Unfolded Protein Response and A Possible Treatment for CFS

[alex3619]

When it comes to mitochondrial proteins there is an issue that some are made in the mitochondria, and some in the rest of the cell and are imported unfolded then folded inside the mitochondria. This might be important, and is the basis for why I say we might have aconitase deficiency.

 

[adreno]

It is my belief that the microbiome plays a huge role in the pathogenesis of ME. This article looks very interesting, as it examines links between bacteria and the UPR:

Nat Rev Microbiol. 2015 Feb;13(2):71-82.

Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?

Celli J1, Tsolis RM2.

Abstract

The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER), which also invokes innate immune signalling in response to invading microorganisms. Although it has been known for some time that the UPR is modulated by various viruses, recent evidence indicates that it also has multiple roles during bacterial infections. In this Review, we describe how bacteria interact with the ER, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR contributes to innate immune responses against invading bacteria.

EDIT: found the full text here:
http://www.immunology-allergy.org/immunoblog/wp-content/uploads/2015/01/celli2014.pdf


List of bacterial pathogens that induce or modulate UPR:

 

[mariovitali]

@adreno

I am currently researching what happens with Orthostatic Intolerance. I had OI too and interestingly, my analysis has shown that prior to OI i had pain at the base of my neck, right hand side. I know i sound strange but bare with me.

I coded a special software that connects to PubMed and donwloads the text from PubMed articles in a CSV format. So far i've downloaded data for the following Topics of interest :

3betahsd.csv
5alphareductase.csv
adrenal_hyperplasia.csv
adrenal_insufficiency.csv
allopregnanolone.csv
amyloidosis.csv
atrial_fibrillation.csv
calcium_homeostasis.csv
car.csv
choline_deficiency.csv
coenzymeq10.csv
creatine_supplementation.csv
curcumin.csv
cyp1a1.csv
cyp1a2.csv
cyp2e1.csv
cyp3a4.csv
d-limonene.csv
dht.csv
dihydroprogesterone.csv
dolichol.csv
er_stress.csv
excitotoxicity.csv
freet3.csv
ginkgo.csv
glutamate.csv
gluten_intolerance.csv
glycosylation.csv
hmgcoa.csv
hpa_axis.csv
hsp70.csv
hydroxysteroid_dehydrogenase.csv
l_carnitine.csv
lipoic_acid.csv
mitochondrial_dysfunction.csv
monosodium_glutamate.csv
mthfr.csv
nadh_human.csv
nadph_human.csv
neurite_outgrowth.csv
orthostatic_intolerance.csv
oxidative_stress_markers.csv
oxidative_stress_protection.csv
p450oxidoreductase.csv
p450scc.csv
peroxynitrite.csv
phenylketonuria.csv
pregnenolone.csv
pxr.csv
rar.csv
resveratrol.csv
rxr.csv
selenium.csv
selenium_deficiency.csv
sensorineural_loss.csv
star.csv
steroidogenesis_human.csv
subclinicalhypo.csv
taurine.csv
testosterone_production.csv
tetrahydrobiopterin.csv
tocotrienol.csv
triiodothyronine_levels.csv
udpgluc.csv
upr.csv
vitamin_d3.csv
zinc_supplementation.csv

As an example, upr.csv (shown in blue above) is a file that contains all articles from PubMed regarding Unfolded Protein Response (UPR) and at the moment of writing it consists of 5153 entries.

So what we can do next, is to see the proportion of a Topic of interest (e.g Orthostatic Intolerance) to all of the Topics that i downloaded from PubMed. So for OI i had the following results :

