mandag den 24. marts 2014

Hypothalamus antibodies, HPA-axis dysfunction and a role for NO, CO, and H(2)S in ME?

From Invest in ME’s homepage:
Invest in ME are working with researchers, as part of the examinations facility proposal and to support the rituximab trial, on a more comprehensive and detailed analysis of antibodies binding the hypothalamus.

This is interesting and wonderful news, and I hope this study will help to make the ME puzzle pieces fit together. I have written a little about it in my previous blogpost - in Danish, sorry- remember "google translate" is a fine invention: Har ME patienter auto antistoffer mod hypothalamus???

There are an abundance of articles about ME and Hypothalamic-Pituitary-Adrenal Axis (HPA-Axis) function. Could antibodies against “something” in the hypothalamus explain the HPA-Axis dysfunctions?

Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome

Does hypothalamic–pituitary–adrenal axis hypofunction in chronic fatigue reflect a "crash" in the stress system?

The role of hypocortisolism in chronic fatigue syndrome

A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome

And will antibodies binding the hypothalamus explain some other hypothesis and observations?

Lately, I have been very interested in the role of nitric oxide (NO), carbon monoxide CO), and hydrogen sulfide H(2)S in the etiology of ME and POTS. Blogposts about it:

Basic knowledge NO - H(2)S - CO interaction - where to begin

ME/CFS, POTS - carotid body and gasotransmitters

ME, POTS, H(2)S, NO - hvad er sammenhængen?

Hydrogen sulfide, ME/CFS, POTS and TRPA1

And my suspicion to dysregulation of NO, CO, and H(2)S in ME and POTS has grown stronger after reading this article:

Roles of nitric oxide, carbon monoxide, and hydrogen sulfide in the regulation of the hypothalamic–pituitary–adrenal axis:

“The importance of NO, CO, and H(2)S in the regulation of the stress axis is beyond dispute, but their specific roles include complex interactions with one another and effects that vary with the characteristics of the stress and type of cell/organisms involved.“

The big question is how this information adds up with Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome?

Any suggestions?

søndag den 23. marts 2014

Har ME patienter auto antistoffer mod hypothalamus???

Den engelske forening Invest in ME, der står bag de årlige internationale ME konferencer i London, oplyser på deres hjemmeside, at forskerne vil lede efter auto antistoffer mod hypothalamus hos ME patienter. Man vil samtidig kigge efter antistoffer mod cytokiner.

Dette projekt vil støtte op om forskningen i Rituximab behandling af ME patienter, idet Rituximab fjerner de antistofproducerende B celler, og hermed generelt har en effekt på autoimmune sygdomme.

Men lige nu er det hypotese, og Invest in ME skriver, at studiet vil tage 15-18 måneder og yderligere 3 måneder til analyse og publicering af en artikel med resultaterne. Det bliver spændende, om forskerne kan finde noget.

Hypothalamus er den nederste del af mellemhjernen, hvorfra hypofysestilken udgår. Området består af en række kerner, som er centre for den overordnede styring af det autonome nervesystem (fx i forbindelse med regulering af blodtryk, kropstemperatur, appetit og tørst).

Der er flere ting, der er interessant ved at forskerne vender deres opmærksomhed mod hypothalamus. ME patienter har ofte den autonome dysfunktion Postural Ortostatisk Takykardi Syndrom (POTS)  som ko-morbiditet.

Autoimmune sygdomme kan somme tider udløses af infektion eller vaccine. Det er lidt mindre kendt, at der faktisk også kan påvises visse typer af auto antistoffer efter hovedtraumer.

Denne artikel: Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity?, oplyser, at hos sportsfolk, der bliver udsat for gentagne stød mod hovedet, kan der påvises auto antistoffer.

Således blev der fundet antistoffer mod hypothalamus hos 13 ud af 61 boksere (21.3%), og antistoffer mod hypofysen hos 14 ud af  61 boksere (22.9%).

Det bliver endnu mere interessant, når man læser denne artikel: Autonomic dysfunction presenting as postural tachycardia syndrome following traumatic brain injury.

