A Reason For Hope

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I have something special to share with you, since hope seems in short supply today. One of our own is a clear beacon of light in the fog. Dr. Michael Snyderman’s one man experiment has been presented here before, last in April, clearly showing a prolonged remission of his CLL due to antiretroviral treatment. Since then, he suffered a relapse, while still taking Retrovir (AZT) and Isentress (raltegravir). After carefully documenting the relapse, he added Viread (tenofovir) and here are his stunning results. This is the strongest proof of concept that we have at this time. It is possible he will be ignored, but by all rights, at the end of the day, he should be credited with changing medical history. He has been very brave and very restrained, having done nothing else for his cancer or his CFS, except for antiretrovirals. His leukemia allows for very precise monitoring, but do not forget that he had ME/CFS for many years prior to CLL, and he has experienced clinical improvement of those symptoms as well. It is a game changer, or should be.

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The parameters are:
  1. ALC. Total lymphocyte count. White blood cell counts (WBC) were determined on a LH 750 Coulter Analyzer. The percentage of lymphocytes was determined with a 200 cell manual differential and the absolute lymphocyte count was determined by multiplication by the WBC. 
  2. CD-19. Total B-cell count. CD19 percentages were determined by flow cytometry and the total count was measured directly.
  3. Trisomy-12 count. Trisomy 12 is a subclone of Dr. Snyderman’s CLL and probably the most aggressive of the CLL clones. The fact that it is also going down is very supportive of the importance of the response. Trisomy 12 percentages were determined by FISH on peripheral blood mononuclear cells and the absolute count was determined by multiplying by the ALC.
  4. γδ (gamma delta) T-cells. This isn’t a cell count, but a quantitative measure of T-cell clonality based on a PCR which detects gene rearrangement.
  5. ZAP 70. Zeta chain associated protein 70, a tyrosine kinase normally expressed by NK and T cells, is required for normal T cell receptor signaling. ZAP 70 is not normally expressed in B lymphocytes, but has been found in a subset of patients with CLL and appears to correlate with survival. Despite the uncertainty concerning normal threshold values, increased levels of ZAP-70 detected by flow cytometry denote a poor prognosis.

From Dr. Snyderman:

The 2nd graph is designed to make just one point. It shows the kinetics of the T-cells compared to the kinetics of the CLL. The importance is enormous. The gamma delta T-cells have never been tracked before. This shows that they can proliferate, not just remain static, but proliferate autonomously, like a neoplasm, albiet a low grade neoplasm.

At least in my case, the clonal gamma delta T- cells cannot be reactive as my plasma is negative for infectious virus; there is nothing there to react against. I hypothesize that rather than just being reactive, the T-cells contain integrated virus and the virus is coding for viral proteins that stimulate cell division and release of cytokines. Because the gamma delta T-cells tend to increase, cytokine levels must be increasing which at least partially explains why CFS patients get sicker and sicker.  Because the cytokines can stimulate cancer, increasing levels of cytokines is one explanation why cancer gets started and then gets worse and worse. Dr. Mikovits is repeating my cytokine signature to prove that the cytokines are back up again.
It looks as though the growth of clonal gamma delta T-cells which are known to make cytokines, coincident with relapse, may have stimulated my leukemia cells to increase. Cytokines are believed to be able to stimulate cancer. This is relevant to CFS because elevated proinflammatory cytokines are part of the reason that CFS patients get sick. Dr. Mikovits said that at the time of my relapse the DERSE cell assay was still negative for infectious virus so the relapse can’t be blamed on viral resistance. It probably represents the clonal gamma delta T-cells being more sensitive to whatever RT leaked through, despite the AZT, and the tenofovir must be able to shut this down. So Gag and Env must not yet be important to my T-cells. When I relapse again, I will test whether Gag and Env have become important, by adding fosamprenavir, which has been shown to inhibit MLV protease. The data suggests that tenofovir is synergistic with AZT and it may be worth considering using the two drugs together in the future to treat XMLV related disorders. Of course this is a one-person study, but as there is nothing unusual about me, it is a rational starting point for further investigation.
The greatly increased risk for B-cell malignancy in CFS may be due to infection of the B-cell line by XMRV’s. Retroviruses have been thought to cause cancer by insertional mutagenisis. This mechanism requires that the retrovirus proviral DNA be integrated into host cell DNA next to a proto-oncogene thereby inducing activation of the proto-oncogene. A more important mechanism with XMRV’s may be the ability of viral proteins to change host cell gene expression. 
Twenty-four to forty-eight hours after a permissive cell line is infected with XMRV, multiple cellular genes are expressed: “10 genes are implicated in cell morphology, 11 genes in cellular development, 12 genes in cell-to-cell signaling and interaction, 11 genes in cellular movement and 13 genes in cellular growth and proliferation” [1]. Spadafaro has shown that reverse transcriptase can cause gene activation and lead to the malignant phenotype [2]. In some retrovirus linked cancers, env [3] and gag [4] may also be important in malignant transformation. 
The finding that a retrovirus did not cause malignant transformation de novo in tissue culture would be irrelevant to the clinical reality of human cancer. It is accepted that multiple events are necessary to convert a cell line into a pre-neoplasm or a clinically important neoplasm. Human cancers have mutated genes and changes in gene expression that could make them permissive to infection by retroviruses. The retroviruses could induce further changes in gene expression that would make the infected cell line behave in a more malignant fashion. The corollary to this is that treatment that would subtract viral influence from a neoplastic cell line could make it behave in a less malignant way. 
A complementary hypothesis is that T-cells are also infected by XMRV’s resulting in a clonal T-cell expansion. The clonal T-cells produce elevated cytokine levels which may be partially responsible for the CFS. Furthermore these cytokines may have a paracrine activity that would stimulate a simultaneous neoplasm to behave in a more aggressive fashion.

Oncology has been focused on the obvious malignancy and cancer is much more complicated than that. No longer can oncology just treat the obvious malignancy. Attention must be paid to treating the clonal T-cells. It goes without saying that the virus also must be treated. We are just looking at gamma delta T-cells now. There may be other clonal expansions that we haven’t looked for yet: clonal alpha beta T-cells, clonal B-cells, clonal monocyte/microglial cells and clonal mesenchymal stem cells. We are just beginning, but at least we are beginning.

1. XMRV infection induces host genes that regulate inflammation and cellular physiology. Lee M, Gusho E, Das Gupta J, Klein E, Silverman R. J Urology 2011, 185(suppl 4):e 113. 
2. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R, Mattei E, Serafino A, Cassano A, Sinibaldi-Vallebona P, Garaci E, Barone C, Spadafora C. Oncogene 2005, 24:3923–3931. 
3. MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, Ross SR, Mon JG. JEM 2005, 201:431-439. 
4. Sequences within the gag gene of mouse mammary tumor virus needed for mammary gland cell transformation. Swanson I, Jude BJ, Zhang AR, Pucker A, Smith ZE, Golovkina TV. J Virology 2006, 80:3215–3224.