amyloidosis.csv : 0.45 %
adrenal_insufficiency.csv : 0.23 %
sensorineural_loss.csv : 0.21 %
5alphareductase.csv : 0.12 %
atrial_fibrillation.csv : 0.12 %
ginkgo.csv : 0.11 %
cyp3a4.csv : 0.08 %
coenzymeq10.csv : 0.07 %
hpa_axis.csv : 0.07 %
adrenal_hyperplasia.csv : 0.07 %
creatine_supplementation.csv : 0.06 %
calcium_homeostasis.csv : 0.05 %
triiodothyronine_levels.csv : 0.04 %
subclinicalhypo.csv : 0.04 %
mitochondrial_dysfunction.csv : 0.04 %
dht.csv : 0.03 %
steroidogenesis_human.csv : 0.02 %
cyp1a2.csv : 0.02 %
gluten_intolerance.csv : 0.02 %
er_stress.csv : 0.02 %
freet3.csv : 0.02 %
pregnenolone.csv : 0.01 %
curcumin.csv : 0.01 %
oxidative_stress_markers.csv : 0.01 %
testosterone_production.csv : 0.01 %
hydroxysteroid_dehydrogenase.csv : 0.01 %
vitamin_d3.csv : 0.01 %
p450oxidoreductase.csv : 0.01 %
glycosylation.csv : 0.01 %
taurine.csv : 0.01 %
glutamate.csv : 0.01 %
hsp70.csv : 0.01 %
nadph_human.csv : 0.00 %
selenium.csv : 0.00 %
3betahsd.csv : 0.00 %
choline_deficiency.csv : 0.00 %
zinc_supplementation.csv : 0.00 %
dolichol.csv : 0.00 %
dihydroprogesterone.csv : 0.00 %
cyp2e1.csv : 0.00 %
rar.csv : 0.00 %
rxr.csv : 0.00 %
cyp1a1.csv : 0.00 %
tetrahydrobiopterin.csv : 0.00 %
hmgcoa.csv : 0.00 %
upr.csv : 0.00 %
lipoic_acid.csv : 0.00 %
resveratrol.csv : 0.00 %
car.csv : 0.00 %
p450scc.csv : 0.00 %
d-limonene.csv : 0.00 %
nadh_human.csv : 0.00 %
excitotoxicity.csv : 0.00 %
allopregnanolone.csv : 0.00 %
monosodium_glutamate.csv : 0.00 %
neurite_outgrowth.csv : 0.00 %
mthfr.csv : 0.00 %
peroxynitrite.csv : 0.00 %
pxr.csv : 0.00 %
phenylketonuria.csv : 0.00 %
udpgluc.csv : 0.00 %
star.csv : 0.00 %
selenium_deficiency.csv : 0.00 %
l_carnitine.csv : 0.00 %
oxidative_stress_protection.csv : 0.00 %
tocotrienol.csv : 0.00 %

Recall that in a previous link i posted, the authors suggest that CFS is a kind of Amyloidosis :

This pilot investigation demonstrated that the CFS, PGI and FM subjects had a significant overlap between their syndromes. Despite the differences in their original case designations, they had very similar responses on questionnaire, quality of life and nociceptive measures. Again, despite the differences in the diagnostic label applied to them for study entry, their cerebrospinal fluid proteomes demonstrated reproducible constituents. The CFS-related proteome was essentially the same for the two independent CFS cohorts. The proteome was remarkable for the number of proteins associated with protein misfolding and cerebrovascular amyloidosis syndromes.
These included gelsolin, amyloid β protein (APLP1), Igλ ,C3, C4, chromogranin B,α2-macroglobulin and α 1-antichymotrypsin antiproteases, the heme and iron scavengers haptoglobin, hemopexin, and orosomucoid 2, angiogenic and antiangiogenic prohormones such as autotaxin and PEDF, and the structural proteins gelsolin, BEHAB and keratin 16. Their presence in the CFS – associated proteome suggested a potential pathophysiological link. We propose the hypothesis that CFS may be a nonlethal, protein – misfolding, cerebrovascular amyloidosis –like syndrome.

http://link.springer.com/article/10.1186/1471-2377-5-22



Upon further inspection i found this link : http://archneur.jamanetwork.com/article.aspx?articleid=567282

PRIMARY amyloidosis is a multisystem disease which may present in myriad ways such as congestive heart failure, purpura, gastrointestinal disturbances, and nephrotic syndrome.1-3 Involvement of the autonomic and peripheral nervous system may also occur. A case of primary amyloidosis is reported in which severe orthostatic hypotension and the restless leg syndrome were the initial manifestations. The restless leg syndrome has not previously been reported in primary amyloidosis. Diagnostic difficulties in this disease, even when its presence is suspected, are emphasized.

You will find both side effects (OI and RLS) in the list of Problems i experienced.

 

[mariovitali]

Here is another type of Analysis that goes through a specific subject. The software was run on 24560 entries regarding 'Amyloidosis' on PubMed.

I marked in red fonts potentially interesting keywords, please let me know what i missed.

