EWOT?

Our current predicament reminds me of the Jack Kornfield book, After The Ecstasy, The Laundry. Retroviral causation is still a possibility, but what to do after that flash of illumination? How do we circumvent the despair that comes with getting it and losing it again? I catch myself stuck in negative thinking, feeling like I have gained so much insight into the illness, but it came too late for me to do anything “important” with it. After I wrote the last blog, I felt guilty. I mean, after where we’ve been together as a community, who wants to read about watching your diet?

I returned to work still improving, but I’m not any more. In fact, following a couple of back to back bugs that my grandson brought home from his first grade class, on top of several months of prolonged stress, I’m back to pretty definitely sick. Therefore, I’ve decided to take the next 6 weeks to rehab myself, rather than dive off the cliff again next week, when I was planning to make my first trip to Tucson. Magical thinking pretty clearly isn’t going to get me through this time. I need to take my own advice. Physician heal thyself.

What do I want to do differently with this time, besides lowering my energy output for a while and being more consistent with oxygen, diet, supplements, neurofeedback, all of which I’ve done before? For some time, I’ve wanted to try EWOT or exercise with oxygen therapy. I use oxygen to prevent PEM, but I have never exercised with it on. It requires a high flow concentrator (> 8L/min) and a mask with a reservoir that will stay on, but not restrict air flow. There is literature to support the idea that elite athletes (and rats) can do more work while wearing supplemental oxygen, though results have been equivocal as to whether exercising while hyperoxic improves performance in the long run.

I have wondered if it might not also be true that our exercise capacity could be increased this way, we who are on the low end of the bell curve. There isn’t much to go on in the literature, but there are a few papers about exercising with COPD and an oldie but goodie about using periodic hyperoxia to improve exercise capacity in CHF.

And this important paper, that addresses the question of how a treatment that increases ROS in the short term, could be good for us? It suggests that periodic administration, as opposed to long term hyperoxia, enhances antioxidant defense mechanisms, essentially a training effect for the body to fight oxidative stress: Effects of exposure of rats to periodic versus continuous hyperoxia on antioxidant potentials and free radical production in relation to ultrastructural changes in myocardial cells.

Hormesis, a concept from toxicology theory, is a blend of less is more and what doesn’t kill you makes you stronger. Modulation of cellular response by the correct amount of stress encourages plasticity in biological systems. Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders. Calabrese et al. Here is an excerpt from the section “Hormesis, Mitochondria, and Neuroprotection”:

Recent findings have overturned the long-held belief that mitochondrial ROS have only a negative impact on cell function and survival. It is now clear that mitochondrial superoxide and hydrogen peroxide play important roles in a range of cellular functions, and can also activate signaling pathways that promote cell survival and disease resistance…Mitochondrial superoxide production is believed to contribute to damage of neurons in conditions ranging from chronic intermittent cerebral hypoxia to Alzheimer’s disease. However, it has been widely reported that transient exposure of neurons to low levels of superoxide that are converted into hydrogen peroxide can protect the neurons against a subsequent exposure to what would have otherwise been a lethal level of stress. This neuroprotective effect of a subtoxic increase in cellular oxidative stress has been termed “preconditioning” by neuroscientists who study stroke, but clearly falls under the broad umbrella of hormesis… [An] example of trans-cellular hormesis mediated by ROS comes from studies showing that oxidative stress can stimulate angiogenesis in the brain…

Here is another dot to connect:

  • Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients.  In summary, patients with MM show impaired oxidative ATP production in their skeletal muscle, consistent with mitochondrial disease. This study has also shown that increased inspired oxygen concentration improves oxidative function in patients with mitochondrial myopathy, but not sedentary healthy individuals. It is hypothesised that the improvement in oxidative function with increased oxygen inhalation could be the result suboptimal oxygen conductance during exercise.
  • Oxygen Therapy for Mitochondrial Myopathy.  Letter to the editor, so no abstract, but here are excerpts: We report on a physician-patient with a diagnosis of undifferentiated autoimmune disease, pandysautonomia, and mitochondrial dysfunction… Her functional capacity has gradually improved, and her prednisone dose has been substantially decreased for the first time in 8 years. She can now drive around town, walk in a shopping mall, and perform some household chores. In addition, the hair that had previously disappeared from her extremities (thought to be secondary to either the autoimmune disease or medication side effect) has regrown. Prior to oxygen therapy, her soft tissues in the extremities were painful with a boggy firmness, a fibromyalgia-like finding also thought to be part of the autoimmune syndrome. This symptom has gradually, but significantly, improved through a combination of body work (osteopathy and massage) and oxygen therapy. Prior to receiving supplemental oxygen, the same type of body work had been only minimally effective… This case report suggests that supplemental oxygen can enable patients to perform higher levels of cardiopulmonary work with less lactic acid accumulation than room air alone. The use of supplemental oxygen may not only improve functional capacity and certain physiologic abnormalities but may also minimize the mitochondrial stress, which has been postulated to increase the proportion of mutant mitochondria.

I mentioned this paper recently, but it bears a closer look: Normobaric hyperoxia treatment of schizophrenia. It showed that schizophrenics improve sleeping with a nasal cannula at 4-6L/min for 7 hours at night (an uncomfortable treatment). The improvement in symptoms was confirmed by a cross-over design of the treatment and control group. The rat study of periodic vs continuous hyperoxia above suggests that the effects demonstrated in this study might be even more profound with a higher dose for a shorter time. Why would oxygen help this group of patients and what does it have to do with us? Schizophrenia is increasingly recognized as a neuroinflammatory disorder associated with HERV activation. Here is a paper suggesting even more common ground… Antibodies to retroviruses in recent onset psychosis and multi-episode schizophrenia. So, another group of patients who have antibodies that cross react with MuLV sequences, at least in the acute phase.

I wish I could share this whole paper here, because it touches on so many of the questions left in the wake of XMRV. It is well worth a careful read in its entirety: Human retroviral sequences associated with extracellular particles in autoimmune diseases: epiphenomenon or possible role in aetiopathogenesis? Perron. There has been quite a lot of work done on MSRV, a retrovirus, which lies at the interface of endogenous and exogenous retroviruses. Since ME is essentially MS light, MSRV is a good model for us, with a 10 year head start from where we stand right now. Some, but not all MS patients studied express viral particles, which may or may not be infectious. That fits the variable epidemiology seen in our families, where some patients are isolated cases, having never known anyone else with the disease, others have partners and children affected, but otherwise no evidence of being contagious, and there are even a few who believe that they have infected many people through casual contact (food sharing). The idea of recombination and copackaging of viral genomes once again brings to mind the issue of vaccines contaminated with genetic material from animal cells.

As part of the complex ‘biological life’ of such retroviruses, it also appears necessary to study copackaged ERV genomes which may account for their potential pathogenicity by e.g., recombinations or propagation of defective clone expressing pathogenic molecules, and may be at the origin of their rapid loss of infectivity by defective interference and/or ERV takeover. The complexity of retroviral genome studies in these situations, represented in this review by IDDMK in autoimmune diabetes and MSRV in multiple sclerosis, can become a major difficulty for a definite conclusion.

The multiple sclerosis-associated retrovirus and its HERV-W endogenous family: a biological interface between virology, genetics, and immunology in human physiology and disease. Dolei/Perron 

The HERV-W family is one of the most studied, after the discovery of its MSRV founder member (Perron et al. 1989, 1997b). Our haploid genome contains about 70 gag, 100 pro, and 30 env HERV- W related regions (Voisset et al. 2000), but numbers can vary (Mirsattari et al. 2001; Zawada et al.2003); in silico expression data indicate that 22 complete HERV-W subfamilies from chromosomes 1 to 3, 5 to 8, 10 to 12, 15, 19, and X are randomly expressed in various tissues (Kim et al. 2008). Presently, this family is active and generates new recombinant copies in cancer cells (Yi et al. 2004), retains characteristics of functional retroviral envelopes (An et al. 2001; Kim et al. 2008), and HERV-W transposition and retrosequence integration have been evidenced in the human genome through interactions with active LINE-1 elements (Costas, 2002; Pavlicek et al. 2002). Thus, non-Mendelian genetic rules can apply to HERV-W elements: a key feature to understanding their biology.