    Random Thoughts Upon Returning To Practice

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    I went down for a while after I wrote the last blog. I was feeling poorly and it was coloring my outlook, so I didn’t want to write anything I’d regret. I’ve been in Kapa’au, on the Big Island, for the last two weeks seeing patients and have felt noticeably better since I arrived. Pretty definite cause and effect. It’ll be interesting to see if it lasts through a third week, when the benefit of the altitude change should be over; this is the first time I’ve stayed so long. I still think that altitude is a major factor for me. My CBC was normal before this trip, for the first time off AZT for 6 months, but also for the first time in years, because my Hct was above reference after my move to Santa Fe, and is now 41, with normal indices.
    When I felt myself dip, I stopped Isentress, because experience has taught me that when things are going south, stop what you can. I was all over the place at the time, but didn’t notice anything I would call better or worse from stopping the drug. As usual with clinical medicine, especially with this disease, there are confounders, so I suppose you could interpret my current upswing as improvement from stopping Isentress, but I really doubt it. I think that it did something at the beginning (but certainly can’t prove it), and then was doing nothing. One of the interesting things that is emerging anecdotally is that the assumption, born from the experience of HIV, that if the drugs work they must be taken forever, could be incorrect for us. There are reports of patients improving from arv’s, going off for one reason or another, and holding the improvement, or even improving further. It is a relapsing remitting illness. Maybe the drugs can induce latency, which can be maintained in other ways. I remain on Viread, considering what is next. Of note is that a few people have improved on arv’s other than the three that Singh found inhibited VP62.
    Here are some cautions about the use of arv’s for ME/CFS, information gathered from our intrepid trail blazers. There are two patients who have had renal function elevation from tenofovir. One discontinued and one reduced to half dose, with return to baseline renal function, but isn’t doing as well clinically as before on the full dose. My understanding is that HIV patients without preexisting renal disease aren’t expected to have this problem, so more frequent monitoring is a good idea for CFS patients. When tenofovir goes bad for HIV patients, it causes a renal mitochondropathy and our mitochrondrial function is already problematic, so we may be more sensitive, as we are to drugs in general. We were checking safety labs every three months and have upped it to every two.
    Arv’s cause a “herx”, or cytokine flare, for most. I have heard of one patient who flared with arv’s, took them only briefly (no AZT), stopped them in April and is still worse than before, at a lower level of function, though seems to be slowly returning to baseline. She says she went into it with her eyes wide open. We all owe her a debt of gratitude.

    My impression is that patients who have had other problems addressed first have an easier time of it, and are more likely to respond. So far, I have not prescribed arv’s, not because I’m unwilling, but because there are other things that are more pressing that need to be addressed now. Neglect and/or the indiscriminate use of dangerous drugs characterize the care most have had to date. 

    My early practice impressions support what I have learned from my email and taking medical information calls for the WPI. We have been incredibly neglected. Doctors hear CFS and they forget everything they do know. They don’t do the regular things. If a healthy woman walks into a doctor’s office complaining of tachycardia and palpitations, with hyperlipidemia and borderline adult onset diabetes, family history of coronary disease, they might worry about it a little, get an EKG, treadmill, maybe try a few things. If a CFS woman walks in, she gets nothing. Doctor goes brain dead. They don’t get it that in addition to our weird symptoms, we get the usual things, sooner and worse. 
    The patients I am seeing are remarkably homogeneous. Clinically however, the money is going to be in the differences, looking at the way the disease has progressed in each person, where the vulnerabilities are, and what can be tipped in the patient’s favor. The most common possible intervention, likely to impact quality of life (besides stopping meds) is hormone replacement/balancing. In my last practice, in addition to other things, I did a lot of weaning patients from meds, with the support of neurofeedback, and also, hormone balancing, for women like myself, who were having a terrible perimenopause, after a normal menstrual and reproductive history. They were mostly in their 40’s. In this practice, I am seeing women who need the same thing, but they are in their 20’s. What was PMS for my generation is now PCOS for the next generation. And men have the same hormone problems, depletion and receptor insensitivity. 
    Bioidentical hormone replacement means using preparations that provide the body with the same molecule it makes on its own. In conventional practice, most doctors use synthetic hormone-like drugs, Prempro, for example, or birth control pills for young women. The Pre is Premarin, which stands for pregnant mare urine; it is a lot like human estrogen, but not the same. The Pro is Provera, a progesterone-like drug, probably responsible for the increased cardiovascular risk found in the Women’s Health Initiative, that killed HRT for the average woman. Bioidentical hormones have never been seriously studied, and probably never will be, because they are naturally occurring substances and therefore, not patentable.
    I am seeing families, husband/wife, mother/daughter; there is a CFS mother/autistic son scheduled for next trip. We are making progress on the family survey, though it isn’t quick, very labor intensive. Everyone helping is sick and we have no funding. Down and dirty… it can take more than 20 years for a spouse to get sick. Kids go down much earlier than their mothers did and are much sicker. If you have CFS, your chances of having an autistic first degree relative is very high. Real numbers forthcoming…
    Yesterday – Ali’s newest FaceBook picture 
    Ali is doing fantastically well. Her MCS symptoms have mostly resolved, to the point that she can get out again and be in places where there are chemical smells, like the hair dresser and the lab. Oxygen has been huge for her. She uses oxygen at 10L/min by non-rebreather mask for about an hour a day. She does it without prompting and she uses it for rescue if she does feel sick. We have it set up with the concentrator in the middle of the house and a long hose that goes anywhere. Then you don’t have to listen to the noise it makes. She tried the chamber once, felt sick from the pressurization, didn’t finish a full treatment and has declined to use it since. She says it is unnecessary, since she is doing so well. I have been using the chamber irregularly, partly because of all the travel. Normobaric oxygen is helpful for me, but a chamber treatment is clearly better. The problem is I don’t do it, because I’m not a great patient:). It’s much easier to use the concentrator alone. Being able to just grab the mask is wonderful, because it’s something immediate that you can do for yourself. It helps me within 10 minutes when I really dip.
    Options for trying oxygen? It comes in big tanks that are inexpensive (~ $20/tank), but at high flows, a tank doesn’t last long. Insurance will sometimes cover oxygen for migraines, otherwise, in most areas you can find an oxygen supply company that will rent you a concentrator for about $200/month. Often they only have ones that go to 6L. The delivery device needs to be matched to the flow rates. A cannula can go up to 6L/min (FiO2, or inspired fraction of oxygen, 24-40%, instead of 21% room air), but is really comfortable only at 2L/min. You can go to 6L/min with a mask (FiO2 up to 50%). A non-rebreather mask has a reservoir that holds the oxygen with a one way valve that lets it come in to the mask with inhalation. There are also valves on the side of the mask that let the exhaled gases out, including CO2. A non-rebreather mask requires a flow rate of at least 10L/minute and gets 60-90% depending on fit. Concentrators are sometimes available used, after people die. They should be serviced before use.
    The only absolute contraindication for hyperbaric (not oxygen alone) is the presence of a pneumothorax. Other contraindications are hereditary spherocytosis, prior treatment with bleomycin or cisplatinum, concurrent treatment with disulfiram, doxorubicin or sulfamylon. Relative contraindications, or conditions requiring close monitoring are problems clearing ears, asthma or anything causing air trapping, and epilepsy or high fever, because high dose oxygen lowers seizure threshold. Pacemakers and implanted pumps should be cleared with the manufacturer. High dose oxygen may accelerate the maturation of cataracts, but isn’t thought to cause them de novo. A disclaimer, like on a drug commercial:).
    I receive mail from people who have asked their doctors to prescribe oxygen for them and been told it’s too dangerous. Please ask them why they think so. Doctors have a visceral fear of oxygen and are not knowledgable with respect to its use. They were taught about COPD and hypoxic drive; COPDer’s who retain CO2 at baseline, in crisis can become obtunded and decompensate further, if given high dose oxygen. Practically speaking, by the time that happens, they are probably going to need intubation anyway, and in reality, even those patients tolerate oxygen just fine when they are not in trouble. I treated people with COPD and CO2 retention with HBOT for brain injury, 1.5 ATA 100% O2 delivered by hood for an hour in a multiplace chamber with attendant present, for 40+ treatments, without problems. 
    We have continued Ali’s modified Meyer’s cocktail (containing Leucovorin 10mg), followed by a glutathione push. She gets a clear lift from the infusions lasting a week or two. She comes to me when she wants one. Because I was going to be away this time for three weeks, she started oral folinic acid 800 mcg daily, then increased to 1600 mcg, and she has continued uphill in my absence.

    Oxygen and folic acid derivatives seem worth a try for pretty much everybody with ME/CFS, except perhaps, if there’s a history of cancer also, further consideration is warranted. Deplin (prescription high dose L-methylfolate), folinic acid, 5-MTHF. Side effects are limited to overactivation/sleep disruption, and are dose related. However, for every intervention, no matter how benign, there seems to be someone who has been made worse by it… Folic acid derivatives should be taken with B-complex and extra B-12. A few people get overactivated with too much B-12, so, as always, it is a good idea to start things one at a time, and if that happens, maybe try again another time at a lower dose.