Here are the most Frequently Occurring words :

['patient', 'amyloidosis', 'amyloid', 'disease', 'study', 'protein', 'renal', 'treatment', 'result', 'association', 'cases', 'clinical', 'show', 'deposits', 'deposition', 'diagnosis', 'systemic', 'increase', 'years', 'case', 'cause', 'found', 'ttr', 'cardiac', 'serum', 'tissue', 'therapy', 'fibrils', 'al', 'level', 'mutation', 'suggest', 'primary', 'cells', 'biopsy', 'ad', 'light', 'type', 'present', 'mice', 'abeta', 'beta', 'cerebral', 'finding', 'cell', 'observation', 'familial', 'syndrome', 'age', 'aa', 'proteins', 'reveal', 'gene', 'involvement', 'plasma', 'group', 'liver', 'secondary', 'symptom', 'disorder', 'formation', 'brain', 'fap', 'report', 'failure', 'caa', 'inflammation', 'multiple', 'chronic', 'common', 'heart', 'reported', 'months', 'methods', 'analysis', 'human', 'different', 'normal', 'lesions', 'function', 'demonstrate', 'chain', 'investigate', 'transplantation', 'evaluate', 'presence', 'effect', 'rare', "alzheimer's", 'myeloma', 'reduction', 'monoclonal', 'compared', 'high', 'condition', 'performed', 'response', 'significant', 'including', 'form', 'data', 'siginificant', 'role', 'severe', 'changes', 'transthyretin', '+/', 'fmf', 'blood', 'survival', 'presented', 'features', 'decrease', 'fibril', 'mechanism', 'characterized', 'evidence', 'risk', 'early', 'complication', 'saa', 'related', 'polyneuropathy', 'induction', 'developed', 'identified', 'bone', 'angiopathy', 'important', 'examination', 'time', 'development', 'kidney', 'vascular', 'plaques', 'specific', 'improve', 'concentration', 'inhibitor', 'factor', 'small', 'diagnosed', 'higher', 'localized', 'dialysis', '10', 'described', 'activity', 'left', 'several', 'positive', 'new', 'control', 'among', 'seen', 'imaging', 'fever', 'mean', 'conclusion', 'factors', 'amyloidogenic', 'system', 'major', 'bind', 'four', 'immunoglobulin', 'detected', 'background', 'staining', 'pathogenesis', 'peripheral', 'red', 'respectively', 'acid', 'conclusions', 'structure', 'proteinuria', 'onset', 'forms', 'review', 'molecular', 'congo', 'hereditary', 'diagnostic', 'variant', 'lower', 'involved', 'beta2m', 'groups', 'dysfunction', 'infection', 'model', 'peptide', 'acute', 'expression', 'known', 'pathology', 'precursor', 'nephrotic', 'previously', 'less', 'controls', 'subjects', 'number', 'confirmed', 'affected', 'skin', 'indicator', 'microscopy', 'chains', 'considered', 'death', 'genetic', 'addition', 'ventricular', 'mass', 'median', 'possible', 'hemorrhage', 'examined', 'senile', 'pulmonary', 'low', 'neuropathy', 'use', 'vessels', 'organs', 'rate', 'often', 'shown', '12', 'cardiomyopathy', 'family', 'progressive', 'based', 'manifestations', 'hemodialysis', 'history', 'biopsies', 'diffuse', 'prevention', 'process', 'followup', 'pathological', 'total', 'aggregation', 'organ', 'mouse', 'obtained', 'types']

These are frequently occurring 2-word phrases :

