Discussion in 'XMRV Research and Replication Studies' started by pollycbr125, Sep 17, 2012.
Dont get me wrong i have a few moments, lol
I think with sleep and cfs its a matter of poor sleep making cfs worse but improving sleep doesnt fix cfs but stops us from functioning at an even lower level. For me without sleep meds i would have alot more brain fart moments, sleep meds arent 100% efective but they do help me.
In fact, I wonder why there hasn't been more research in this area? Because from my own experience, and reports from others here, while sleep meds definitely improve that hideous wakey-wakey all-night jamboree, they never get us to the full, non-REM deep sleep phase. The reason why this is disrupted, and how to fix it, might at least bring significant relief to the cognitive disabilities we all have to (unhappily) face on a daily basis.
And surely it will be found that whatever neurotransmittters/hormones/processes are involved are also involved in other processes that are being disrupted. Rich VanKs theory covers a bit of that, as does Marty Pall's, but why there has not been more focused research on getting us back into deep, restorative sleep is kind of astounding. I would think that would be Number One palliative approach--which could lead to curative if the source of said sleep disorder was unravelled.
Just a thought before I caffeinate this morning
We now know that the SCN that regulates sleep patterns is VERY vulnerable to oxidative stress, and this throws off liver metabolism as the SCN regulates fat metabolism in the liver.
So wouldn't it make sense to consider this angle more closely, and consider, if we can't overcome the OS, supplementing the appropriate neurotransmitters/peptides/liver support? As nice as an induced coma sounds to me right now, that line of research might prove more fruitful...
A coma does sound restful, induced or otherwise.
Ah, let's not forget that after a nice comatose rest, we'd all be deconditioned and therefore in need of GET. Ya just can't win with these folks, imo.
There is no doubt that CFS is hardly a single entity, but this does not negate the obligation to continue study of the results based on the dual positivity findings. It is imperative to continue and I think Dr Lipkin has not been appropriately cautious in this regard.
I dont think ketamine will reduce brain inflammation (aldo it could theoretically reduce excitotoxity)This is something i think some of us don't realise enough; every type of cell in our brain is in some way connected to the immune system or its messenger molecules.
Bellow are some scentences i got out of a review.
First of all the cells in the brain; Astrocytes, Microglia, Oligodendrocytes, endothelials cells (on BBB), neurons
Astrocyes are capable of expressing the full aray of immune signaling and detection systems.
In addition astrocytes play a role in maintaining glutamate homeostasis. The 2 main glutamate transporters who actively re uptake glutamate are primaily expressed by astrocytes.
...any change in local or general central immune signaling can have a profound impact on astrocyte function
Microglia; phagocytic cells
Oligodendrocytes; very sensitive recipients of immune signaling
Endothelial cells migth contribute to immune signaling within the CNS. After a tissue insult and the ensuing release of peripheral and central immune signals, the thight junctions become leaky, exposing the CNS to peripheral immune signals.
Neurons; the following neuronal changes have been reported in response to proinflammatory cytokines: up-regulation of cell surface expression of AMPA receptors, upregulation of NMDA receptor, down regulation of GABA.
Cytokines receptors exhibit high affinity.
Because of this high affinity, very low concentrations
of cytokines can cause a biological effect,
often at levels undetectable by current quantification
techniques. Within the CNS, cytokines can bidirectionally
communicate with each of the cell populations outlined
above, performing critical roles in homeostasis,
physiological responses to stress and immunological
challenges, and pathological conditions. These actions
occur via specific cytokine receptors and via direct cytokine
modulation of other receptor functions, such as
NMDA receptor cell surface expression and phosphorylation
So what i basically mean by this, is that the immune system can easily mess up the brain, which is probably going on in our cases.
At that time (when Goldstein designed his theory) not that much was known about the (chronic) effect of the immune system on the brain.
He started treating from a very distal point in the pathway, on symptomatic level, which was not healing but maybe the best he could do at that time.
I think he still deserves a massive amount of respect for what he has done.
My favourite quote from Ian Lipkin re CFS/ME, from the press conference, talking about his previous investigations into CFS/ME in the 1990's:
"The one thing that did impress me was that there was an enormous amount of immuno-activity that appeared to be non-specific in these individuals.
So at a time when people were saying that this was a psycho-somatic disorder, I said:
Two thirds to three quarters of the individuals whom we studied had polyclonal B cell activation.
They're sick. We don't know why, but they are sick."
That two thirds corresponds to the two thirds who responded to Rituximab in the Fluge and Mella study.
Consider - rituximab is a b-cell depletion therapy. And the Lipkin patients had polyclonal b-cell activation.
Seems like too much of a coincidence, doesn't it?
Systemic autoimmune disease arises from polyclonal B cell activation.
D M Klinman and
A D Steinberg
The number of B cells producing antibodies reactive with any of seven autoantigens or two conventional antigens was compared at the single-cell level to the total number of Ig-secreting B cells present in the spleens of NZB, MRL lpr/lpr, and BXSB autoimmune mice. The proportion of lymphocytes producing antibodies of each specificity, expressed as a percentage of the total B cell repertoire, was virtually identical among autoimmune and congenic nonautoimmune animals. Furthermore, B cells and serum antibodies reactive with conventional antigens increased commensurately with those reactive with autoantigens. These results indicate that systemic autoimmune diseases arise from polyclonal B cell activation.
There has also been this discussion about the immunomodulatory effects of antiretroviral drugs on another forum.
If antiretrovirals do have these immunomodulatory effects, wouldn't that be documented in HIV literature?
So a similar response could have already been noted and be known.