POTS kan udvikles efter infektion, og for nylig er udvikling af POTS sat i forbindelse med HPV vaccine. Og så denne artikel med, at POTS også kan udvikles efter hovedtraume.

Der er ligesom nogle sammenhænge her, som ser meget spændende ud.

Og det er kun toppen af den viden, som vi skal til at sætte os ind i med dette lille hint fra Invest in ME, om hvad retning forskningen nu tager. 

FORDI der er flere interessante sammenhænge. Bloggeren Cort Johnson har twittet: TWEETING THE STANFORD SYMPOSIUM FOR CHRONIC FATIGUE SYNDROME

Han har twittet, at forskerne har fundet forhøjede niveauer af leptin hos ME patienter. Leptin er et hormon, der påvirker hypothalamus. Højt niveau af leptin hang sammen med mere udmattelse hos ME patienterne. Vi må afvente den videnskabelige artikel til at se nærmere på den sammenhæng.

Men så er det, at man ikke kan lade være med at google, om der mon skulle være nogen generel sammenhæng mellem leptin og autoimmunitet. Jeg fandt lige den her artikel: Is leptin a key mediator in the link between immune responses and metabolism in autoimmune diseases of the central nervous system?

Vi skal naturligvis ikke benytte de her informationer til at drage forhastede konklusioner. Den sporadiske viden, som jeg har samlet her, skal blot anvendes til at blive nysgerrig og søge mere viden. Hvis vi skal have løst ME gåden, er vi nødt til hele tiden at kombinere viden på forskellige måder og se om det fører til troværdige hypoteser, som er værd at teste ved videnskabelige forsøg.


Jeg håber så meget, at Danmark også snart ”kommer ind i kampen” og kan bidrage til forskningen. 

lørdag den 22. marts 2014

De amerikanske sundhedsmyndigheder tager initiativ til at hjælpe ME patienter

De amerikanske sundheds myndigheder U.S. Food and Drug Administration (FDA)[1] har taget initiativ til at hjælpe patienter med sygdommen Myalgisk encephalomyelitis (ME) ved at støtte op om udvikling af medicin til denne invaliderende sygdom: "Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS)". [2]

Det er således en vejledning til medicinindustrien, som FDA udvikler – ikke medicinen i sig selv. Når medicin producenter udvikler medicin afprøves effekten af denne i kliniske forsøg (studier). Disse forsøg skal have nogen rammer, så myndighederne kan være sikre på, at forsøget er sat rigtig op og viser om medicinen er effektiv eller ej.

I et mødereferat fra FDAs hjemmeside[3] kan man bl.a. læse følgende konklusion (oversat):

Vi erkender, at der ikke er nogen godkendte behandlinger til CFS og ME og dette udgør en betydelig bekymring for folkesundheden. En række enkeltpersoner og grupper spiller en vigtig rolle i udviklingen af nye lægemidler. Vi er forpligtet til at finde veje til at samarbejde med de berørte parter for at fremme udviklingen af brugbare behandlingsmuligheder for CFS og ME.

FDA har nu udgivet udkastet til disse retningslinjer for industrien[4] om, hvorledes man skal udvikle medicin til ME patienter. Udkastet er offentliggjort med henblik på at indsamle kommentarer, og er således ikke i en endelig version, der kan anvendes.

Vejledningen lægger stærkt vægt på, at når en gruppe af patienter skal udvælges til et klinisk forsøg, skal de være velkarakteriserede.

F.eks. nævnes det i linje 102, at man ved kliniske studier skal angive, om man har med ME/CFS patienter at gøre, eller om det er ME/CFS patienter med ko-morbiditeten Postural Ortostatisk Takykardi Syndrom (POTS).

I linje 131 nævnes det, at der bør anvendes objektive målemetoder for at eftervise om en medicin har effekt. I linje 195 nævnes det, at patienternes motions-kapacitet målt på en kondi-cykel (ergometriske målinger) kan anvendes, som metode til at påvise reelle forbedringer, som følge af medicinsk behandling.

Jeg synes, at den her vejledning er et godt skridt på vejen til at højne niveauet for forskning i ME: Skarp, præcis definition af patientgruppen og konkrete fysiske målinger om en given behandling giver forbedringer.

