Machine Learning-assisted Research on ME/CFS

[mariovitali]

I just realised another possible connection with microglia activation (VanElzakker). LXR was identified by Network Analysis in May 2017 :

Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2.
Secor McVoy JR1, Oughli HA2, Oh U3.
Author information

Abstract
BACKGROUND:
The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis.

https://www.ncbi.nlm.nih.gov/pubmed/25889344

 

[mariovitali]

Latest results : Hypoperfusion which is researched by Dr VanElzakker gets a very high ranking along with rbainstem, vagus nerve and cholinergic signalling.


I am currently looking at the connections of hydroxyproline and proline metabolism in general :

 

[mariovitali]

I am currently working in identifying more subgroups of issues responsible for ME (hypothesis). @wigglethemouse i haven't forgotten to see how mast cell actication could be fitting the greater puzzle of ME but please read below.


There are many of these issues that have been identified by researchers lately, two examples are Glycogen Storage Disease and Iron metabolism as identified by Birch et. al. As discussed i am using a custom-made Information Extraction system that looks at millions of PUBMED articles that tries to identify most interesting -in the context of ME- research papers.

This is one that i found lately, which discusses about mevalonate (aka Isoprenoid) pathway, a topic which was identified previously from Network Analysis. You may find several posts regarding the mevalonate pathway on PR as well.

Interestingly, some well known viruses downregulate the mevalonate pathway thorough induction of interferon : https://mbio.asm.org/content/8/4/e00576-17

The paper selected by the IE System can be found here : Note that it was selected through topics that did not include "Chronic fatigue syndrome" :

https://www.ncbi.nlm.nih.gov/pubmed/26983655

Abstract
BACKGROUND AND AIMS:
The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome (CFS). The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has any correlation with these disease states.

METHODS:
The isoprenoid metabolites - digoxin, dolichol and ubiquinone - RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free radical metabolism, glycoconjugate metabolism and RBC membrane composition were also assessed.

RESULTS:
Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG-CoA reductase activity and serum digoxin levels were increased in CFS. There were increased levels of tryptophan catabolites - nicotine, strychnine, quinolinic acid and serotonin - and decreased levels of tyrosine catabolites -dopamine, norepinephrine and morphine - in CFS. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual glycosaminoglycans (GAG) fractions and lysosomal enzymes in CFS. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in CFS. The biochemical patterns in CFS correlated with those obtained in right hemispheric dominance.

Now there are some entries about right hemispheric dominance which sound strange. There are however many interesting parts in the text and i wish someone with knowledge could have a look (the ever existing problem) :

The plasma membrane neurotransmitter (on the surface of the glial cell and presynaptic neuron) is coupled to a Naþ gradient which is disrupted by the inhibition of Naþ-Kþ ATPase, resulting in decreased clearance of glutamate by presynaptic and glial uptake at the end of synaptic transmission (38). By these mechanisms, inhibition of Naþ-Kþ ATPase can promote glutamatergic transmission. The elevated levels of the positive NMDA modulators quinolinic acid, strychnine and serotonin can also contribute to NMDA excitotoxicity.

Glutamate, again (?)


note the mention on of Na,K-ATPase :

The activity of HMG CoA reductase and the concentration of digoxin and dolichol were increased in CFS. The concentration of serum ubiquinone, the activity of erythrocyte membrane Na /K ATPase and serum magnesium were decreased (Table 1).