An autoimmune disease prevented by anti-retroviral drugs
Gabriele B Beck-Engeser,1 Dan Eilat,2 and Matthias Wablcorresponding author1
1Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414, USA
2Department of Medicine, Hadassah University Hospital and The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
Received September 12, 2011; Accepted November 8, 2011.
Both Aicardi-Goutières syndrome, a Mendelian mimic of congenital infection, and the autoimmune disease systemic lupus erythematosus can result from mutations in the gene encoding the enzyme Trex1. In mice, the absence of Trex1 causes severe myocarditis. The enzyme is thought to degrade endogenous retroelements, thus linking them to autoimmune disease. However, inhibition of reverse transcription by the inhibitor zidovudine (AZT) did not ameliorate the disease, weakening the link to retroelements.
Here, we show that two other FDA-approved drugs that inhibit reverse transcriptase can ameliorate the myocarditis in Trex1-null mouse.
The result suggests that retroelements contribute to this hereditary form of autoimmunity, and that treatment with retroelement inhibitors might ameliorate Aicardi-Goutières syndrome in humans.
We first determined that the combination of Truvada and Viramune is effective against MLV. Using flow cytometry, we titrated the drug concentration for its ability to inhibit expression of green fluorescence protein encoded by MLV provirus upon infection; the EC50 was well below 100 nM (Figure (Figure1A).1A). When fed to Trex1-deficient mice at a dose comparable to that given to patients with HIV, the drugs substantially reduced mortality (Figure (Figure1B).1B). On sections ). On sections of the heart from 9-month old treated mice, there were some mild patchy inflammatory infiltrates with little myocyte injury; but the difference to the marked inflammatory infiltrates with myocyte necrosis and dropout in 7-month old non-treated mice (at 9 months all untreated mice were dead) was striking (Figure (Figure1C1C).
Almost half of the human genome consists of retroelements, many of them active. There are several ways that retroelements might trigger an autoimmune response, including (i) sensing of retroelement RNA and cDNA, (ii) generation of mimetopes through error-prone reverse transcription of mRNA encoding retroelement proteins, and (iii) insertional mutagenesis. We showed here that a hereditary autoimmune inflammation in the mouse that is likely caused by accumulation of retroelement cDNA can be treated with reverse transcriptase inhibitors. Other autoimmune diseases might be amenable to different interventions of retroelement activities.
Long-Term Evaluation of Cellular Immunity during Antiretroviral Therapy and
Immunization with Human Immunodeficiency Virus Type 1 (HIV-1) Env
Glycoprotein in HIV-1 – Infected Persons
Patients treated with zidovudine alone or in combination with the immunogen showed improvement
of T lymphocyte responses and transient reduction of viremia
Hi currer, that percentage keeps coming up - roughly 70-80% with finding after finding. I have always wanted them to compare findings in the same patient cohort so that we can find out if many things co-occur or not. It could simply be coincidence. Until they do we will not know for sure if these problems cluster. Bye, Alex
rPolyclonal B cell activation is not a peculiar characteristic to a particular infection, as many viruses, bacteria, and parasites induce a strong polyclonal B cell response resulting in hyper-γ-globulinemia. Here, we discuss the different roles proposed for polyclonal B cell activation, which can be crucial for early host defense against rapidly dividing microorganisms by contributing antibodies specific for a spectrum of conserved structures present in the pathogens. In addition, polyclonal B cell activation can be responsible for maintenance of memory B cell responses because of the continuous, unrestricted stimulation of memory B cells whose antibody production may be sustained in the absence of the antigens binding-specific BCR. Conversely, polyclonal activation can be triggered by microorganisms to avoid the host-specific, immune response by activating B cell clones, which produce nonmicroorganism-specific antibodies. Finally, some reports suggest a deleterious role for polyclonal activation, arguing that it could potentially turn on anti-self-responses and lead to autoimmune manifestations during chronic infections
So if one seems to have problems making antibodies would that mean there are issues with b-cells. I say this because i have tested positive to ebv in the past but now dont make any antibodies at all and in oslers web this was a common occurrance in many from the Tahoe outbreaks. So not just ebv antibodies but maybe other antibodies to other infections or even vacines etc??
Autoimmunity, Polyclonal B-Cell Activation and Infection
It is widely believed that autoimmunity is an integral part of the immune system, and that genetic, immunologic, hormonal, environmental and other factors contribute to the pathogenesis of autoimmune disease. Thus, autoimmune disease may represent an abnormal expression of immune functions instead of loss of tolerance to self, and it can be organ specific or systemic in its manifestations. We review the various factors that contribute to the development of autoimmune disease; we also review the mechanisms of polyclonal B-cell activation, with emphasis on the role of infectious agents. We consider systemic lupus erythematosus in humans and in experimental animals as prototypic autoimmune disease, and we summarize data to indicate that polyclonal B-cell activation is central to the pathogenesis of systemic autoimmune disease. The effect of polyclonal B-cell activation, brought about by injections of a B-cell activator - lipopolysaccharide from Gram-negative bacteria—is sufficient to cause autoimmune disease in an immunologically normal host. In fact, autoimmune disease can be arrested if excessive polyclonal B-cell activation is suppressed; alternatively, autoimmune disease can be exacerbated if polyclonal B-cell activation is enhanced
Tweets from CII
As usual, Carl Zimmer nails it: The Slow, Slow Road to De-Discovery
http://bit.ly/PGYICECII @carlzimmer #MECFS#CFS #ME #XMRV #pMLV
Also check out the comments section. Some great science writers weigh in:
Link to article (in Discover Magazine):
Read these links. But no-one in the discussion points out that xmrv is a genuinely new recombinant virus, and created inadvertently, too.
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