Ofte vælger danske myndigheder at benytte udenlandske vejledninger. F.eks. henviser Sundhedsstyrelsen ofte til de engelske NICE guidelines for ME/CFS. Man kan derfor håbe, at Sundhedsstyrelsen også vil henvise til denne vejledning, når den foreligger i en færdig udgave.

Relaterede blogposts:

Amerikanske myndigheder har focus på udvikling af lægemidler til ME/CFS
Bage- eller badevægt? Hvordan måler man effekten af en behandling?


Referencer:

[1] U.S. Food and Drug Administration
http://www.fda.gov/

[2] Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS)
http://www.fda.gov/Drugs/NewsEvents/ucm319188.htm

[3] CFS and ME Meeting Summary, April 26, 2014
http://www.fda.gov/Drugs/NewsEvents/ucm386705.htm

[4] Guidance for Industry Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis: Developing Drug Products for Treatment
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM388568.pdf

onsdag den 19. marts 2014

Inspiration til forskning i ME på dagens høring

dagens høring i folketinget om funktionelle lidelser blev der fra publikum siden givet inspiration til forskning i ME. En fra publikum henviste til forskning i tau protein og hovedtraumer. Jeg vil gerne bakke op om dette gode forslag og har her fundet lidt artikler om emnet.

Her er en artikel om emnet "tau og hovedtraumer":
Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development

Og der er forskere, der kigger på biomarkører inden for dette felt:
"One of the most promising metabolite biomarkers of injury is brain N-acetylaspartic acid (NAA)" 


Og man kan læse mere om NNA her.

Forskning i ME/CFS har vist dette:
"Seven patients with chronic fatigue syndrome (CFS) were matched with ten healthy control subjects of similar age. Hippocampal volume, obtained from magnetic resonance images using an unbiased method, showed no difference between the two groups, whereas proton magnetic resonance spectroscopy showed a significantly reduced concentration of N-acetylaspartate in the right hippocampus of CFS patients (p = 0.005)."
Reference: Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome.

Der er sammenhæng mellem tau proteiner, CDK5 og hyperphosphorylation i Alzheimers. Denne interessante sammenhæng kan man læse om her:  The role of CDK5 and GSK3B kinases in hyperphosphorylation of microtubule associatedprotein tau (MAPT) in Alzheimer's disease

Og så bliver det rigtigt spændende, fordi
"the Cdk5 signaling pathway, was found to be significantly enriched (p=0.00009) for proteins identified in the pooled cerebrospinal fluid proteome from Chronic Fatigue Syndrome patients."


Lidt mere om det spændende emne her: CDK5, ME and TRPA1

Det vil være en glædelig nyhed, hvis dagens høring kan medføre, at interessen for forskning i ME/CFS bliver vakt. Så tak til politikere for at have arrangeret høringen, og især tak til Liselott Blixt for slutbemærkningen  i denne artikel fra TV2 nyhederne: Politikere om funktionelle lidelser: Der skal gøres noget nu

mandag den 17. marts 2014

CDK5, ME and TRPA1

Cyclin-dependent kinase 5 (Cdk5) is as an essential kinase in sensory pathways. Cdk5 is implicated in almost every aspect of neuronal development and neural functions. It is implicated in cognitive functions such as learning and memory formation.

The Cdk5 signaling pathway has been linked to neurodegenerative diseases (Parkinson's and Alzheimer's disease), and dysregulated Cdk5 activity is associated with neuronal death.

Cdk5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis

In the study, Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome, the Cdk5 signaling pathway, was found to be significantly enriched (p=0.00009) for proteins identified in the pooled cerebrospinal fluid proteome from Chronic Fatigue Syndrome patients. We do not know what influence this enrichment has in CFS patients, but let us take a look upon Cdk5 research.