[('epidermolysis', 'bullosa'), ('bence', 'jones'), ('ligamentum', 'flavum'), ('pyoderma', 'gangrenosum'), ('magnetic', 'resonance'), ('polymyalgia', 'rheumatica'), ('dimethyl', 'sulfoxide'), ('vena', 'cava'), ('ankylosing', 'spondylitis'), ('carpal', 'tunnel'), ('gelatinous', 'droplike'), ('congo', 'red'), ('enzymelinked', 'immunosorbent'), ('corpora', 'amylacea'), ('polyarteritis', 'nodosa'), ('tracheobronchopathia', 'osteochondroplastica'), ('escherichia', 'coli'), ('organomegaly', 'endocrinopathy'), ('pars', 'plana'), ('von', 'willebrand'), ('rotator', 'cuff'), ('circular', 'dichroism'), ('neurofibrillary', 'tangles'), ('hematoxylin', 'eosin'), ('positron', 'emission'), ('erythrocyte', 'sedimentation'), ('constrictive', 'pericarditis'), ('potassium', 'permanganate'), ('substantia', 'nigra'), ('cyanogen', 'bromide'), ('choroid', 'plexus'), ('white', 'matter'), ('carbon', 'dioxide'), ('nonhuman', 'primates'), ('lupus', 'erythematosus'), ('autosomal', 'dominant'), ('95%', 'ci'), ('beta2', 'microglobulin'), ('electrospray', 'ionization'), ('speckle', 'tracking'), ('mediterranean', 'fever'), ('ret', 'protooncogene'), ('bloodbrain', 'barrier'), ('lymph', 'nodes'), ('sound', 'speed'), ('atomic', 'force'), ('amino', 'acid'), ('ulcerative', 'colitis'), ('computed', 'tomography'), ('dentate', 'gyrus'), ('spongiform', 'encephalopathies'), ('bone', 'marrow'), ('heparan', 'sulfate'), ('lactate', 'dehydrogenase'), ('angina', 'pectoris'), ('plasminogen', 'activator'), ('orthostatic', 'hypotension'), ('ml/min/173', 'm2'), ("wegener's", 'granulomatosis'), ('ejection', 'fraction'), ('mayo', 'clinic'), ('250', 'words'), ('diabetes', 'mellitus'), ('cutis', 'laxa'), ('sodium', 'dodecyl'), ('penetrating', 'keratoplasty'), ('betapleated', 'sheet'), ('electron', 'microscopy'), ('relapsing', 'polychondritis'), ('multiple', 'myeloma'), ('lichen', 'amyloidosus'), ('bundle', 'branch'), ('seminal', 'vesicle'), ('cerebrospinal', 'fluid'), ('light', 'chain'), ("waldenstrom's", 'macroglobulinemia'), ('intervertebral', 'discs'), ('dodecyl', 'sulfatepolyacrylamide'), ('fractional', 'shortening'), ('per', 'cent'), ('cutis', 'dyschromica'), ('marginal', 'zone'), ('interventricular', 'septum'), ('confidence', 'interval'), ('nonsteroidal', 'antiinflammation'), ('nervous', 'system'), ('western', 'blotting'), ('sclerosing', 'cholangitis'), ('formalinfixed', 'paraffinembedded'), ('paired', 'helical'), ('isoelectric', 'focusing'), ('left', 'ventricular'), ('nephrotic', 'syndrome'), ('nausea', 'vomiting'), ('lymph', 'node'), ('undetermined', 'significance'), ('muscularis', 'mucosae'), ('post', 'mortem'), ('atopic', 'dermatitis'), ('proportional', 'hazards')]

And finally these words co-occur with the keyword symptom(s)