None of the known stably inserted HERV-W elements is replication-competent (Blond et al. 1999): a study of HERV-W intragenomic spread (Costas, 2002) confirmed that, in the few individuals used for genomewide analysis, the sequenced HERV-W elements lack intact open reading frames (ORFs) in all genes within a single copy. This finding, and the unusual short period of evolutionary time of HERV-Ws (5 million years, estimated on average integration age of different subfamilies), suggested that MSRV might be either an exogenous HERV-W, as in animal ERVs (Palmarini et al. 1996), or a nonubiquitous replication-competent member, or a partly defective but nonubiquitous copy seldom complemented within the HERV-W family (Perron et al. 1997b, 2000; Komurian-Pradel et al. 1999; Dolei, 2005; Serra et al. 2003). Today, though reasonable arguments in favor of the existence of a replication-competent HERV-W member, which might even be ‘‘exogenous,’’ have been provided (Belshaw et al. 2005; Costas, 2002; Perron et al. 1997b, 1992), the very nature of MSRV remains to be confirmed by future studies (Voisset et al. 2008).

They can follow viral load in patients and there is clinical correlation… From the same paper:

A direct parallelism was found between MSRV positivity and load (in blood, CSF, and brain samples) and MS temporal and clinical stages, as well as active/remission phases (Dolei et al. 2002); at MS onset, 50% of CSFs were MSRV positive, and positivity increased with pro- gression. Importantly, MSRV presence in CSF at MS onset was related to poor prognosis; starting from otherwise comparable conditions, after 3 and 6 years mean EDSS (expanded disability status scale), an- nual relapse rate, therapy requirement, and progres- sion to secondary-progressive MS were significantly higher (Figure 2) in patients with detectable MSRV CSF load at onset (Sotgiu et al. 2002, 2006a).

A recent study (Mameli et al. 2008) found that plasmatic MSRV load of naive patients with active MS was directly related to MS duration; longitudinal evaluation of patients during 1 year of IFNb therapy showed that MS progression index (EDSS/MS years) was reduced for the majority of patients, whose viremia became rapidly undetectable. Notably, one patient had atypically high viremia at enrolment and, after initial virus inhibition and clinical benefit, had MSRV reemergence, accompanied by strong progres- sion with therapy failure. The authors concluded that evaluation of plasmatic MSRV could be considered the first prognostic marker for the individual patient to monitor disease progression and therapy outcome (Mameli et al. 2008).

Just published: HERVs Expression in Autism Spectrum Disorders. Balestriere et al, an addition to the growing literature supporting the idea that activated HERVs are involved in autoimmunity, an appealing idea, providing an explanation of why the immune system might become confused as to what is self and what is not. The authors of this paper found increased expression of HERV-H, one of the HERV families implicated in complex chronic disease, in autistics as compared to controls. They also report expression inversely proportional to age and proportional to disease severity.

Our answers lie at the interface of retrovirology, genetics, molecular medicine  and toxicology. The further I go in my attempt to understand the problem on a biochemical level, the less optimistic I am with respect to so called “targeted therapies”. We simply aren’t smart enough and the system we are trying to influence is too complex. This is why therapies that affect the system globally are so attractive. Which brings me back to EWOT. Perhaps the poor, misunderstood Dr. Wessely could let his patients try some oxygen with their GET, now that he says he thinks they do in fact have some sort of a physical problem, in addition to being lazy, crazy and faking.

So, EWOT for ME? I ordered a couple of masks to try. Now I’ve really gone and done it. Set myself up by telling you all about it:). I will report back soon.

