/2015/10/21/trial-by-error-i/) but the actual trial data was still not available. Academicians and patients alike unsuccessfully tried to get access to anonymised PACE data for years, and the PACE researchers did their absolute best to prevent that from happening -- including labelling legitimate requests for anonymised trial data (that they were obliged to publish) and criticism of their study as "vexatious" and "harassment" in a BMJ feature article (https://doi.org/10.1136/bmj.d3780). The Information Commissioner's Office ordered the PACE researchers to release the trial data, the researchers appealed that decision -- and got laughed out of court. The tribunal concluded that there indeed was a very strong academic interest in the data being released, that it was sufficiently anonymised to prevent re-identification, and went as far as to say that the PACE researchers were overly disparaging of patient groups and skeptical researchers -- and that legitimate requests for trial data and criticism of the PACE study did not constitute harassment.
Given how hard the PACE researchers tried to prevent release of the anonymised trial data, the results of the independent re-analysis (http://dx.doi.org/10.1080/21641846.2017.1259724) should not be too surprising. There was no basis for an in-flight change to criteria and protocols and CBT/exercise did not provide a statistically significant change in recovery. There are other serious issues with the PACE study's methods that are addressed in http://www.virology.ws/2017/03/13/an-open-letter-to-psycholo... or in the independent reanalysis linked (and there's a quite decent timeline and overview of the PACE trial here: http://me-pedia.org/wiki/PACE_trial).
Serious biological research (not nonsense by CBT-obsessed wankers who lie with statistics) into CFS continues and there's indeed many findings on potential biomarkers for CFS -- more keeps getting published, 10.1186/s40168-017-0261-y nor 10.1186/s12967-017-1161-4 weren't there last time I looked into this, for example. There's robust evidence of biomedical anomalies in CFS patients -- far more than enough for CFS to be considered a legitimate medical syndrome and not a psychiatric/psychological/"somatic" syndrome. That we haven't yet identified a biomarker useful for diagnosis nor know an aetiology certainly shouldn't disqualify CFS from being a medical syndrome!
Since there's plenty of evidence against the PACE trials' findings -- why do CFS patients object to it? After all, papers regularly do get proven wrong or have their findings revised, it's kinda how science operates. It's not the actual publication of the PACE results that have caused harm -- it's how the results were used. Since PACE was the first clinical trial of its scale on CFS patients, its findings ended up single-handedly defining clinical policy, treatment recommendations, and public policy relating to welfare and insurance. CBT and making patients do physical exercise is infinitely cheaper than any sort of medical treatment; and if the PACE trial happened to find that those will help people with CFS "recover" and get back to work, well, that's just a happy coincidence. That CBT is useless and excessive physical exercise harmful to CFS patients is immaterial; there's research that says it helps, so if you're a recalcitrant patient who complains, you're clearly not doing the CBT or the exercise enough! Similarly, the mere belief that CFS has a physical (and not psychological) cause is explicitly called out as one of the "harmful beliefs" that CBT is to neutralise -- disagreement with the treatment method (or familiarity with current medical research) is itself a sign that you're not taking CBT seriously.
It is not just through treatment guidelines (and denial of medical access beyond CBT and forced exercise) that the PACE results have materially harmed patients. Extremely unusually for a clinical trial, PACE was funded by the UK DWP -- and could not have returned better results to justify the DWP's agenda of cutting disability spending: http://www.centreforwelfarereform.org/uploads/attachment/492... . The DWP wanted findings to show that CBT and GET would get disabled people off benefits; and the PACE researchers (by changing the protocol/criteria halfway through) handed that to DWP on a silver platter. That CBT/GET are, in reality, useless (at best) is immaterial here -- DWP doesn't give a flying fuck whether people actually do get better or even manage to survive without disability benefit, they only needed these published findings to justify benefit cuts.
Something is wrong in this country....
Are there any other substances out there that inhibit ATP signaling?
As far as I know, though, the drugs studied that inhibit purinergic signaling have only been approved for anti-platelet purposes.
Things to note:
- Administered solely by injection.
- Not FDA approved.
> Unlike treatment for African sleeping sickness, which involves multiple, higher doses of suramin over a period of time and frequently results in a number of adverse side effects ranging from nausea and diarrhea to low blood pressure and kidney problems, researchers said the single, low dose of suramin used in the ASD trial produced no serious side effects beyond a passing skin rash.
That's an intriguing symptom, given that many inflammatory/autoimmune conditions cause peripheral neuropathy. I wonder if what is being described is the "unblocking" of peripheral nerves, causing a flood of signal-distorting noise as they re-join the nervous system.
As an autistic adult, it's really frustrating how high-functioning autistics and caretakers of low-functioning autistics constantly talk past each other and refuse to acknowledge that the other exists.
The focus on children is likley caused by the medical siloing of patients into pediactric and adult. Also researchers may want to focus on harm reduction, ie by preventing or amelirating autisitic symptoms in children it is likley to also prevent the downstream effects to their nervous systems. But certainly if researchers want to get a better understanding of treatment efficacy, adults should also be included in trials.
Our current diagnostic grouping of symptoms into an autisic spectrum is imperfect, I would be very supprised if autisim as we understand it today is caused by one thing. So if this research becomes a treatment it will likley only be benificial for a certain percentage.