('presenting', 866.5096524553942)
('neurological', 772.2762548855774)
('signs', 698.9435666927636)
('patient', 289.90586308408376)
('neurologic', 253.52153931647996)
('depressive', 251.73294556963708)
('presented', 251.39168634597382)
('duration', 212.94034807790166)
('improve', 200.60981442928914)
('gi', 188.82830095338625)
('cardiac', 179.63319736005113)
('transient', 178.20810531046573)
('autonomic', 163.54396899962416)
('psychiatric', 156.57761508044254)
('constitutional', 154.81307674303332)
('relieve', 150.44690916876374)
('asymptomatic', 144.48725405858875)
('relief', 144.0213336604417)
('compressive', 143.20954696597454)
('articular', 141.80031323051634)
('include', 139.34490562559301)
('laboratory', 136.56279545509693)
('respiratory', 135.3202866965354)
('systemic', 132.35832261651734)
('irritative', 126.25252040686456)
('osteoarticular', 125.43630041553841)
('main', 121.97515109527137)
('neuropathic', 120.10820088772198)
('onset', 119.3996753418687)
('joint', 117.91946890300883)
('pain', 115.55754520798483)
('hyperviscosity', 112.6022054168799)
('variety', 112.12981714239208)
('ich', 109.15501127345127)
('musculoskeletal', 108.13239559494895)
('voiding', 106.46809904583034)
('obstructive', 102.32179306753571)
('peripheral', 99.58445575861668)
('obstruction', 99.28880688656801)
("patient'", 96.75104076409434)
('finding', 95.74842965887727)
('ocular', 94.69913158802767)
('congestive', 94.12017056650815)
('treatment', 94.05346228868284)
('sicca', 93.07283470039135)
('vague', 91.18039812030047)
('frequent', 89.6212133361129)
('airway', 85.5697164739694)
('multiple', 84.40164109794328)
('contiguous', 83.91124102292315)
('failure', 83.32709371910776)
('suggestive', 81.9842196516216)
('resolution', 80.6826780332079)
('nonspecific', 78.52130391057429)
('severity', 78.35109963894473)
('generally', 77.84188373282522)
('arthritic', 76.84665483828597)
('lobar', 76.04481926333682)
('disappeared', 73.18061612258498)
('improvements', 72.39118514944673)
('wm', 71.34320433575229)
('extracardiac', 69.22166743697038)
('commonest', 69.02235693568875)
('recognition', 68.89190833584587)
('depend', 68.10089115327328)
('intracerebral', 67.3568165455004)
('dyspnea', 66.8663376451934)
('hematuria', 66.39378143210095)
('major', 64.58379944951697)
('dementia', 63.94902301760966)
('began', 62.9060314347152)
('absence', 62.45685908732383)
('amyloidosis', 62.317972966801506)
('fap', 61.06675104079506)
('prominent', 59.45681608689503)
('gastrointestinal', 59.40553423946423)
('experienced', 58.88330504026102)
('occur', 58.40145340142964)
('included', 57.664638542191646)
('objective', 56.19653978860427)
('attributed', 54.81008602176934)
('somatic', 54.34565902054625)
('recurrence', 52.557840860325015)
('heart', 52.124510826092575)
('vary', 51.629912517883156)
('disease', 51.047198254600715)
('age', 50.850331826616426)
('cns', 48.465174010675895)
('free', 48.363642291466235)
('carpal', 45.63572183560114)
('hypotension', 45.545138097100605)
('bowel', 45.51016506445798)
('appearance', 45.26162738352566)
('occurred', 44.157236509739704)
('orthostatic', 44.14822385298535)
('presentation', 44.059741835625864)
('progressed', 43.84299847691282)
('gradually', 43.69227133184485)
('traps', 43.69227133184485)
('often', 43.59039824533978)
('generalized', 43.52158491902097)
('manifested', 42.81310249727264)
('dra', 42.65755913676014)
('develop', 42.449226804294725)
('time', 42.33443498305718)
('mild', 42.228231827432936)
('overt', 42.111514488331785)
('weight', 41.79193788418692)
('led', 41.55320800604645)
('rise', 41.3038888639461)
('addition', 41.30028365392767)
('radiological', 40.95237840870458)
('abdominal', 40.27084982428487)
('severe', 40.25947805122913)
('sensory', 39.4309821349042)
('appeared', 39.30746744504293)
('despite', 38.98176301642556)
('diagnostic', 38.957332841586776)
('started', 38.84652867672569)
('family', 37.00981833029585)
('admitted', 35.0531837391902)
('tract', 34.65718668629082)
('date', 34.58298297412455)
('characteristic', 34.37635818131166)
('died', 33.40448969767378)
('focal', 32.87868199194197)
('cts', 32.86950421168103)
('carriers', 32.25043421336713)
('motor', 32.2294623468319)
('primary', 32.13933492026396)
('like', 31.841364151444143)
('pressure', 31.526944431205155)
('echocardiographic', 31.47241342653175)
('present', 30.56959555715425)
('effective', 30.495976395149437)
('clinical', 30.167039026244638)
('familial', 29.955416396415977)
('common', 29.86903618473236)
('typical', 29.788356222240292)
('course', 29.126782087686383)
('neuropathy', 29.081884377145357)
('dialysisrelated', 28.646895016795767)
('variable', 28.41438348018319)
('required', 28.27628431724583)
('late', 28.09376579769072)
('evidence', 27.03713910458118)
('man', 26.907381065899656)
('combination', 26.822907090352647)
('arthritis', 26.65447759965051)
('unusual', 26.40478812898583)
('none', 25.963004363281346)
('marked', 25.809000616442454)
('chest', 25.540274674909526)
('markers', 25.43634843919623)
('recurrent', 25.42711911401034)
('years', 25.378149016921427)