This study about Alzheimer's disease, Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction, give us some interesting information, that might be relevant in ME/CFS research:

  • Deregulated (Cdk5) may cause oxidative stress by compromising the cellular anti-oxidant defense system
  • Cdk5 dysregulation upon neurotoxic insults results in reactive oxygen species (ROS) accumulation in neuronal cells because of the inactivation of peroxiredoxin I and II
  • Cdk5 inhibition rescues mitochondrial damage upon neurotoxic insults

And the researchers have a hypothesis: active Cdk5 → ROS → excess ROS → mitochondrial damage → ROS → hyperactive Cdk5 → severe oxidative stress and cell injury → cell death

More information from Neurotoxicity induces cleavage of p35 to p25 by calpain:

  • Cdk5 has a neuron-specific activator p35. Cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease.
  • Conversion of p35 to p25 causes prolonged activation and mislocalization of cdk5.
  • In cultured primary cortical neurons, excitotoxins, hypoxic stress and calcium influx induce the production of p25. 

This article, Oxidative Stress in Neurodegeneration, has a very fine figure explaining, when the neurons are stressed, there is an increase in Ca2+ leading to activation of calpain, a protease. Calpain cleaves p35 to p25 deregulating Cdk5 activity as p25 forms a hyperactive and more stable complex with Cdk5. Cdk5/p25 activity causes aberrant phosphorylation of various proteins leading to conformational changes inducing gain of toxic function. Misfolded proteins lead to self-aggregation thereby overwhelming the system by blocking transport and disrupting synaptic activity. This ultimately leads to degeneration of neurons and finally be the cause of various neurodegenerative diseases like AD, ALS, PD, and HD.


Figure 1: Summary of role of Cdk5 in physiology and pathology
Reference: Varsha Shukla, Santosh K. Mishra, and Harish C. Pant, “Oxidative Stress in Neurodegeneration,”Advances in Pharmacological Sciences, vol. 2011, Article ID 572634, 13 pages, 2011. doi:10.1155/2011/572634

But ME/CFS is different from the neurodegenerative diseases mentioned here. Perhaps there is a shared biochemistry involving dysregulation of Cdk5 signaling pathway. The (p=0.00009) mentioned above must mean something. I have written a lot about TRPA1 and ME and comorbidities. If my guessing is on the right track, there could be a TRPA1 - Cdk5 connection. So I googled!

And look what a fine piece of work, I found: A dissertation (dec 2011) by Michael Sulak from Kent State University: MODULATION OF TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY A, MEMBER 1 (TRPA1) ACTIVITY BY CDK5

The goal of this work was exactly what I was looking for (the TRPA1 - Cd5k connection): “The overall goal of this investigation is to identify the role of cyclin-dependent kinase 5 (Cdk5) in the modulation of transient receptor potential cation channel, subfamily A, member 1 (TRPA1) activity in sensory neurons.”

Highlights from the results of Michael Sulak’s work:

  • Inhibition of Cdk5 activity attenuates TRPA1 agonist-induced increases in [Ca2+]i in DRG neurons.
  • The results of the investigation provide physiological evidence for Cdk5 regulation of TRPA1 activity in DRG neurons, and are consistent with a regulatory mechanism involving direct phosphorylation of the receptor by Cdk5.
  • Notably, no previous studies have implicated Cdk5 as a modulator of TRPA1 activity, nor have previous studies provided evidence for phosphorylation of TRPA1 residues by any kinase. 
  • The possibility that TRPA1/TRPV1 cross-talk may play a role in Cdk5 modulation of nociception therefore exists, and is a notion worthy of examination – especially considering the fact that both receptors have now been separately found to be influenced by Cdk5 activity

And this study (jan 2014), ERK MAP Kinase Activation in Spinal Cord Regulates Phosphorylation of Cdk5 at Serine 159 and Contributes to Peripheral Inflammation Induced Pain/Hypersensitivity, concluded, that their findings suggested that p-Cdk5S159 regulated by ERK pathway activity may be a critical mechanism involved in the activation of Cdk5 in nociceptive spinal neurons. And this could contribute to peripheral inflammatory pain hypersensitivity.

Can this mechanism be involved in the pain in ME? Can the Cdk5 regulation of TRPA1 activity be involved in the chemical hypersensitivity in ME/MCS? In other symptoms? In any of my TRPA1 hypothesized connections to ME comorbidities?