    I have been deeply touched by the many expressions of concern I have received from readers during my short writing hiatus. It is amazing to me that so many people I’ve never met aren’t strangers, but friends sharing a common experience. So here we are, together again, waiting to see what will unfold in Ottawa.

    Exciting news from Dr. Snyderman coming soon…

    Where To Now?

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    Life is full of misery, loneliness, and suffering – and it’s all over much too soon.
    ~ Woody Allen

    Humor and music get me through, so here is tonight’s song:
    Where to now St. Peter by Elton John

    Every time I write a blog I feel like it might be my last. How could I have anything left to say? Then the next one appears in my head, generally pretty much fully formed, and I need to write it. It’s a strange process to reveal one’s personal journey so publicly. But your letters have made it well worth putting up with the unpleasantness and infighting. The feedback that my writing has helped someone’s isolation, or helped medically in some way, means everything to me. One of the worst things about getting sick for me was being unable to be of service.

    Writing this blog has required a willingness to be wrong. As I’ve said repeatedly, I could be wrong about anything, though it seems unlikely that I’m wrong about everything. If I am, I figure I can still become Jamie Jones and move someplace where there is no internet:). There must be somewhere on earth one could still go and live completely unplugged:). There are inconsistencies inherent in blogging, writing on different days from different moods. When I sit down to write, I try to center myself so I can find what is true for me at that moment. It isn’t about building a flawless argument over time. It is a moving target. I have made being honest more important than being perfectly consistent, but there isn’t much I’ve written that I’d retract. I’m not as angry now as I was when I wrote certain things, so I might be gentler if I wrote some of it today, but not so different in substance.

    I received a lot of mail today concerned that I sounded depressed and hopeless yesterday. I am neither. I am sad and, unfortunately, somewhat sicker than I was a couple of months ago. And really tired of this fight, because absence of proof is not proof of absence and we’ve got something serious, most likely of retroviral origin. Something I now have to treat, with or without all the answers. Like all of us, I hope that the BWG and Lipkin are positive studies. But if they aren’t, it doesn’t change a thing for me, except for the timeframe in which I can reasonably expect help and change. As Karina so eloquently said in the comments of the last post:

    I have accepted that I have to live with this disease and I will most probably die from it too. As ridiculous as it sounds accepting that is somehow giving me some peace of mind.
    I am no longer trying to reach for the stars but try to reach for the possible.
    I worry less…..
    But I still worry for our children
    and for our children we must continue to fight…. 

    I took a big emotional hit in early July, and my declines are always a month or two after a major physical or emotional stressor, so right on time. I am sorry that arv’s didn’t protect me. Until now, it has seemed to me that I was more resilient than expected. But I am not depressed and I certainly still have hope. My coping mechanism is always to look for meaning in my predicament. However, I am getting real about what I can expect, personally and professionally. Baby steps. I’ve put a lot of energy into understanding the unfolding science. The heady days of discovery seem to have wound down to this period of uncertainty. My focus has turned to the clinical now. I have a limited bag of tricks at my disposal, but not an empty one. I don’t feel in any way powerless. The patients I’m seeing have some maneuvering room and we will work with what we have.

    We are biding our time, for these myths to unwind…

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    Mood music for this post: Messages by Xavier Rudd

    So much contentiousness from people who are essentially on the same side! Let’s assume the worst case for the moment, that RRM is right. XMRV doesn’t pan out for the Blood Working Group or Lipkin. Where does that leave us? Where does that leave RRM, who has an affected loved one? Anyone arguing their points here is personally invested. So, hypothetically, XMRV is dead, a lab contaminant, and not as good at infecting live humans as it is at infecting human cells in tissue culture, so not a direct threat. Then what? Does it get put to bed again? That’s already happened a few times in the last 40 years. We still have millions of sick people for whom a retroviral etiology makes more sense than anything else. As a clinician, it is the best we’ve ever had as a model to develop an approach to treatment. Quite a lot is known about what similar viruses do in animals. Why don’t they spend the money to do the definitive deep sequencing we need rather than a couple of million dollars, and a bunch more time, to see whether a few scientists can do the same thing reproducibly? What if they don’t? While new babies are born with it and new people go down with it.
    Andrew Mason’s excellent work is an important signpost. It suggests the likelihood of human infection with more than one family of retroviruses. If it’s true that retroviruses have been introduced through vaccines, then it would be expected to encompass more than murine retroviruses, as the cells used come from different phylogenetic orders. This is the frontier of future medicine. It changes the playing field. Or should. Once allowed into mainstream thought it will inform not only every facet of healthcare, but will illuminate genomics and evolutionary theory. 
    With passage of time, it becomes increasingly apparent how naive I was when all this began with respect to the pace of science. Max Planck said, “Science progresses one funeral at a time.” I am coming to terms with the fact that the glacial pace of progress means it will probably be too late for me and many others. For now, the best I can do as a clinician is to keep my patients as comfortable as possible while they are under siege, until the cavalry finally appears over the hill. It’s been a long time coming. 
    The model I’ve written about for the last year and a half, and outlined in the last post, is the most workable we’ve had for an explanation and approach to the neuroimmune illnesses, now rampant in some of our families. Many talented people have identified pieces of the puzzle over the years, measuring downstream effects of particular tributaries, each adding to the rushing river of illness. The fact that it isn’t one virus fits well with the clinical diversity, though I still maintain that, with respect to the chronic fatiguing illnesses, the various syndromes tend to converge over time into a rather clinically homogenous whole. Different paths to a similar place.

    Keeping It Simple

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    It was good to hear from “John” again in the comments this morning. My head has been so completely in the clinical world since I wrote that post, that it’s hard for me to come back to it. I’d rather step back and take a look at the big picture. I’m sorry if it’s too loose for you John. I’m a doctor again. I don’t have the time that I did to read the pure science in exquisite detail trying to divine the truth from little bits and pieces of incomplete information. Not my job. Thanks for the input though, and may you never need my services:). Fortunately, the patient community still has a few friends in the scientific world and we will continue to rely on them to help us. Dr. Mikovits and I continue to “translate” for one another.

    What if everybody was trying to figure out what is, instead of what isn’t? It is a public health emergency, though it is truly the proverbial closing the barn door when the horse is long gone. Pandora’s box is open for the duration. A retroviral etiology made sense almost two years ago when the Science paper was published, and it still makes sense. So whether XMRV is XMRV’s or HGRV’s or XMLV’s, and whether VP62 is or isn’t the same as XMRV, and which ones have or haven’t been fully sequenced… Einstein said, “If you can’t explain it simply, you don’t understand it well enough.” I’m not saying I understand more than a little, but what I do understand is pretty simple. So here goes, an hypothesis, without references this time. Most of it is referenced somewhere on this blog (which has a search feature on the sidebar).
    People have written asking me to write a For Dummies post. For those of you not inclined towards the biological sciences, the following Wikipedia articles are background reading that help to put the rest of this post in context:
    Cell
    DNA
    Protein biosynthesis
    Retrovirus
    Mitochondria
    Mitochondrial DNA

    All organisms have a strategy for perpetuating themselves. Viruses are the simplest, carrying out their tasks by hi-jacking cellular machinery from the host. Retroviruses have a very efficient evolutionary strategy, inserting into the host genome. Simple animal retroviruses, in particular murine leukemia viruses, MLV’s or MuLV’s insert in places in the host DNA called CpG islands, start transcription sites, where they activate genes, presumably to create favorable conditions for them. They become endogenous when transmitted vertically. Endogenous means that the viral sequences are present in every cell in the body. Once endogenous, a retrovirus can be fully replicative or not. If not, it may still be able to generate viral proteins if activated, setting up a cycle of persistent immune activation as the body tries to deal with the foreign products. It may be measurable in the form of antibodies and sometimes antibodies are generated in response to self, producing the low level autoimmunity seen so commonly in this patient group.