Today’s song: Fire And Rain by James Taylor

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8 thoughts on “EWOT?

  1. I had been wondering about exercise with oxygen too. I will be very interested to see how it goes for you Jamie. In the meantime get some rest. xo

  2. Great article! I’m so glad we discussed this recently as I have continued to refuse to give up my exercise (Muscle Balance and Function Development) that I have been doing under the guidance of a trainer since a few years after I got sick around 1998. This individualized program was critical in getting me out of pain due to the initial injury and recovering a good bit of my functional level. I’ve tried the EWOT twice with my non rebreather mask and found it easy to use and like the idea of getting increased O2 while exercising. Will report on the results soon.

  3. A study on HERVs if you haven’t seen it.

    Endogenous retroviruses in systemic response to stress signals.
    Cho K, Lee YK, Greenhalgh DG.

    Abstract
    Infection of germline cells with retroviruses initiates permanent proviral colonization of the germline genome. The germline-integrated proviruses, called endogenous retroviruses (ERVs), are inherited to offspring in a Mendelian order and belong to the transposable element family. Endogenous retroviruses and other long terminal repeat retroelements constitute ~8% and ~10% of the human and mouse genomes, respectively. It is likely that each individual has a distinct genomic ERV profile. Recent studies have revealed that a substantial fraction of ERVs retains the coding potentials necessary for virion assembly and replication. There are several layers of potential mechanisms controlling ERV expression: intracellular transcription environment (e.g., transcription factor pool, splicing machinery, hormones), epigenetic status of the genome (e.g., proviral methylation, histone acetylation), profile of transcription regulatory elements on each ERV’s promoter, and a range of stress signals (e.g., injury, infection, environment). Endogenous retroviruses may exert pathophysiologic effects by infection followed by random reintegration into the genome, by their gene products (e.g., envelope, superantigen), and by altering the expression of neighboring genes. Several studies have provided evidence that ERVs are associated with a range of pathogenic processes involving multiple sclerosis, systemic lupus erythematosus, breast cancer, and the response to burn injury. For instance, the proinflammatory properties of the human ERV-W envelope protein play a central role in demyelination of oligodendrocytes. As reviewed in this article, recent advances in ERV biology and mammalian genomics suggest that ERVs may have a profound influence on various pathogenic processes including the response to injury and infection. Understanding the roles of ERVs in the pathogenesis of injury and infection will broaden insights into the underlying mechanisms of systemic immune disorder and organ failure in these patients.
    http://www.ncbi.nlm.nih.gov/pubmed/18317406

  4. I have a very progressive pulmonologist after reading all this! I will still send him links to articles.

    I am on oxygen at all times to support my mitochondria (2L/M) and he advises 4L/M with increased activity for up to 30 minutes or in intervals during relapse. Of course I am monitored with arterial blood gas testing to make sure my body is not retaining CO2.

    I have been very pleased. I am not exercising, but my PEM is improved in that symptoms are less severe. Anything that helps!

  5. J,

    Your song choices say it all… by themselves.

    And you are a one-woman ‘Shawshank Redemption” (film, just substitute ME/cfs as prison)

    The research in this post explains why the hair vanished from my legs and arms !

    So does lower elevation help ME/cfs????????????????????????????????

    Not sexy, strolling with a nose-hose and mini-tanks of O2 .

  6. Yes, lactoferrin reduces bacteria, fungus , virus, retrovirus, ….–ALL pathogens.

    Just vary the dosaging upwards from the maintenance dose ( 250 mg per day ) according to virulence, etc.

    Also once a day —tip head back for 1 drop up each nostril of 1100 PPM colloidal silver (iherb.com).

    “TIS THE SEASON” (flu)

  7. Please note regarding my comment above:
    I am on oxygen at 2L/M with a suggested increase to 4L/M while active per my pulmonologist. I DO NOT have any diagnosed lung disease according to my pulmonologist. He just feels that the oxygen will support mitochondrial function.
    OF NOTE: my residence is at an altitude of 4800 ft. Thanks

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