Here is where it gets more interesting. From another paper :

The role of red blood cell deformability and Na,K-ATPase function in selected risk factors of cardiovascular diseases in humans: focus on hypertension, diabetes mellitus and hypercholesterolemia.
Radosinska J1, Vrbjar N.
Author information

Abstract
Deformability of red blood cells (RBC) is the ability of RBC to change their shape in order to pass through narrow capillaries in circulation. Deterioration in deformability of RBC contributes to alterations in microcirculatory blood flow and delivery of oxygen to tissues. Several factors are responsible for maintenance of RBC deformability. One of them is the Na,K-ATPase known as crucial enzyme in maintenance of intracellular ionic homeostasis affecting thus regulation of cellular volume and consequently RBC deformability. Decreased deformability of RBC has been found to be the marker of adverse outcomes in cardiovascular diseases (CVD) and the presence of cardiovascular risk factors influences rheological properties of the blood. This review summarizes knowledge concerning the RBC deformability in connection with selected risk factors of CVD, including hypertension, hyperlipidemia, and diabetes mellitus, based exclusively on papers from human studies. We attempted to provide an update on important issues regarding the role of Na,K-ATPase in RBC deformability. In patients suffering from hypertension as well as diabetes mellitus the Na,K-ATPase appears to be responsible for the changes leading to alterations in RBC deformability. The triggering factor for changes of RBC deformability during hypercholesterolemia seems to be the increased content of cholesterol in erythrocyte membranes.

Note that the paper shown above involves specific patient groups (hypertension, diabetes mellitus etc).


This is an example on how the IE system can potentially connect some of the findings we are presented with.

 

[wigglethemouse]

There are many of these issues that have been identified by researchers lately, two examples are Glycogen Storage Disease and Iron metabolism as identified by Birch et. al.

This was a very small sample and very preliminary data. Most Glycogen Storage Disease mutations require an autosomal recessive pattern, i.e. both copies of gene affected. Birch et al will need to follow up with transcriptomics, proteomics and Glycogen testing to prove that the mutation is affecting the disease to be sure.

Now my turn to take a hard right turn . Given the recent CCI news, I remembered about the Perrin point and poor lymph flow again. According to @Hip roadmap document
https://mecfsroadmap.altervista.org/

Lymph fluid obstruction/stagnation
Osteopath Raymond Perrin has found that ME/CFS patients have improved, and some have even been cured, by a massage technique that he developed for treating ME/CFS, which is designed to circulate lymph fluid. Perrin theorizes that lymph stagnation prevents proper cerebrospinal fluid drainage, thus creating a toxic build-up in the central nervous system that underpins or contributes to ME/CFS.

More info on the Perrin point from @Hip here
https://forums.phoenixrising.me/thr...your-left-breast-diagnostic-for-me-cfs.56148/

Perhaps worth looking out for lymph drainage in your brainstem search...................

 

[Perrier]

Just a digression, but has anyone here been helped by the Perrin technique? What is the general opinion of this approach? Thanks.

 

[wigglethemouse]

This is one that i found lately, which discusses about mevalonate (aka Isoprenoid) pathway, a topic which was identified previously from Network Analysis.

Very interesting @mariovitali . I read this on Wikipedia (for other readers)
https://en.wikipedia.org/wiki/Mevalonate_pathway

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria.[1] The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, heme, vitamin K, coenzyme Q10, and all steroid hormones.[2]

Interesting given the lipid and heme findings in metabolic studies, and Jonas Berquists interests in the steroid hormone abnormalities.

"The role of red blood cell deformability and Na,K-ATPase" is interesting. Amit Saha (of recent ME RBC studies) is on twitter (@babyy_po) if you wanted to share anything with him there.........

I also thought Na,K-ATPase is interesting in relation to the nanoneedle salt test i.e. the pumping out of sodium. It's talked about that it's the lack of ATP that could be the issue with patient cells on the nanoneedle, but that is only a theory and has not been proven yet. Could just as equally be an issue with this Na/K pump. Here is a link for people to read up on Na,K-ATPase. It's really quite interesting.
https://en.wikipedia.org/wiki/Na+/K+-ATPase

 

[mariovitali]

@wigglethemouse if Amit Saha is going to be more receptive if you tell him, please do so. I added Na/K pump for scoring to Machine Learning to see what kind of ranking it will get and to see what other connections it has. I am using several different techniques to see its connections but for now the most important connection of Na/K pump is glutamate. Here is the number of connections with other topics in descending order.

glutamate
lactate
glutathione
pyruvate
glutamine
acetate
nitric_oxide
liver
creatine_kinase
dopamine
ammonia
nmda
reactive_oxygen_species
acetylcholine
excitotoxicity
quinolinic_acid
digoxin
norepinephrine
magnesium
isoprenoid
arginine
adenosine_triphosphate

I see also a number of reasons on why magnesium may have a very important role (not a suggestion to supplement).