    The axiom we were taught that viruses don’t jump species turns out to be untrue. Simple animal retroviruses are infectious to human cells in tissue culture. Animal cells have been used to grow live attenuated virus since at least the early ’30s. The first paper reporting the use of yellow fever vaccine, attenuated in mice, was published in 1932. Vaccines were tested on nurses and doctors. The first outbreak of a disease similar to ours was at LA County Hospital in 1934. The first cases of autism were described in the early ’40s. Kanner’s earliest paper on “infantile autism” was published in 1946. It has been known for a very long time that there were animal retroviruses present in the cells used to produce vaccines, but the assumption was made that it was an insignificant risk compared to the good done by vaccinating.

    In general, nature maintains a balance by killing off the weak organisms. There have probably always been a few ME patients, women with failure to thrive, “the vapors”, so the potential was there, the “jump” had already occurred, but then, we had to improve on Mother Nature. So we gave it an incredible leg up. Mainlined it into almost everybody. And not just one virus, but lots of them, some capable of recombining with each other, so that everybody’s infection is a little different. The result? An unbelievable increase in the incidence of all kinds of chronic diseases. Neuroimmune, autoimmune, genetic illness, cancer. It really hurts that I’m so old as to remember how different it was 35 years ago, when I was in medical school. I can actually remember being taught to do a review of systems when taking a history so as not to miss anything, generally expecting it to be negative. A negative review of systems is a relative rarity now, even in children.

    Regardless of what is there precisely, with respect to viruses and pieces of viruses, there are generalizations that can be made about the common pathophysiology seen in animals and humans. In mice, similar viruses can produce neurodegeneration or cancer. The viruses that produce neurodegenerative disease cause inflammation, with vascular permeability in the central nervous system. Other MuLV’s cause lymphoproliferation and malignant transformation.

    Take a look at the following table:
    NIH publication. Increase in cancer incidence 1950-1989. Ries et al.

    So where do the dots connect clinically for ME/CFS? Simply put…

    1. Persistent immune activation due to foreign viral product fueling inflammation. This happens in HIV disease. The way their disease is playing out, with proper treatment, they die sooner of the usual things. That’s the way our disease plays out without treatment, since untreated the disease doesn’t kill you like HIV. Rather taking the more colorful symptoms out of it, the expectation is earlier onset of cardiovascular, neurodegenerative disease and cancer. Vascular permeability, as in the mouse models, fits. Leaky endothelial junctions in the brain, gut, elsewhere.

    2. Symptoms consistent with inflammation in the brainstem and other structures in the CNS. In particular, most of the “mysterious” symptoms of the illness, that have confounded doctors for so long, can be tied anatomically to a strip of dorsal brainstem, which is housed in a tight bony canal and sensitive to any swelling. Structures in close proximity include the cranial nerve nuclei, carrying all the senses above the neck, the spinothalmic tract, carrying sensory information from below the neck to the brain, including pain and temperature sense, the reticular formation, controlling sleep and arousal, and relay nuclei for the autonomic nervous system, regulating all the involuntary functions of the body, including vascular stability and endocrine control. Nuclei in the brainstem are responsible for the production of neurotransmitters, norepinephrine (the locus coeruleus), serotonin (the raph nuclei), and dopamine (the substantia nigra), so dysfunction affects everything which is experiential. There is also a venous plexus that would be subject to compression, consistent with the recent findings that venous insufficiency, poor drainage, is common. The feeling of “brain swelling” that many report is probably accurate, like all the “crazy” sensations that patients describe. Structures in close anatomic proximity to this strip of tissue are the cerebellar peduncles, the amygdala, hippocampus and pituitary.

    3. Gene activation. In addition to making viral proteins or particles, simple animal retroviruses turn on genes, which may be clinically important, depending upon the functional integrity of the gene in question. Certain genetic disorders, such as Marfan’s and Ehlers Danlos, and certain autoimmune disorders, such as Hashimoto’s thyroiditis and Sjogren’s, are certainly over-expressed in the patient group. Methylation is necessary for proviral latency and it is clear that many of us have genetic methylation defects. However, it’s not as simple as methylating, as it isn’t desirable to induce latency in tumor suppressor genes.

    4. Lymphocyte abnormalities, proliferation, depletion, dysfunction. Currently a focus of my reading, including clonal expansion. Rather than butcher it, I’m going to hold off on this one for now.

    5. Mitochondrial dysfunction. The mitochondria are the energy factories of cells. ATP, the energy currency of the body, is produced from glucose in an oxygen dependent chemical reaction. Aerobic metabolism is much more efficient than anaerobic metabolism, to which the body must convert when not enough oxygen is present. Oxygen gets into mitochondria by diffusion along a pressure gradient, needing to cross the mitochondrial membrane. The internal mitochondrial membrane contains phospholipids called cardiolipins, and anticardiolipins turn up on the list of associated auto-antibodies seen in ME/CFS. MtDNA (mitochondrial DNA) is a circular chromosome which is inherited from the mother, unlike the nuclear chromosomes which come from both parents, so mtDNA is not subject to genetic recombination. Maternal inheritance certainly fits the epidemiological picture. MtDNA maintains genetic integrity, so it would be a safe place for a retrovirus to stow aboard.

    Andrew Mason MD, from the University of Alberta, has been publishing on a human beta retrovirus associated with PBC (Primary Biliary Cirrhosis). It is similar to MMTV (mouse mammary tumor virus), which was known as the “milk factor” before anybody knew what a retrovirus was. PBC is associated with an AMA (anti-mitochondrial antibody). In the following papers, he makes his argument for an HBRV (human beta retrovirus) and it all looks pretty congruent with our HGRV hypothesis, including his rationale for the use of antiretrovirals.

    An excerpt from the last paper:

    HBRV and the mitochondrial phenotype 

    Arguably, any causative agent linked to PBC should be associated with the aberrant expression of pyruvate dehydrogenase (PDC)-E2 on the cell surface of biliary epithelium and in lymphoid tis- sue, a highly specific PBC phenotype that is thought to lead to the formation of AMA. In vivo, HBRV is detected in PBC patient’s cells with aberrant PDC-E2 expression. In vitro, homogenized PBC patients’ lymph nodes, the conditioned supernatants containing HBRV and even pure MMTV have all been shown to trigger the mitochondrial phenotype in healthy biliary epithelium, whereas control lymph node homogenates and other viruses do not. Importantly, no in vivo patient data exist to link the mitochondrial phenotype with either bacteria or xenobiotics; indeed the idea of molecular mimicry has been circulating for over 50 years and never proven. 

    Of interest, betaretroviral infection has also been linked to the mitochondrial phenotype in several immunodeficient mouse models that spontaneously express AMA. For example, MMTV p27 capsid and gp52 envelope proteins have been detected in lymphoid tissues and biliary epithelium that also express aber- rant PDC-E2. Furthermore, we have found that the development of AMA mirrors anti-MMTV production. Indeed, MMTV has been shown to be central in triggering viral cholangitis in the NOD.c3c4 mouse model of PBC, as highly active antiretroviral therapy and MMTV neutralizing antibodies abrogate cholangitis. Of interest, NOD.c3c4 mice treated with lamivudine and zidovudine (Combivir) develop viral resistance with mutations in the YMDD region of the reverse transcriptase gene, similar to muta- tions found in hepatitis B virus or HIV occurring as a result of antiviral therapy. 

    Translational studies 

    Using the NOD.c3c4 mouse model with MMTV infection, how- ever, we have found that highly active antiretroviral therapy with Truvada and Kaletra is efficacious without the development of resistance. Recently, the same combination has been reported to normalize hepatic biochemistry in a PBC patient with HIV and HBRV co-infection. Accordingly, a randomized controlled trial with Truvada and Kaletra is planned to treat patients with PBC who are unresponsive to ursodeoxycholicacid (UDCA). Indeed, it is notable that clinical trials ultimately led to the recognition that H. pylori infection caused peptic ulcer disease and the proof that a viral association with PBC may be resolved in a similar fashion. 