Is the Cdk5 upregulation in ME responsible for other phosphorylations? What might Cdk5 further have on its conscience? To be continued…

torsdag den 13. marts 2014

EQ-5D Scores for Danish ME/CFS patients 2013-2014

PhD Fellow Michael Falk Hvidberg from Aalborg University, Danish Center for Healthcare Improvements is behind this new Danish report:

Danske ME/CFS-patienters helbredsrelaterede livskvalitet (EQ-5D) og livstilfredshed 2013-2014

The title translated: Danish ME/CFS patients' health-related quality of life (EQ-5D) and life satisfaction from 2013 to 2014.

EQ-5D™ is a standardised instrument for use as a measure of health outcome, - it provides a simple descriptive profile and a single index value for health status.

The ME Association in Denmark has taken the initiative to launch this Danish study in collaboration with the author, PhD Fellow Michael Falk Hvidberg from Aalborg University, who are working with the quality of life of chronic diseases.

The ME Association distributed a questionnaire to the members and 94 participated in the study. Data collection occurred from ult. 2013 to early 2014.

The study shows ME/CFS patients have the lowest quality of life compared to 21 diseases. In fact, quality of life for ME/CFS patients is significantly lower for 17 of the 20 diseases. This is regardless of whether you look upon the average or median.

Figure 1 from page 8 in the report. EQ-5d-based quality of life and disease.

Thank you to PhD Fellow Michael Falk Hvidberg from Aalborg University and the ME association in Denmark for this report.


Further reading:

Comparison of Euroqol EQ-5D and SF-36 in patients with chronic fatigue syndrome

Health-related quality of life in patients with chronic fatigue syndrome: An international study

Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups






mandag den 10. marts 2014

Autoimmunitet mod adrenoreceptorer

Som det fremgik af mit indlæg ME, POTS og autoimmunitet kan adrenoreceptorer være mål for et autoimmunt angreb.

Adrenoreceptorer hører til den gruppe af receptorer, der kaldes for G-protein-koblede receptorer eller sommetider for syv transmembrane receptorer (7TM receptorer). Tallet 7 refererer til, at receptoren gennemløber cellemembranen syv gange, - lidt ligesom en snor, der bugter sig frem og tilbage. Se dette billede: G protein koblet receptor. Det betyder, at der dannes 3 løkker, på engelsk loops, både på ydersiden og indersiden af cellemembranen. De 3 loops på ydersiden af celle membranen kaldes for ekstracellulære loops. Og de 3 loops på indersiden af celle membranen kaldes for intracellulære loops.

Denne artikel, Mechanism of GPCR-Directed Autoantibodies in Diseases, forklarer, at autoimmune angreb mod G-protein koblede receptorer ofte er rettet mod andet ekstracellulære loop.

Og denne artikel, Autoimmune mediated G-protein receptor activation in cardiovascular and renal pathologies, forklarer, hvordan auto antistoffer rettet mod receptorene, kan virke som enten agonister eller antagonister og hermed skabe sygdom. Lidt populært forklaret, så "tænder" en agonist for receptoren og antagonisten "slukker". Som eksempel nævnes Graves sygdom, hvor antistoffer stimulerer (tænder) den G protein koblede thyroid stimulerende hormon receptor, THSR.

I artiklen, Autoimmune Basis for Postural Tachycardia Syndrome, som jeg omtalte i indlægget
ME, POTS og autoimmunitet er det nævnt, at de undersøgte POTS patienter havde autoantistoffer mod den G-protein koblede adreno receptor β1AR.

Og her har jeg fundet en artikel, hvor man har har testet, hvad antistoffer mod β1AR giver af symptomer hos rotter:
Antibodies against the second extracellular loop of β1-adrenergic receptors induce endothelial dysfunction in conductance and resistance arteries of the Wistar rat.

Bemærk titlen! Det er antistoffer mod andet ekstracellulære loop på β1AR, der er tale om.

Jeg synes artiklen er meget interessant, idet det viste sig, at antistofferne påvirkede arterierne, så der opstod ændringer i endothelium-afhængig NO signalering. Det er jo en ganske interessant iagttagelse, idet fejl i endothelium-afhængig NO signalering indgår i Olav Mellas og Øystein Fluges hypotese om ME.

Er der mon noget viden fra denne artikel, der kan kaste lys over sygdomsmekanismen i ME og POTS?