 

[Amw66]

Magnesium is the one supplement that is instantly noticeable if we miss it. It is key to so many reactions.
Lower core body temperature probably doesn't help either

 

[wigglethemouse]

@wigglethemouse if Amit Saha is going to be more receptive if you tell him, please do so.

Done.

Thank you for sharing! I will discuss this with my colleagues

 

[mariovitali]

Dear all, i would like to provide a short update. I begin with a number of entries of potentially higly significant abstracts to ME/CFS from PUBMED (using an Information Extraction system) . I provide some of them below (cc : @wigglethemouse )

('Isoprenoid pathway dysfunction in chronic fatigue syndrome.,"BACKGROUND AND AIMS: The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome (CFS). The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has any correlation with these disease states. METHODS: The isoprenoid metabolites - digoxin, dolichol and ubiquinone - RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free radical metabolism, glycoconjugate metabolism and RBC membrane composition were also assessed. RESULTS: Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG-CoA reductase activity and serum digoxin levels were increased in CFS. There were increased levels of tryptophan catabolites - nicotine, strychnine, quinolinic acid and serotonin - and decreased levels of tyrosine catabolites -dopamine, norepinephrine and morphine - in CFS. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual glycosaminoglycans (GAG) fractions and lysosomal enzymes in CFS. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in CFS. The biochemical patterns in CFS correlated with those obtained in right hemispheric dominance. CONCLUSIONS: The role of hypothalamic digoxin and neurotransmitter-induced immune activation, altered glycoconjugate metabolism and resultant defective viral antigen presentation, NMDA excitotoxicity and cognitive and mitochondrial dysfunction in the pathogenesis of CFS is stressed. CFS occurs in individuals with right hemispheric dominance."\n')

There are several things which do not seem right in the paper cited above. It may have interesting information however such as Na,K-ATPase and its relationship with Cell deformability. Here is an interesting dialogue of @wigglethemouse with a stanford researcher on Twitter, let's hope something comes out of this :

('"A scarlet pimpernel for the resolution of inflammation? The role of supra-therapeutic doses of cobalamin, in the treatment of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic or traumatic shock.","Cobalamin carrier proteins,the Transcobalamins (TCS), are elevated during trauma, infections and chronic inflammatory conditions. This remains un-explained. It is proposed that such TC elevations signal a need for cobalamin central to the resolution of inflammation. Thus Cobalamin may regulate the transcription factor, NFkappaB, activation or suppression of which determines the inflammatory response and its resolution. Such regulation may involve at least 5 separate mechanisms: (i) hormone-like regulation of TNFalpha, through reduction of excess NO by cobalamin, as well as through the selective inhibition, in tandem with glutathione, of inducible nitric oxide synthase; (ii) quenching of nitric oxide radicals and reactive oxygen species, enhanced by cobalamin\'s glutathione sparing effect; (iii) the promotion of acetylcholine synthesis, central to the neuro-immune cholinergic anti-inflammatory pathway; (iv) the promotion of oxidative phosphorylation; (v) and a bacteriostatic role of the TCS released by neutrophil secondary granules during phagocytosis, which also appears to modulate the inflammatory response. TC elevations are dependent on NFkappaB activation, through crosstalk between NFkappaB and Sp1, another member of the helix-loop-helix protein family, which directly mediates transcription of the TCII gene. Sp1 also has binding sites on the TNFalpha and EGF gene promoters. NFkappaB may thus ensure sufficient cobalamin to determine its own eventual suppression. Cobalamin\'s established regulation of EGF may additionally preserve normal function of macrophages and the coagulation cascade in wound healing. By regulating NFkappaB, Cobalamin may also be the as yet unidentified mediator needed to potentiate the anti-inflammatory action of eicosanoids derived from omega-3 essential fatty acids. Moreover, animal and human clinical data suggests that high dose cobalamin may prove a promising approach to SIRS/sepsis/septic and traumatic shock."\n')