    In summary, there are converging data to suggest a mechanistic link of betaretrovirus infection with the mitochondrial phenotype of PBC in co-culture studies and in a mouse model. However, we still lack firm patient data linking virus with disease. Accordingly, before we can endorse the argument that the evidence supports a viral aetiology for primary biliary cirrhosis, further studies will be required to definitively demonstrate integrations sites in diseased biliary epithelium and the serological reactivity to HBRV in the majority of patients with PBC.

    The Shifting Paradigm

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    I’ve been informed that the management at the WPI has decided that there will be no group in the clinic. The physicians will practice independently, rather than as the academic department I had envisioned. Thus there is no need for a clinical director and I have been given my pink slip, returning to volunteer status. I am disappointed by this decision, but remain completely supportive of the institute’s goals and the scientific effort. I still hope that further consideration will be given to my ideas in the future, when there are fewer obstacles than now, believing that a group would be a better way to manifest the translational research goals of the institute. I’ve launched the Physician Working Group and hope that the sharing of ideas in an ongoing way by this international group of medical practitioners will bear fruit.

    I am relieved that there is no longer a question of who I am speaking for here. I write from my multiple perspectives as a doctor, a patient, the mother of a patient, the wife of a nearly recovered but symptomatic patient and the mother of a healthy son with subclinical signs of the illness. My practice is growing and my intention is to share my clinical impressions going forward. This is the 97th blog I’ve written in 15 months. I’ve never gone back and reread it, but from where I stand now, other than changing the URL to the plural, treatingxmrvs, I still believe pretty much what I’ve written. I am continually refining, but the basic concept hasn’t changed. Our illness is of retroviral origin, plus genetics, environment, injury. But a paradigm shift will be required to understand what has happened. That’s why the etiologic agent has been so hard to find. It isn’t one virus, one illness as required by the old paradigm. There’s too much sequence diversity, as Judy Mikovits and Frank Ruscetti have been reporting since the first negative studies. Too many viruses and parts of viruses. And people are working on it. A group in Wisconsin just uploaded sequences to GenBank that suggest more diversity than everybody has been looking for in all the negative PCR studies: Partial molecular cloning with novel consensus PCR primers of the murine JHK retrovirus of human origin, a variant of the Xenotropic murine leukemia virus-relatedvirus (XMRV): Xenotropic MuLV-related virus 5′ LTR, partial sequence; and gag protein (gag) gene, partial cps

    The current technology is knocking at the door of solving it. Deep sequencing is beginning to be available, but still very expensive. XMRV has not yet been fully sequenced. VP62 was made in a lab from pieces of viruses taken from multiple tumors. Does it even occur naturally? It has been shown to be infectious in monkeys, but their antibodies don’t detect the strains present in humans, suggesting it’s different than whatever is infecting those humans. Zhang et al’s findings indicate that normal correct lab technique for retroviruses isn’t good enough for XMRV’s, which are not fastidious like HIV. Normal technique does not prevent spread throughout a clean lab in a matter of days. Therefore the contamination issues are serious and our best hope is that somebody develop a reliable serology test that picks up the whole group. A sensitive enough RT (reverse transcriptase) assay seems like it should work too.

    Oddly, just as I was writing this, the following came through on Co-Cure:

    The FDA is investigating vaccines for contamination by a variety of latent viruses, including XMRV.  They believe that cancer- and tumor-causing latent viruses may become active during the vaccine manufacturing process, and that some of these viruses are hard to detect with standard methods. 

    “Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered human retrovirus that has been found in both chronic fatigue syndrome and prostate cancer patients. Although these findings need further confirmation, there is a potential safety concern regarding XMRV in cell substrates used in vaccines and in transmission by blood transfusion and blood products. We are developing sensitive detection assays for XMRV to evaluate cell substrates and investigate virus transmission by blood transfusion in a monkey model.”

    Read the entire article at
    http://www.fda.gov/biologicsbloodvaccines/scienceresearch/biologicsresearchareas/ucm127327.htm

    This is truly wonderful news!

    From Age of Autism and Kent Heckenlively:
    FDA to Investigate Vaccines for XMRV Retrovirus

    Consensus

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    A consensus means that everyone agrees to say collectively what no one believes individually.
    ~ Abba Eban

    At the end of the comments from the last blog, the conversation turned to the new International Consensus Criteria for ME: Myalgic Encephalomyelitis: International Consensus Criteria. Carruthers et al. I’m glad that this is becoming a place where we can consider the issues together. My personal reaction to the paper was mixed. While I found it immediately useful for sending to uninformed doctors who might recognize their patient in it, it excludes a lot of patients who will therefore be hurt by it, if anyone pays any attention to it, which they probably won’t. In particular, it excludes a large subset of patients who had gradual onset or recovered to a great extent following a first crash. I didn’t meet criteria for the first decade of my illness. I certainly do now, but if this had been the case definition, the same things would still have happened to me with respect to disability coverage, disbelief and misinformed treatment by physicians.

    For the first ten years of my illness, I had no PEM. I could bench press over a hundred pounds, rode on the back of a tandem for an hour or more a couple of times a week, played tennis, could scuba dive and ski. But if I worked a full, normally intense day, I’d get a headache and a hypertensive crisis (up to 220/140). So I was forced to circumscribe my life in ways that didn’t trigger it. I worked in a clinic attached to my home to keep the day short and reduce stress. Ken Wilber’s functional bubble: link to letter and check out his very cool website www.kenwilber.com. I had episodes of severe anxiety, autonomic dysfunction (cyclic vomiting, not OI or POTS) and bizarre sensory symptoms (dysgeusia, globus hystericus, hyperesthesia, hypoesthesia in a dermatomal distribution). Also flu-like malaise. I didn’t meet the new ICC criteria during any of that time. I now have or have had literally everything on the list, except, for some peculiar reason, I’m still sharp, never “foggy”, and my memory is pretty good, as good as it ever was anyway. I wonder why I’m different in that respect, when otherwise I’m classic, and the only thing I can come up with is lots and lots of exposure to high dose oxygen.

    The problem with this newest case definition is that it allows minimization of the huge number of affected people by looking only at the tip of the iceberg. In the past, I haven’t been too interested in what they call it; it seemed like little more than semantics to me. I thought that case definitions would surely take a backseat to viral load measures. But it hasn’t happened yet. When I read the Science paper, one of my first thoughts was, thank God, my daughter will be able to walk into any doctor’s office and say, I have XMRV, without being subjected to ridicule, but that hasn’t happened yet either. We are forced back to case definitions, the search for markers to prove a biological basis and fiddling around the edges with respect to treatment. Now in practice again, I can’t bring myself to use CFS as a diagnosis, because it’s a perjorative and will be used to deny my patients treatment. There is no code for ME, but all the components of the illness can be coded separately.

    Ali went out with us for lunch yesterday for the first time since the fall, and still feels well after. She seems ready to cross that line again. She said that the things we’ve done with her have been real quality of life improvements, especially if you use hours of suffering as a meter. Glycemic control, hormone balancing, recently high dose oxygen and Meyer’s cocktail plus glutathione infusions, are the things she listed. There is no way to know how much antiretrovirals may be contributing at this point. We’ve considered going off, especially in light of the money involved, but have decided not to rock the boat. In my case, I think it’s worth taking for prophylaxis now that I’m exposed to patients, and they to me.  The trend in HIV is moving towards the use of antiretrovirals for prophylaxis and earlier treatment of infected individuals to prevent spread. The findings of Zhang et al that XMLV’s are highly infectious in a laboratory setting, as well as the isolation of XMRV from tracheal secretions, Xenotropic Murine Leukemia Virus–related Gammaretrovirus in Respiratory Tract. Fischer, suggest that HGRV’s may be spread by casual contact. The cluster outbreaks support this as well. Since many spouses and children are clinically well, host susceptibility is a bigger factor than presence of virus. Like HTLV, most infected people don’t become ill. 