('progression', 25.082789321781156)
('status', 24.777201012768813)
('organ', 24.670245922322284)
('consistent', 24.63733599215368)
('frequency', 24.504864764179555)
('appear', 24.240561289590275)
('history', 24.14140317264288)
('abnormalities', 24.118927556089815)
('progressive', 23.943595964160448)
('suggest', 23.519640947775486)
('developed', 23.497940975169058)
('lead', 23.274210754177332)
('surgical', 23.068695104731535)
('usually', 23.062817942934654)
('available', 23.034686862346575)
('upper', 22.95395608318161)
('20', 22.814939076715593)
('new', 22.37140505002751)
('attacks', 22.139576281828223)
('range', 21.960385317937764)
('risk', 21.868395544043477)
('skin', 21.58427011435665)
('weeks', 21.132143327179197)
('acute', 20.88010879340691)
('additional', 20.55955077215621)
('occurrence', 20.37364490997017)
('noted', 19.102641867393036)
('background', 18.862690151273146)
('individuals', 18.200154406023092)
('frequently', 17.7809154323763)
('even', 17.68398182696743)
('since', 17.396981664303212)
('early', 17.02108742852202)
('several', 16.88983729777334)
('cause', 16.740775977293268)
('13', 16.362036420462694)
('elevation', 16.172044960989744)
('aim', 16.170965615209262)
('initial', 16.089942501695347)
('mm', 16.085399710052254)
('inflammation', 16.055912961445916)
('nephrotic', 15.743833197127564)
('body', 15.614359417308753)
('fmf', 15.505319644914579)
('management', 15.332325076185953)
('stage', 15.206205849287784)
('dysfunction', 15.186457021230439)
('cognitive', 15.081356613251609)
('leading', 14.762549986388889)
('provide', 14.714231191916575)
('review', 14.518903275964313)
('development', 14.507291320028752)
('examination', 14.337581765135614)
('association', 14.311494519373163)
('proteinuria', 14.228555987520743)
('urinary', 13.56538506825945)
('ra', 13.535522021510662)
('four', 13.483089770686998)
('polyneuropathy', 13.1121179785315)
('autopsy', 13.051429713413436)
('followup', 13.046401236017179)
('related', 13.009343743941805)
('prevention', 12.99512155357543)
('fever', 12.877683570603843)
('manifestations', 12.82572088837906)
('cardiomyopathy', 12.642059171544556)
('left', 12.067008473680442)
('colchicine', 12.011964210086173)
('described', 11.905615493185476)
('10', 11.838986156553762)
('muscle', 11.804094032347553)
('localized', 11.628175961758913)
('hemorrhage', 11.626210726415486)
('median', 11.565562910292169)
('death', 11.252354306833382)
('transplantation', 11.219595735971367)
('therapy', 11.134064627759862)
('subjects', 11.062736199217106)
('woman', 10.855793270788553)
('six', 10.420553259720856)
('lower', 10.308309083692436)
('recent', 10.019176435794263)
('prognosis', 9.755343427868914)
('involvement', 9.50900026334092)
('diagnosis', 9.48064383619285)
('reported', 9.247189883601852)
('outcome', 9.033446957158255)
('abnormal', 9.01928243148388)
('conclusion', 8.723537145090672)
('obtained', 8.577342474618424)
('cases', 8.522259928745424)
('features', 8.1598685207972)
('evaluate', 7.907507216910268)
('low', 7.442936911796988)
('pulmonary', 7.31435877500717)
('considered', 6.962862753260849)
('indicator', 6.951784230898596)
('liver', 6.9400162462224735)
('affected', 6.907629200171508)
('specific', 6.790714822423938)
('less', 6.733522636663711)
('conclusions', 5.730460825325078)
('monoclonal', 5.655007601903815)
('complication', 5.462785899916192)
('result', 5.134230616691124)
('mean', 5.073293537257387)
('decrease', 5.0727939749613284)
('presence', 5.043033006211793)
('syndrome', 4.944868496122023)
('control', 4.74495594390072)
('disorder', 4.703676525638439)
('secondary', 4.443613453443694)
('+/', 4.390850945343706)
('dialysis', 4.3664297134193575)
('diagnosed', 4.262835555627195)
('group', 4.234951292367818)
('cerebral', 4.037012455392103)
('siginificant', 3.746383079161024)
('months', 3.7071625383954956)
('significant', 3.5259226004266377)
('rare', 2.759688131964044)
('survival', 2.3380232188423697)
('demonstrate', 2.1844266629199467)
('different', 1.9008578633084454)
('changes', 1.879839585232851)
('data', 1.6291085944780557)
('form', 1.599879893140944)
('including', 1.5602569555144976)
('condition', 1.4115288925264258)
('compared', 1.3651748350570454)
('reduction', 1.2167359025630624)
('show', 1.1499626309351036)
('myeloma', 1.0817958717896792)
('renal', 1.0762655277223416)
('mutation', 1.0739398089630496)
('effect', 0.9777184012564755)
('investigate', 0.8900587994809479)
('study', 0.7371896688967503)
('function', 0.6398747936306934)
('reveal', 0.6037049821853415)
('lesions', 0.5878274319791563)
('analysis', 0.5200128165297402)
('methods', 0.5163874247993396)
('ttr', 0.5150527522360067)
('chronic', 0.42078808041384974)
('aa', 0.35503896461369777)
('amyloid', 0.3383363287465375)
('found', 0.3097440633622215)
('observation', 0.28559500268323434)
('report', 0.2823486898707048)
('al', 0.19056031267243778)
('ad', 0.15473190314393603)
('type', 0.14249111403924752)
('plasma', 0.068773051622677)
('increase', 0.06792608016939328)
('gene', 0.057942048987213335)
('biopsy', 0.03771985128809541)
('case', 0.020768998005903372)