The paper can be found here (Sci-hub) : https://sci-hub.tw/10.1016/j.mehy.2006.01.036 . It has some really interesting figures which i cannot copy-paste here.


Interestingly SP1, EGF and HMGB1 (mentioned in the paper) have been also previously identified by Machine Learning as research targets. :








And we also have the following :

('Evidence for a central cholinergic deficit in congenital ornithine transcarbamylase deficiency.,"Congenital ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle enzymes in humans. A large percentage of survivors of neonatal OTC deficiency suffer severe developmental disorders, including seizures, mental retardation and cerebral palsy. Neuropathological studies reveal ventricular enlargement, cerebral atrophy and delayed myelination, as well as Alzheimer type II astrocytosis. Using the sparse-fur (spf) mouse model of congenital OTC deficiency, studies of central cholinergic integrity revealed a developmental delay in choline acetyltransferase activity and of high-affinity [3H]-choline uptake in several brain structures. Subsequent studies of muscarinic cholinergic binding site distribution showed a widespread loss of M1 sites, consistent with cholinergic cell loss. These alterations are similar to those reported in Alzheimer\'s disease, suggesting that the severe cognitive dysfunction in congenital OTC deficiency may at least partly result from a muscarinic cholinergic lesion. Possible mechanisms involved in the pathogenesis of cholinergic cell loss in congenital OTC deficiency include ammonia-induced inhibition of pyruvate and alpha-oxoglutarate oxidation, resulting in decreased synthesis of acetyl CoA and a cerebral energy deficit, as well as NMDA receptor-mediated excitotoxicity. Treatment of spf mice with acetyl-L-carnitine (ALCAR) results in partial recovery of the developmental choline acetyltransferase deficit, suggesting a potential therapeutic benefit of ALCAR in congenital OTC deficiency. Other therapies currently used include ammonia-lowering strategies (using sodium benzoate or sodium phenylacetate) and, in severe cases, liver transplantation."\n')

('Effects of naltrexone on lipopolysaccharide-induced sepsis in rats.,"Naltrexone, an opioid antagonist, has been reported to possess an anti-inflammatory effect via blockade of opioid receptor. The aim of this study is to evaluate the protective effect of naltrexone on LPS-induced septic shock in rats. Sepsis was induced by administration of LPS (10 mg/kg, i.v.) in anesthetized rats. Results demonstrated that pretreatment with naltrexone (10 mg/kg, i.v.) significantly ameliorated hypotension and bradycardia of rats 6 h after LPS administration. In isolated blood vessel, study showed that pretreatment with naltrexone significantly improved norepinephrine-induced vasoconstriction and ACh-induced vasorelaxation in aorta of endotoxemic animals. Naltrexone significantly reduced the elevation of serum glutamate-oxalacetate transaminase and glutamate-pyruvate transaminase (as index of hepatic function) induced by LPS. The infiltration of polymorphonuclear neutrophils into liver 48 h after LPS treatment in mice was also reduced by naltrexone. On the other hand, naltrexone significantly decreased the levels of plasma TNF-alpha and inhibited overproduction of superoxide anions in aortic rings. However, naltrexone did not suppress the overproduction of NO (measured by its metabolites nitrite/nitrate in plasma) and iNOS expression in lungs induced by LPS. In in vitro study, naltrexone did not attenuate non-enzymatic iron-induced lipid peroxidation in rat brain homogenates. In conclusion, pretreatment with naltrexone significantly improved circulatory failure and hepatic dysfunction in sepsis. These effects were associated with reduction of TNF-alpha levels and superoxide anion formation, which may be attributed to antagonism of opioid receptors."\n')

('Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress.,"The term \'\'adrenergic\'\' originates from \'\'adrenaline\'\' and describes hormones or drugs whose effects are similar to those of epinephrine. Adrenergic stress is mediated by stimulation of adrenergic receptors and activation of post-receptor pathways. Critical illness is a potent stimulus of the sympathetic nervous system. It is undisputable that the adrenergic-driven \'\'fight-flight response\'\' is a physiologically meaningful reaction allowing humans to survive during evolution. However, in critical illness an overshooting stimulation of the sympathetic nervous system may well exceed in time and scope its beneficial effects. Comparable to the overwhelming immune response during sepsis, adrenergic stress in critical illness may get out of control and cause adverse effects. Several organ systems may be affected. The heart seems to be most susceptible to sympathetic overstimulation. Detrimental effects include impaired diastolic function, tachycardia and tachyarrhythmia, myocardial ischemia, stunning, apoptosis and necrosis. Adverse catecholamine effects have been observed in other organs such as the lungs (pulmonary edema, elevated pulmonary arterial pressures), the coagulation (hypercoagulability, thrombus formation), gastrointestinal (hypoperfusion, inhibition of peristalsis), endocrinologic (decreased prolactin, thyroid and growth hormone secretion) and immune systems (immunomodulation, stimulation of bacterial growth), and metabolism (increase in cell energy expenditure, hyperglycemia, catabolism, lipolysis, hyperlactatemia, electrolyte changes), bone marrow (anemia), and skeletal muscles (apoptosis). Potential therapeutic options to reduce excessive adrenergic stress comprise temperature and heart rate control, adequate use of sedative/analgesic drugs, and aiming for reasonable cardiovascular targets, adequate fluid therapy, use of levosimendan, hydrocortisone or supplementary arginine vasopressin."\n')

('Quinolinic acid accumulation during neuroinflammation. Does it imply excitotoxicity?,"It is often proposed that quinolinic acid (QUIN) contributes to the pathophysiology of neuroinflammation because this kynurenine pathway metabolite is a selective agonist of N-methyl-D-aspartate (NMDA) receptors, and both its brain tissue and cerebrospinal fluid concentrations increase markedly with inflammation. However, whether or not the extracellular levels of QUIN reached during neuroinflammation are high enough to promote excitotoxicity, remains unclear because QUIN is a weak NMDA receptor agonist. We have addressed this issue by evaluating the extracellular concentrations of QUIN that must be reached to initiate potentially excitotoxic changes in the cerebral cortex of rats, under normal conditions, and when superimposed on another insult. We have also examined the increase in extracellular lactate associated with the perfusion of increasing concentrations of QUIN through a microdialysis probe. The extracellular EC50 for induction of local depolarisation was 228 microM with QUIN alone; that is, about 30 times the levels of QUIN measured previously in immune activated brain. Furthermore, at least 20 microM extracellular QUIN needed to be reached to reduce K+ induced spreading depression, an unexpected effect since spreading depression is inhibited by NMDA receptor antagonists. Our data suggest that, although synthesis of QUIN from activated microglia and invading macrophages can increase its extracellular concentration 10-100-fold, the levels that are reached in these conditions remain far below the concentrations of QUIN that are necessary for excessive NMDA receptor activation. However, the possibility that QUIN accumulation may be a deleterious feature of neuroinflammation cannot be ruled out at this stage."\n')