    Careful history taking suggests  that HGRV’s can turn on and off, in a minor way, for a very long time without becoming a big problem. My history suggests this, with intermittent symptoms that went back to childhood, yet I considered myself healthy and had no medical record at all, except for pregnancies, until I became ill at 41. My husband has lots of symptoms, but doesn’t have ME or CFS by anyone’s criteria. I was intrigued by this paper about nail changes in CFS: Secondary structural changes of proteins in fingernails of chronic fatigue syndrome patients from Fourier-transform infrared spectra. Sakudo. I had nail changes that started maybe a decade before I knew I was sick, so over 25 years ago. I wore acrylic nails to hide it for a few years. I couldn’t find an explanation, except a little bit in Chinese medicine which is concerned with such things, but knew it meant that something wasn’t quite right. I have no lunulas now. Nail beds are short, not wide like clubbing. Nail plates curl at the end. I have Raynaud’s, subclinical for years, occasionally visible in the last few years. I think that the changes are probably due to cellular hypoxia at the periphery exacerbated by vascular instability.

    There is one anecdotal report of a young patient who improved dramatically on AZT/raltegravir, stopped the drugs after 6 months and has maintained the improvement. Our assumption that the drugs would need to be taken forever, because that’s how we treat HIV, may be completely erroneous. After following a small group of patients informally for a year and a half, my impression remains that the drugs move the illness, but we don’t know how to use them. Dr. Snyderman’s data is certainly compelling, posted last April here in Another Perspective. HIV doses may be wrong for us. There is one report of someone who has improved on very low dose AZT alone. CFS doctors have long known, start low, go slow, but because that is a no no for HIV, there is no experience so far. AZT has been used for HTLV:

    The last two papers suggest that low dose AZT may be useful. AZT works for Adult T-cell leukemia/lymphoma (ATLL), a lymphoproliferative malignancy that develops in a subset of HTLV–infected individuals after a long period of latency. Mahieux suggests that in this setting, it works not through antiviral effect, but through an anti-proliferative effect, requiring long term treatment to activate tumor suppressor genes. An explanation is offered for why some patients with ATLL respond to AZT and some don’t, response to treatment being dependent upon an intact tumor suppressor gene. AZT shortens telomeres in fresh ATLL cells, eventually inducing senescence and death of infected cells. Patients with mutated tumor suppressor genes don’t respond. The relative contribution of proliferation versus viral replication likely varies between infected people, possibly determining in which direction the disease progresses, ATLL or HAM/TSP, cancer vs neurodegenerative outcome.

    In the meantime, Simon Wessley wonders why people are angry with him when he says that we’d rather have an incurable retrovirus than admit that we are mentally ill: BBC news (audio). Dr. Wessely, it’s because a psychiatrist without compassion is a terrifying thing indeed. Meaningful psychiatric care, safe rehab, disability coverage, the simplest supportive interventions have been denied us for decades, but we’re supposed to thank Dr. Wessely for taking an interest in us. Go push your worthless theories in some other arena, or suffer the reaction. We’ve had enough of your “help”. Enough of your blame. When I first became ill, any real doctor could tell that there was nothing wrong with me. And I was a real doctor… The nephrologist who fancied himself an astute diagnostician was sure I had a pheochromocytoma or carcinoid tumor, but after he did all his fancy tests and couldn’t find anything, he concluded, “You’ve lost your nerve.” My hypertensive crises were diagnosed as “white coat hypertension”. How right he was, though my fear of white coats certainly turned out to be justified.

    Life Goes On

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    In three words I can sum up everything I’ve learned about life. It goes on.  ~ Robert Frost

    The week before I left to come to Hawaii was a difficult one for me. I took a series of emotional hits in quick succession, then had to leave home to take care of patients here, alone with no support. I arrived feeling sicker than I had in many months. My first patient was a well known advocate in our community, and I will always remember that she was there when I got off the plane, as well as her caring in the first difficult days. She knows who she is, a very special woman.

    Childbirth was the initial trigger for my illness, and a concussion once, but sustained emotional stress was involved in my worst declines. So I was a little concerned, as was my family. I did dip a little, predictably, but I’ve been able to function throughout and am feeling better again. More resilient than expected. Able to weather some difficult stuff without going down, a degree of stability necessary for the patients who are choosing to put their trust in me. At least they can be sure they are sitting with a doctor who cherishes every encounter, whatever the future may hold. I know what it’s like to be unable to work. Actually, I know what it’s like to be unable to roll over. I get a little frustrated sometimes at having to pace myself pretty extremely when I’m at risk, like now, but if I stick to very restricted hours and activities, particularly when I don’t have help, I can do the things I need to get done in the physical world. The medicine is the easy part. A reflex. So far caring for my own patients is sustaining me. As always, I work diligently to stay focused on what I can do, rather than what I can’t, and I don’t allow myself to sweat the small stuff.

    A few people wrote that they were disturbed that I said I didn’t expect a cure. I should have said in my lifetime or in the foreseeable future. In the same way that HIV patients are incurable, yet attain functional cures for long periods of time with treatment, I expect that a similar degree of successful management of the disease will be possible for ME/CFS patients. The politics and regulatory issues are a nightmare, as I’ve learned firsthand through my association with the WPI. Coming here to see patients one-on-one feels like respite compared to that. The hardest thing for me to absorb is that a giant hand came down and hit the pause button on the science, and therefore the search for appropriate specific treatments, until Lipkin opens the envelope and declares a winner. We have the technology! It’s just money and priorities. If everybody would wake up and recognize it for the public health disaster that it is, it would take a couple of years to get a handle on what’s there from an infectious disease standpoint, a couple more to figure out the basic pathophysiology and a couple more for compassionate use treatments to be available. But it doesn’t look like that is what is going to happen. The psychiatrists will have their way for a while longer. We will have a new diagnosis, CSSD, Complex Somatic Symptom Disorder. New name for Munchausen’s.

    The best news is that my Munchausen’s by proxy is in remission:). Ali is doing very well again, with large amounts of supplemental oxygen. We put the concentrator in the middle of the house with a long hose allowing her to be wherever she wants to be. She has been using it at 10 L/min for about an hour a day, more if she has breakthrough symptoms. She has needed no prompting, but wants to do it, because it makes her feel better. She has also had a few Meyer’s Cocktail plus glutathione infusions that seemed helpful, supportive, but she hasn’t had any for 4 weeks now and continues to improve with oxygen being the only new treatment. Her MCS symptoms, or hyperosmia, have almost resolved. She was able to go to a party for a few hours at a neighbor’s house last week where she was exposed to perfumes without problems. She hasn’t tried the chamber yet, but I have asked her to figure out if pressure adds anything for her, since she is much more sensitive than I am. As for me, I do think I benefit from the effect of coming to sea level from altitude (my house in Santa Fe is at 7000 ft). It most likely would be short-lived if I stayed, but should happen each time I come here, planning to use oxygen when I return to elevation. The travel really doesn’t bother me much anymore. I use the wheel chair service and am grateful for it. Supplemental oxygen during flight would protect against adverse effects of hypobaria and hypoxemia, but it is very expensive and a hassle. If I just pretend I’m home on the sofa, play with my iPhone and let them transport my body, the travel doesn’t seem to be a problem for me.