 

[adreno]

@mariovitali

So what do you make of this data?

 

[mariovitali]

I believe that the Researchers who saw CFS as a kind of Amyloidosis and discuss Unfolded Protein Response have hit Bull's Eye. The analysis shows (but of course can't confirm) that there are so many common features between Amyloidosis and CFS.

The same -possibly- applies for the Post-Finasteride Syndrome (PFS) and also for Permanent side effects of Accutane (Depression, Brain Fog, Neurological Problems).

The fact that i recovered from a Condition spanning more than 7 years is not a coincidence. I tried hundreds of Supplements and Medications, injected HCG for Hypogonadism, received Thyroid Medication...i was a mess. And within 2 months everything normalized.

I am running several other types of Analysis and i will post them here to discuss.

 

[adreno]

It seems to me that UPR is a feature, rather than a cause, of many human inflammatory and autoimmune diseases. There may be several pathways leading to this. Also, it might not be equally easy for everyone to normalize the UPR. In particular because we don't know what causes it in ME.

 

[mariovitali]

The initial results from people i talk to are very promising and I will try to have them write here their first impressions.

Regarding the possibilty of people feeling better with this regimen i am very optimistic and the reason is that i started having problems since 1999 (that was my first crash with Finasteride and what triggered CFS) and i got cured.

If it was possible to overcome this after so many years of problems, i believe ther are very good chances for others living a normal life as well.

 

[mariovitali]

I would like to explain to you why whenever i made the decision to change to a more Healthy Lifestyle my Health was deteriorating even more. I was "lucky" to have a feedback mechanism that would signal the beginning of Side Effects : I would get short Tinnitus (2-3 seconds) in one of my ears (usually the left one) and then problems would begin :

-Loss of Libido
-Impotence
-Neurological Problems
-Depression
-Anxiety
-Orthostatic Intolerance
-Thyroid Problems

..and the list goes on.

At some point I had Thyroid problems and somewhat elevated total Cholesterol. My Endo told me that i should stop eating Foods High in Cholesterol, Exercise and lose weight.

So, i decided to change my Lifestyle as follows :

a) Eliminate Foods High in Cholesterol
b) Go to Gym 3 times a day
c) Eliminate too much Sugar and Carbohydrates from my Diet and focus on eating Protein and Vegetables
d) Taking Whey Protein after Gym
e) When i wanted something sweet i would have Sugarless Chewing Gum (with Aspartame)

It was at that particular time (apart from when i stopped taking Propecia for my hairloss) when i saw my Health deteriorating with Tinnitus incidents hitting me almost every day. Let's see why :


a) Foods high in Cholesterol and Sugar boost HmG-CoA activity which is beneficial for us. When i decided to change my diet (=eliminate Sugar and too much Cholesterol) i also stopped HmG-CoA activity, which made me feel worse.

b) Intense Exercise and Resistance Training increases Oxidative Stress.

c) Whey Protein possibly overloaded my Body with Proteins that could not be properly folded (?)

d) Aspartame further impaired my problematic BH4 Production due to my GCH1 Mutation

So This lifestyle resulted in feeling even more fatigued! I was trying to say this to Doctors and they wouldn't believe me. Instead when i was eating Food high in Cholesterol, Sweets/Cakes and wasn't exercising i was feeling great!

It all now makes sense.

 

[Ema]

Possibly saffron might help?

J Immunol. 2011 Nov 1;187(9):4788-99. doi: 10.4049/jimmunol.1004111. Epub 2011 Sep 30.
Neuroinflammation and endoplasmic reticulum stress are coregulated by crocin to prevent demyelination and neurodegeneration.
Deslauriers AM1, Afkhami-Goli A, Paul AM, Bhat RK, Acharjee S, Ellestad KK, Noorbakhsh F, Michalak M, Power C.
Author information

Abstract
Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1-expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1-expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.

 

[mariovitali]

@Ema

Yes it could help. Very interesting, Thanks Ema.

 

[adreno]

Possibly saffron might help?

It seems crocin is even available in tablet form:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637903/

 

[Ema]

It seems crocin is even available in tablet form:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637903/

Is it possible that crocin equals Tylenol/acetaminophen? Or are these two different substances with the same name?

"Crocin is an analgesic and an anti-pyretic drug that goes under several brand names depending on the country that it is being marketed. In Brazil, Canada and South Korea and in the United States, Crocin is called Tylenol and Panadol. In the United Kingdom and in India it is called Crocin. Corcin contains paracetamol, which is also called acetaminophen in North America. Crocin is produced mainly in India and leads the market in its production."

 

[adreno]

Is it possible that crocin equals Tylenol/acetaminophen? Or are these two different substances with the same name?

They must be different. Quite confusing...seems crocin is both an ingredient as well as a product name.

 

[JPV]

I think that Crocin happens to also be a brand name for an unrelated Indian Acetaminophen product.