('alpha7-cholinergic receptor mediates vagal induction of splenic norepinephrine.,"Classically, sympathetic and parasympathetic systems act in opposition to maintain the physiological homeostasis. In this article, we report that both systems work together to restrain systemic inflammation in life-threatening conditions such as sepsis. This study indicates that vagus nerve and cholinergic agonists activate the sympathetic noradrenergic splenic nerve to control systemic inflammation. Unlike adrenalectomy, splenectomy and splenic neurectomy prevent the anti-inflammatory potential of both the vagus nerve and cholinergic agonists, and abrogate their potential to induce splenic and plasma norepinephrine. Splenic nerve stimulation mimics vagal and cholinergic induction of norepinephrine and re-establishes neuromodulation in alpha7 nicotinic acetylcholine receptor (alpha7nAChR)-deficient animals. Thus, vagus nerve and cholinergic agonists inhibit systemic inflammation by activating the noradrenergic splenic nerve via the alpha7nAChR nicotinic receptors. alpha7nAChR represents a unique molecular link between the parasympathetic and sympathetic system to control inflammation."\n')

There are many more available, i am trying to implement a better scoring system which will help in better selection.


I am also very happy to say that @Ben H will be also helping out with the execution of additional machine learning techniques that may help for creating hypotheses to the origin(s) of ME/CFS. Thank you @Ben H !

 

[lansbergen]

Thus, vagus nerve and cholinergic agonists inhibit systemic inflammation by activating the noradrenergic splenic nerve via the alpha7nAChR nicotinic receptors. alpha7nAChR represents a unique molecular link between the parasympathetic and sympathetic system to control inflammation.

The immunemodulator I use is a alpha7nAChR agonist.

 

[lansbergen]

The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042938/

Thus, vagus nerve and cholinergic agonists inhibit systemic inflammation by activating the noradrenergic splenic nerve via the alpha7nAChR nicotinic receptors. alpha7nAChR represents a unique molecular link between the parasympathetic and sympathetic system to control inflammation.

The immunemodulator I use is a alpha7nAChR agonist.

 

[lansbergen]

Thus, vagus nerve and cholinergic agonists inhibit systemic inflammation by activating the noradrenergic splenic nerve via the alpha7nAChR nicotinic receptors. alpha7nAChR represents a unique molecular link between the parasympathetic and sympathetic system to control inflammation.

The immunemodulator I use is a alpha7nAChR agonist.

More presice, a positive allosteric modulator.

In other words , levamisole is a key for the a7nAChR backdoor.

 

[lansbergen]

More presice, a positive allosteric modulator.

In other words , levamisole is a key for the a7nAChR backdoor.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162128/
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor- targeted therapeutics: advantages and limitations

 

[mariovitali]

Here is an update with the latest results.


The latest runs suggest a central role for glutamate metabolism. Glutamate has been found to be elevated in ME patients from some ME/CFS researchers. Also, we have new entries for Nitric Oxide metabolism and signalling, L-Arginine and vasoconstriction.

Regarding L-Arginine, I was very happy to read that there is upcoming research on this area by Dr Mercedes Rincon,I will definitely be watching this one :

Dr Mercedes Rincon is a Professor of Medicine, Division of Immunobiology Medicine at the University of Vermont. Her project is called “Exploring an Anti-Citrullinated Antibody Signature in MECFS”. This project seeks to argue that ME/CFS is not only an inflammatory disease, but that a subpopulation of patients possess a ME/CFS-specific antibody to a protein which has an abnormal switch of one amino acid (arginine) with another (citrulline). This will be done by measuring antibodies specific to citrullinated proteins from blood serum samples provided by the UK ME/CFS Biobank.

https://cureme.lshtm.ac.uk/researchers/our-collaborative-researchers/

Regarding Glutamate metabolism, an email was sent to Professor Bergquist for possible existence of hypoxanthine,xanthine and uric acid in cerebrospinal fluid. More specifically, this paper was sent to him :

Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases.
Stover JF1, Lowitzsch K, Kempski OS.
Author information
Abstract
Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase. Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls. Lactate is only elevated in meningitis. Normal lactate dehydrogenase (LDH) levels and absent correlation between the albumin ratio and neurochemical parameters exclude an artificial increase due to cell lysis and barrier damage. Absent correlation between neurochemical parameters within each patient group is most likely related to preserved glial and neuronal uptake mechanisms. CSF hypoxanthine, xanthine, and uric acid levels appear superior to lactate in reflecting glutamate-mediated excitotoxicity in neurological patients.