    And lest anyone think that mouse retroviruses are not part of the picture whilst we are waiting for Dr. Lipkin, reminiscent of Waiting for Godot:), take a look at this important paper: Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts. Zhang/Gazdar. It’s reads like science fiction if one considers the consequences of this wee oversight, realizing that mouse xenografts have been used since at least the 40’s, though I still think the early yellow fever vaccine work was probably the beginning of human assistance in the natural process. Or it may have begun even further back, with the selective breeding of mice in the early 20th century, mice that were unable to survive in the wild, producing infectious viruses to which they are not susceptible due to receptor mutations. The use of animals, including mice, for the production of vaccines started in the early 30’s or before. Yellow fever was attenuated in mice and injected into monkeys and humans. See previous blogs here, here and here. Also there must have been lots of experiments at the time that didn’t make it into print. The records from the Rockefeller Institute would probably shed a lot of light. This paper was published in 1932 and the first documented outbreak of Epidemic Neuromyasthenia at LA County Hospital was in 1934: Vaccination Against Yellow Fever With Immune Serum And Virus Fixed For Mice. Sawyer/Lloyd. J Exp Med. 1932 May 31;55(6):945-69. Infectious mouse retroviruses probably infected humans before that, but at very low levels, since the sick mice died like they were supposed to. 

    Hats off to Zhang et al for their vital work, and for calling a spade a spade. Finally someone stating the obvious. 22Rv1 doesn’t explain away all the ruckus, nor was it the incredibly rare event postulated by Paprotka et al. Like XMRV, it is a signpost to a much greater problem. It is the patients that are contaminated, and not by just one virus. Many infectious retroviruses. Just because way back when, Coffin, Stoye, Heneine and the gang all said it couldn’t happen, doesn’t mean that it didn’t. Some choice comments from the Zhang paper:

    ERVs represent remnants of ancestral germline infection by exogenous retrovirues and after integration into the genome are transmitted vertically as proviruses. Murine leukemia viruses (MLV) as ERV provirus forms are present at about 60 copies per mouse genome from which up to 15 copies are related to infectious xenotropic murine leukemia viruses (XMLV)… Thus, active mouse ERV provirus present in common inbred mouse tissues can be the origin of XMLV or recombinant polytropic MLVs which are infectious to human tissues implanted in laboratory mice.

    Earlier studies have documented that XMLV type-C retrovirus particles were indentified in human xenograft cultures derived after xenografting in immune-compromised mice… NCI-N417 SCLC cell line was established from a mouse xenograft by the Gazdar lab at the National Cancer Institute (NCI) in the early 1980s and this cell line was subse- quently found to contain XMLV a few years later.

    Reports of XMLV strains being present in human xenograft cultures appeared in the 1970s…

    Our results indicate that human tumor cells frequently become infected with MLV virus after xenografting and subsequent culture. We have observed that mouse stromal cells may persist in culture for lengthy periods. Mouse stromal cells, while they contain abundant provirus forms of MLV, including ecotropic, polytropic and xenotropic strains, seldom spontaneously release large amounts of infectious virus (authors’ unpublished findings). Virus infection of xenografted cells may require activation of XMLV virus by chemical or immunological induction in mouse and by prolonged mouse and human cell contact. Viral transfer may occur in the mouse host or during subsequent xenograft culture. Our findings of infectivity of XMLV-positive supernatant fluids demonstrated that XMLV can readily infect other human cultures without presence of mouse cells or other aiding factors, indicating that these viruses are highly infectious.

    In conclusion, our studies demonstrated that several MLV strains were present in over one fourth of xenograft cell lines. Infected cell lines were identified in most laboratories working with or establishing xenograft cultures, indicating that such contamination was widespread. Infected cultures usually release large numbers of infectious virions, and intra-laboratory spread of MLV virus to other cell lines maintained in the same facilities may occur, confirming the highly infectious nature of MLV virus. Retroviruses have been associated with multiple diseases including solid and hematologic malignancies, AIDS as well as with non-malignant diseases. The high susceptibility of human cells to infection with XMLV, the high levels of reverse tran- scriptase activity present in culture supernatant fluids and the demonstrated infectivity of the shed virions suggest that such viruses may present potential biohazards to laboratory person- nel involved in cell culture facilities or to those handling human xenografts. In addition, the effects of the integrated provirus or the released virions on the biology of infected tumor cells are unknown. Provirus integration into the genome is not random, and occurs preferentially at transcription start sites, CpG islands, DNase-hypersensitive sites and gene-dense regions, suggesting that provirus integration may influence transcription in the host cell. Thus laboratories handling or culturing human xenografts should monitor for monitoring personnel for viral antigens or antibodies to them. 

    The Treasure Hunt

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    I was in Reno last week. It was an honor to be there to meet Dr. Lipkin and hear about the study from the horse’s mouth. I also had the rare opportunity to listen to him brainstorm a little with Frank Ruscetti. It had a historically important feel to it. Dr. Lipkin is committed to being the perfect referee, “agnostic”, but I thought I saw the glint of desire to dive in to the discovery process. Dr. Ruscetti is a rare human being who sees his work in the context of the big picture. He is a realist, who never loses site of the patients that are the reason for the work in the first place.

    The study, at a cost of $2.3 million, is designed to answer two questions:
    1. Do XMRVs, and/or polytropic MLVs, exist in humans?
    2. If so, do they occur at higher rates in CFS patients than healthy non-contact controls?

    25 patients and 25 controls are being selected by 6 doctors, Montoya, Kamaroff, Bateman, Klimas, Levine and Peterson. Inclusion criteria are very restrictive to a particular subset of CFS that includes sore throat and lymphadenopathy. Samples will be split in Dr. Lipkin’s lab and two from each patient will be sent to 3 labs, the WPI, Lo/Alter and Switzer, where each lab gets to do their own thing. The study will be concluded to be positive if any lab can find 2 positives from the same patient. Discordant results will be decided with a third specimen.

    I think we are OK, that it’s a fair playing field. The most commonly asked question in the patient community right now is with respect to the possibility of specimen tampering at points of inception. Even if that did happen at one or two sites, it would skew the stats, but wouldn’t cause the study to be completely negative. It is wrong that so much rides on one study, that nothing else will go forward until it is completed, and that one man has been made judge, jury and executioner, though I came away with the impression that he was a good choice for a difficult task.

    Drs. Mikovits and Lombardi, Max, Shanti and Svetlana, have their work cut out for them, 600 specimens, each needing multiple tests. The best possible outcome for the patient community is that the WPI finds XMRVs/HGRVs at a higher rate in patients than controls, that Lo/Alter find the Ps at a higher rate in patients than controls, and that Switzer finds nothing, as expected. Dr. Lipkin mentioned more than once that, when the study is over, there will be a valuable repository of specimens remaining to look for what is there, should the study be entirely negative. At the end of his public lecture, he said that if anyone in the audience wanted to write a check for a million dollars, he’d find out what’s going on; good news, though the comment caused me pain personally, confirming what we all know, that we have the technology, but it isn’t being applied. He lectured about past virus hunts that only took days, also rather painful for this audience to hear. Almost the best news for me was that he said that CFS “smells viral” to him. He is involved in autism research and said that he suspects thimerosal in vaccines may in fact be implicated, not a popular stance with the vaccine companies. Let us hope that when this exercise is over, “the virus hunter” will be inspired to hunt viruses for us.

    I had an opportunity to discuss antiretrovirals with Dr. Lipkin and to share my personal experience. He stated his disapproval vehemently. I told him that we had significant anecdotal experience at this point and it appears to be better than placebo, though disappointing in speed and scope of response. I stated my opinion that prescribing arv’s constitutes the usual and customary off-label use of drugs, a decision to be reached between doctor and patient. We obviously disagree completely in terms of whether or not the prohibition against these particular drugs is justified, but, even though he had strong feelings on the subject in the present tense, he concluded it needs to be studied, though everybody agrees that, in the current economic climate, there’s no money for what will need to be a long, complicated study. I didn’t get the impression that he was in any way discounting the possibility of a family of retroviruses with too much sequence diversity to be found when looking with our current lenses.