 

[mariovitali]

More info on Crocin :

Crocin is a natural carotenoid chemical compound that is found in the flowers crocus and gardenia.[1] It is the diester formed from the disaccharide gentiobiose and the dicarboxylic acid crocetin. It has a deep red color and forms crystals with a melting point of 186 °C. When dissolved in water, it forms an orange solution.

Crocin is the chemical ingredient primarily responsible for the color of saffron.

http://en.wikipedia.org/wiki/Crocin

 

[JPV]

I just noticed that Cort posted this in the newsletter back in 2010. Judging by the lack of comments, it didn't seem to generate much interest at the time...

Proteins on the Brain’: A Breakthrough for ME/CFS?

In 2008 I participated in Dr. Baraniuk’s spinal tap study at Georgetown University in Washington, D.C. Some readers mayamyloids, CFS and the brain remember how exciting Dr. Baraniuk’s first proteome study was; it was the easy winner of the 2006 Phoenix Rising Paper of the Year. The study suggested that chronic fatigue syndrome (ME/CFS) patients had unusual proteins in their cerebral spinal fluid.

These results suggested that clumps of abnormally folded proteins could be causing small punctures in the blood vessels of ME/CFS patients brains. These punctures, in turn, could cause blood to leak out into the brain causing the symptoms of ME/CFS. This, the first attempt at finding a protein (as opposed to gene) signature, was stunningly successful in its ability to clearly elucidate a possible cause of chronic fatigue syndrome.

Unique Protein Signature? – These proteins consisted of the following:

• two proteins suggesting a protease antiprotease imbalance is present. This implicates increased production of elastase, an enzyme Dr. De Meirleir believes plays a role.
• several proteins suggesting small amounts of bleeding in the brain could be caused by the aggregation of proteins (amyloids) in the blood vessesl.
• Another protein suggests increased free radical production is present
• Another suggests that problems with the vasoconstriction of the blood vessels and damage to the cells lining the blood vessels (the endothelial cells).
• Another protein is associated with inflammation
• One protein suggesting altered rates of cell suicide (apoptosis) are present

Amyloid Proteins: The amyloidic proteins appear to be the key elements of the protein signature; the inflammation, hemorrhagic elements, increased cell death and free radical production could all derive from the body’s attempt to recover from damage done by amyloid proteins in the brain and CFSamyloidic proteins bunching up, impeding blood flow and finally puncturing the blood vessel walls in the brain.

Amyloid proteins are proteins that generally get folded improperly as they are being made. Since shape in a protein is everything – proteins trigger cellular activity by locking into each other like 3-dimensional keys – improper folding can turn a protein useless or even dangerous.

The types of amyloid proteins Dr. Baraniuk found in chronic fatigue syndrome (ME/CFS) patients are unique to the brain. These same general types of proteins are also found in neurodegenerative diseases such as Alzheimer’s and Down’s syndrome.

Improperly folded proteins can cause two major problems; (a) because the proteins are not doing the job they’re supposed to do they can cause vital processes to be neglected and (b) if they’re not removed quickly enough they can build up and cause damage.

Focus on the Brainstem – In particular he’s focused on the gating mechanisms in the lower part of the brain that filter the amount of information that the upper part of the brain receives. He believes that the neural circuits running from the spinal cord to the brainstem are not working properly and that the system that should close and latch those gates is dysfunctional. These gates filter out unnecessary information and protect the brain from being flooded with too much information. He believes they’ve been left wide open in chronic fatigue syndrome (ME/CFS). The most critical neural circuit appears to be the Papez Circuit which ties together the anterior cingulate, amygdala and hippocampus. It’s associated with heightened awareness and anxiety and effects autonomic nervous system functioning.

 

[mariovitali]

I just finished another set of analysis and i was hoping that i could take some feedback from all of you regarding some questions that i have :

a) Do you feel that CFS symptoms are less noticeable while you have a Cold / Flu?
b) Do you feel generally better during the summer and worse during the winter time?
c) How many of the childhood illnesses have you had?


Thanks in advance

 

[JPV]

a) Do you feel side effects or the intensity of side effects is the same when you have a Cold / Flu?
Not really.

b) Do you feel generally better during the summer and worse during the winter time?
I find extremes either way to cause discomfort. Humidity is draining for me and the cold aggravates my neurological issues.

c) How many of the childhood illnesses have you had?
All I really remember is having either Measles or Chickenpox (not sure which one) and Mono.

 

[mariovitali]

a) Do you feel side effects or the intensity of side effects is the same when you have a Cold / Flu?
Not really.

Let me re-phrase the question : I've found that whenever i was sick with Flu i never had any symptoms. Does this apply to you as well?