In his very kind and immediate reply, he explained that he will look more into this once he is back from his vacations.

Here are the latest results, depicting the features selected by certain feature selection methods. You will find many known entries :

pns = parasympathetic nervous system
crh = corticotropin-releasing hormone






Hypoperfusion, brainstem and the vagus nerve are still being selected in the highest positions (VanElzakker). Observe how nitric oxide and vasoconstriction are part of some results. Entries relevant to inflammation appear frequently.
@wigglethemouse you may also see BDNF in the results . I still do not understand why norepinephrine and epinephrine are part of the results.

Regarding indoleamine and kynurenine : they continue to be identified by network analysis as important "pieces of the puzzle" however i postulate that the reason is ultimately glutamate metabolism and the connection with quinolinic acid (Dr Phair is aware of this connection) :

 

[wigglethemouse]

Good stuff @mariovitali . Can you explain the three groupings in your screenshot - not the results, but what are the groupings showing - Chi Square, Consistency Evaluator, Information Gain.

 

[mariovitali]

Good stuff @mariovitali . Can you explain the three groupings in your screenshot - not the results, but what are the groupings showing - Chi Square, Consistency Evaluator, Information Gain.

These are all feature selection methods. They are aimed to select features with high importance for the problem at hand. In this application we wish to identify which features (where a feature can be any biological concept) are relevant to ME symptoms.

I tend to use several tools and combine different methods. The one shown is from a Data Mining tool called "Weka".To anyone interested, here is a description of some feature selection methods :

https://www.matec-conferences.org/articles/matecconf/pdf/2016/05/matecconf_iccma2016_06002.pdf

 

[wigglethemouse]

@mariovitali In Alain Moreau's Stanford Symposium presentation he showed this slide where 3 out of 4 twin families showed a mutation in SLC1A2 related to Glutamate clearance in the brain. Glutamate keeps popping up!

 

[mariovitali]

@wigglethemouse Thank you for this "catch". I think it is also interesting that Na,K ATP-Ase is associated with SLC1A2 aka EAAT2 aka GLT-1 :

https://en.wikipedia.org/wiki/Excitatory_amino_acid_transporter_2

GLT-1, the major glutamate transporter, is expressed at perisynaptic astrocytic processes (PAP) and axon terminals (AxT). GLT-1 is coupled to Na+/K+-ATPase (NKA) α1–3 isoforms, whose subcellular distribution and spatial organization in relationship to GLT-1 are largely unknown. Using several microscopy techniques, we showed that at excitatory synapses α1 and α3 are exclusively neuronal (mainly in dendrites and in some AxT), while α2 is predominantly astrocytic.

https://academic.oup.com/cercor/article-abstract/29/8/3331/5107846?redirectedFrom=fulltext

EDIT : The above possibly refers to mice

 

[mariovitali]

Dear all,


Here is the latest update. cc @wigglethemouse , @Perrier @Ben H , @rvallee , @ScottTriGuy


I believe that significant progress has been made ( meaning for symptoms related to myself ,so n=1 !). In order to better understand how is all connected i've been crashing myself purposely to perform root cause analysis.

For this reason - with a little help from technology - i am trying to identify how different promising research targets (hypoperfusion, sepsis, inflammatory response,hypoxia, glutamate and others etc) fit the picture. I would like to provide a small example of the work i've been doing. Please see below :



The map shows a learned network of interactions between these topics using machine learning(the best way to put it). Observe how inflammatory response is connected with sepsis and the gut / albumin. Why the connection with albumin ? Perhaps because inflammation lowers albumin levels. My first question is : Do we find hypoalbuminemia or even hyperalbuminemia to ME patients ?