    It was my 5th trip to Reno in 10 months. It was short, but the most stressful for me so far, maybe because it felt so important, though it was good stress, not bad, while it was happening. I felt “on”, but not anxious or consciously uncomfortable. I returned home still feeling strong. The day after I got home to Santa Fe, the Las Conchas wildfire started, now the largest in the history of the state of NM, over 100,000 acres, threatening the town of Los Alamos and Los Alamos National Labs. The air quality has been extremely poor. Here is a picture taken from our house, the night the fire started. The smoke is pluming all over Santa Fe and environs, making the air quality unacceptable for people with pulmonary disease. Mitochondrial disease too, I’d bet.

    Despite lots of oxygen, which helps everything during administration and for a while after, I’ve been in crash mode for six days now. First time I’ve gone down for more than a day since December, when I caught a cold after my second trip. No cold now; just CFS. I don’t like to report bad news if it takes away hope, but my commitment is to reporting the truth. Sleep, always a sentinel symptom for me, was the first to go. Then pain, nausea and orthostatic intolerance have put a serious damper on things. Cognition is the last to go for me, thanking God for the not small favor. Clearly, I am still at risk, despite dramatic improvement over the last year.

    Ali has been doing better since starting Meyer’s cocktail with Leucovorin, plus glutathione, IV pushes and supplemental oxygen by high flow concentrator (10L/min delivered by non-rebreather mask). She does an hour or so of oxygen a day, and the effects are so immediate and positive that she doesn’t have any resistance to doing it. At this point, we both consider the concentrator a no-brainer. She hasn’t tried the chamber yet. I’ve been going in about twice per week and using normobaric oxygen by mask about twice a week as well, and I haven’t decided yet whether I think the chamber adds enough to justify the expense/trouble or not. Ali had a friend visit her for 10 days recently. She used supplemental oxygen ad lib the whole time, was much more active than she has been able to be since last fall, and didn’t crash afterwards. She remains more resilient, despite the fire. She is wanting to get out of the house and just ordered some protective masks that she hasn’t tried yet, which people are wearing in Santa Fe now anyway.

    Ali’s MCS symptoms are subsiding somewhat and, if not triggered, she is doing really well. She can wear clothes from the dryer again, though choice of laundry products is crucial. She and I both believe that her symptoms are not triggered by chemicals per se, but certain strong odors, so hyperosmia, much the way some patients have hyperacusis and photophobia, which are also cranial nerve dysfunctions. I believe these sensory symptoms to be related to dysregulation of the cranial nerve afferants, which are relayed through nuclei in the dorsal brain stem, and then to the thalamus, which integrates sensory information to the cortex, regulates arousal/sleep and organizes/controls the timing of the brain’s circuitry. The heightened signal triggers what can be thought of for practical purposes as a subclinical seizure. For some, the instabilities in the brain stem can progress to observable atypical seizures or even full blown tonic-clonic seizures. Here is a study by Frank Duffy at Harvard showing coherence abnormalities on QEEG (measured on the cortex), in patients with CFS, not seen in depressed patients: EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients. Duffy/Kamaroff. Inability to detox properly is likely a piece too, but in Ali’s case, I think that the reactive dysautonomia is triggered by input from the first cranial nerve, rather than a reaction to a toxic substance.

    I leave for Hawaii later this week to see patients, looking forward to sea level and clean air. My patients all know I’m sick. When I hear their histories, I often remember exactly how that symptom felt to me, even though my illness has changed a great deal as it has progressed. They know that I don’t have the answer and that I don’t believe there will be a cure. Healing and curing are not the same thing. What we do have to fight with is a coherent model from which to plan a strategy for each person from where they are now. It will be two years soon since Lombardi et al was published; it has been nearly shot down by politics, not science, and  nothing has changed from a treatment point of view, other than antiretrovirals haven’t turned out to be the slam dunk for anyone, including me, that we needed. Of course there are hundreds or thousands of drugs sitting on pharmaceutical company shelves right now that might work, but so far, nobody is looking.

    Despite my disappointment (not surprise) that the science is not keeping up with the medical need, I remain hopeful and determined. It won’t be fast enough, but I do believe they will get it right this time, even if the route is circuitous. The scope of the discovery is spectacular in terms of the impact it will have on our understanding of chronic disease. It will transform many fields of medicine, but especially psychiatry, which still views our symptoms as arising from a defect of character. We are the ultimate mind body experiment, and it’s not about character, or lack thereof, that our psyches are too closely linked to soma, the body. There is a biological basis. Heightened senses come with the territory. The misunderstanding, even derision, from our supposed caregivers has caused great harm. It is one of the most painful truths in my life that should I be forced to seek help from my colleagues in the conventional medical world, they will likely laugh at me, not to mention do the wrong thing. But there is redemption in turning suffering into meaning, in using painful experience to become wiser. The disbelief has caused terrible isolation. Healing, separate from curing, is possible, in connection with the truth, and in connection with other people who understand and care.

    *    *    *

    We must never forget that we may also find meaning in life even when confronted with a hopeless situation, when facing a fate that cannot be changed.  For what then matters is to bear witness to the uniquely human potential at its best, which is to transform a personal tragedy into triumph, to turn one’s predicament into a human achievement.  When we are no longer able to change a situation- we are challenged to change ourselves…
    ~ Viktor Frankl in Man’s Search for Meaning


    Recent FAQs about the clinic at the WPI

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    1. How can I be seen at the WPI?
    There is already a long wait list. Patients will be contacted on a first come, first serve basis to be scheduled for the doctor of their choice. If you would like to be added to the wait list, please email, rather than call, your request to the WPI office: info@wpinstitute.org

    2. Do I have to be XMRV positive to be seen?
    No. Our physicians will treat ME/CFS and related neuroimmune illnesses, without respect to the results of any particular test.

    3. What treatments will be offered? Will antiretrovirals be prescribed?
    Each physician will treat their own patients. There will be no set protocol. Our physicians will be practicing in an environment that supports openness to all options. All decisions will be made within the context of a physician patient relationship at a particular moment, as always. Antiretrovirals are not promised, nor will they be forbidden. Off-label use of drugs is the usual and customary practice of medicine. We see ourselves as working within the context of a public health crisis. We believe that ME/CFS patients with severe disease should have the right to compassionate use of unproven drugs.

    4. What will be different than the care I’ve had in the past?
    The group nature will encourage a deeper insight into the illnesses at hand, and provide each physician with exposure to the treatment approaches most likely to be effective. Daily interaction between physicians and scientists will cross-fertilize the thinking of both, impacting patient care directly. Our doctors will be part of an international consortium of practitioners sharing experiences in our Physician Working Group. Records will become part of our database, which, with time, will grow to include a very large number of patients treated by a group of doctors, enabling us to look at outcomes in a broader way than is possible for a single doctor. Adverse outcomes will be reviewed and discussed within the group.

    5. Will there be clinical trials?
    As all of us know too well, there is no slam dunk, quick and easy trial to do. Tenofovir is probably worthy of study, but until we have a way to monitor, the clinical response is too incomplete and too slow for a short, simple study, given that any study we do now must be possible with extremely limited funds. Dr. Snyderman is interested in studying lenalidomide and we are looking at that. We are open to all options, but unfortunately, pharmaceutical options for study are limited at this time.

    6. Is it going to be an alternative medicine clinic?
    It will be a “conventional” medical facility, located on a medical school campus, with physicians who are CAM, complementary and alternative medicine, aware.

    7. Will insurance be accepted?
    No. A superbill will be provided for submission to insurance. Current Medicare and Medicaid reimbursement rates make it impossible for us to accept insurance and provide patients with the time consuming care necessary to impact the illness.

    8. Can I see you or be supervised by you in Reno?
    No. I’m not licensed in Nevada and getting a new license there with a “practice gap” will take some time. My duties in Reno are administrative. I have started a private practice on the Big Island, where I am licensed. Each physician in Reno will be responsible for seeing and following their own patients.

    The enormity of the need feels a lot like charging hell with a bucket of water, considering our limited resources, but we’re going to do it anyway, as we start seeing patients one case at a time.