We next see the connection with "ckd" which is chronic kidney disease, a topic which i have mentioned many times. Here is where eGFR may be coming to the picture. Do ME patients are found with significantly lower eGFR than Healthy controls? We move through ckd to angiotensin, endothelin to vasoconstriction which leads (?) to hypoxia and hypoperfusion (?).

Please note, this is just an example of the tools that we already have and no one is currently using. These tools are supposed to work with the help and guidance of medical professionals.

I hypothesise the following for further research :

a) The Inflammatory response is a key piece of the puzzle. Proposed topics here are IL-6 and TNF-α
b) The same applies for glutamate/kynurenine metabolism. The common factor of these two is excitotoxicity and tinnitus may be related to vasocontriction / hypoxia/ excitotoxicity or even hypoperfusion
c) Metabolism of Nitric oxide : more work is needed here

I can induce the perfect storm if i eat too much protein (whey protein has a negative effect too), Parmesan cheese (contains glutamate) and many other glutamate sources. Please have a look here :


https://www.msgtruth.org/what-foods-should-i-avoid


and also the "Umami" database :


https://www.umamiinfo.com/umamidb/search/

I cannot really suggest you try a glutamate-full diet because it may induce a severe crash (if the theory is applicable). Whatever i write here is not a suggestion to try but for informational purposes only.

I move on to -yet- another available tool that is not currently being used to speed things up. I will provide an example based on the above. As discussed, inflammatory response may be a key topic related to ME pathology. Imagine being a researcher and you wish to see which compounds have an effect on ameliorating the inflammatory response. At the moment of writing, "inflammatory response" has 72479 entries on PUBMED. Using an Information Extraction tool, we are getting the following excerpts which contain (almost) exactly what we need.

**************************************************** : Improvement**********************************************

. Magnesium sulfate (MgSO4) has been known to ameliorate maternal, fetal and gestational tissue-associated inflammatory response.

**************************************************** : Improvement**********************************************

. Resveratrol significantly improved kidney function and lowered serum and kidney tissue inflammatory cytokine levels. Consistently, resveratrol prevented endotoxin-induced disruption of endothelial cell permeability and inhibited inflammation of kidney tissue.

**************************************************** : Improvement**********************************************

. In these patients N-acetyl cysteine and vitamin administration can be considered as an effective method for improvement of oxidative status.

**************************************************** : Improvement**********************************************

. CONCLUSIONS: IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically ill patients.

**************************************************** : Improvement**********************************************

, patients improved after therapy with high-dose thiamine.

**************************************************** : Improvement**********************************************

. Oral or parenteral therapy with high-dose thiamine was started. RESULTS: The therapy led to an appreciable improvement of fatigue.

**************************************************** : Improvement**********************************************

. Inhibition of arginase with an arginase-specific inhibitor, N(omega)-hydroxy-nor-L-arginine, ameliorates the DNCB-induced inflammatory response. Our results demonstrate that HPV16.

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. From these results, we conclude that supplementation of EGCG improves glucose tolerance, insulin sensitivity, and endothelial function.

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. CONCLUSION: These findings suggest that treating infants undergoing CPB with a lipid emulsion containing omega-3 improves fatty acid status and results in a lower inflammatory response after surgery.

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. The restoration of their levels by either exogenous administration of these mediators or feeding omega-3-enriched diets, improves the inflammatory status of adipose tissue and ameliorates metabolic dysfunction.

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. However, the human data are inconclusive as to whether omega-3 PUFA supplementation at this dosage is effective in attenuating the inflammatory and immunomodulatory response to exercise and improving exercise performance.

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. Acetyl-L-carnitine treatment decreases the severity of mental and physical fatigue, depression cognitive impairment and improves health-related quality of life.

The list above is not the complete output. The extraction of this information from 72479 PUBMED abstracts required a total runtime of 1 minute and 24 seconds.