X Rx

Moved...

2012-01-07T20:17:00.003-07:00

We have outgrown Blogger, with hundreds of comments per post. I have set up a website for my practice (under construction) on Weebly, and plan to continue blogging from there. The new blog has threaded comments, which I hope will facilitate the discussion.

The URL for the new blog is: X-Rx.net/x-rx-blog.html

An Olive Branch

2011-12-29T15:13:00.013-07:00

Hoping that everyone can relax a little, here's yesterday's song that I couldn't figure out how to post from my iPhone. We could use a little levity, I think.

She Blinded Me With Science

by Thomas Dolby

YouTube link (embedded video having difficulty on some systems)

When I started writing this blog, it was with a sense of astonishment that the physicians treating the patients, Lyme and CFS, didn't seem to recognize that they had a new quiver for their arrows. The few that did were quickly censured, or swore a few patients to secrecy. I had been housebound, sometimes bedbound, for years and never expected to return to work, so I didn't care who I pissed off. Anything was better than the isolation. The good thing about not caring was that I learned to write authentically.

During my 25 years in practice, I didn't interface at all with the scientific community. Doctors only. I had no idea about the realities of this parallel universe that so impacts what clinical choices are open to us. I thought that the Science paper would be hailed as a great breakthough; scientists and doctors would come together, bringing different things to the table. The pace of progress would accelerate. If only that had happened!

The scientists that I've criticized by name were Coffin, Stoye and Racaniello. The first two put themselves out there very early on in a way that appeared designed to stop progress. They also have a long history of publishing things together that minimized the risk, so aren't clean on the issue and their opinions shouldn't carry much weight. Dr. Coffin also took it upon himself to try to limit treatment options, my pet peeve.

Professor Racaniello is a media figure, so fair game. I admit to being influenced by hurt feelings in his case, because I wrote to him when I started arv's, in the midst of the first blush of excitement, wanting to have a discussion with him about the science and he shut me down, much the way Jason did. And to me, the tee-shirt still seems over the top thoughtless, though I think now that he probably didn't understand what he was doing. There are signs that he is growing, e.g. publishing Dave Tuller's important piece on his blog.

I was angry at Dr. Singh when she published her negative paper, for the reasons I expressed back then, but essentially the same thing again; scientists trying to call the clinical shots, though in this case I understand that she felt that her former paper was too strongly in favor. I sent her testimonials from patients improving on arv's at that time. My understanding from Dr. Enlander is that she is back on the case. I thought her a lovely person when I met her and I am glad she is again working on our behalf. The Mt. Sinai initiative is very exciting. It is difficult not to fantasize about Dr.'s Shadt and Lipkin putting their heads together.

And Jason. Sorry Jason, I didn't mean to hurt your feelings. I hope you learned something from our scuffle. No hard feelings on my end.

I hope I haven't forgotten anyone. A virtual olive branch offered to all, even those most aghast at my choices...

Believe it or not, there are scientists that share with me, and I protect their privacy. I swear I'll disavow knowledge of our friendship to my dying day if that's what any scientist willing to share wants. At risk of scaring off the people we want to be here, there is a tracker on the blog, that allows me to see the IP address, location and the name of the server that loads each blog page, as well as how many prior visits from that address. Institutional servers give the name of the institution. There are at least a dozen readers at the NCI and another dozen who connect from NIH servers in a few different cities. A couple at the CDC in Atlanta. Readers at many universities and teaching hospitals, including a few at Columbia and Harvard. Cancer institutes around the country. Only a few of these people participate in the discussion. This is a potentially powerful thing. When I worked for the WPI, one of things I most wanted to do was establish lines of communication between physicians and scientists with all kinds of points of view. There is little to be learned from consensus when the truth isn't even on the table. If there is a way to salvage some part of that dream, I'd like to.

Many of the scientists came to read about Dr. Mikovits' travails, but I am asking them to think about the science with us. In particular, I'd like to know your reactions to Dr. Snyderman's data. Please adopt a handle and share with us. Your secret is safe with me. I ask you for the sake of the patients that you are now beginning to know, be bold. I realize that you are constrained by the knowledge that a patient community can do what we did, but there are 17 million patients worldwide in the ME/CFS cohort alone, who need creative thinking from you. There is every indication that our disease is reversible until it is very advanced. The unclaimed talent in the patient community is staggering, if only the disease could be calmed, not even cured. Look at me. I am productive after years of being almost unable to care for myself, let alone anyone else.

I would like to put an end to the discussion about the lab science in the Science paper, the WPI, VIP Dx. Nobody knows the answers, including the protagonists. I certainly have no basis for evaluating any of it. I defer to the scientific community to figure it out; discussing it here is not productive. At this point, it is non-contributory and boring. Take it someplace else. This is also not the place to argue about whether Dr. Mikovits should be canonized or not, though she is my friend, and I am very sorry for what is happening to her. But from a clinical point of view it is irrelevant. This blog is about developing a model for treatment and how to best live with the disease.

Thank you to our mold warriors for giving it another shot here, and for keeping it appropriate this time. I for one, think that your experiences of improvement without medication are significant. I also understand why you feel the need to tell others in the hope of reducing their suffering, as well as your frustration when you feel you aren't being heard. I have been interested in Ritchie Shoemaker's pioneering work, since 2002 when we shared a couple of patients with Ciguatera poisoning.

And a big thank you to In Vitro Infidelium for the considered comment this morning. No invective or politics at all. Just a reply about the scientific discussion at hand. It was a breath of fresh air. Thank you for the excellent paper by Voisset et al. The quote you lifted in your comment is precisely the point. Although it clearly isn't a simple, straight forward infection, there is epidemiological evidence that it is an emerging disease of very great proportions, not a stable situation. AIDS isn't simple and straightforward either, without a test, in that infected people can remain apparently healthy for a long time, or even indefinitely. Only a small percentage of people with HTLV ever become clinically ill from it. Inbred sick mice don't get sick from their MLV's, but wild mice and some other rodents can. All I am asking for is that it be studied, not shut down if this attempt fails. Also, that our therapeutic options not be limited by how slow the science will be to unfold, even in a best case scenario in which Dr. Lipkin finds something.

My hat is off to Dr. Lipkin. His finely worded communication to the patient community brought tears to my eyes. The only thing I would take exception with at all was the use of the word definitive. If by some quirk of fate, this study is completely negative, we beg you, use those specimens to take the next step.

Today's song: Learning to Fly

by Tom Petty

The Tip Of The Iceberg

2011-12-28T19:10:00.001-07:00

We are driving from Dallas to Santa Fe today, so I have only an iPhone to write on. I started this as a comment to respond to In Vitro, but got carried away. It is off the cuff and there are unsubstantiated statements (and probably typos), so I anticipate critcism. Yes, this is loose. I am ever hopeful of a meaningful discussion between scientists, doctors and patients, so I tolerate all the ugliness in the comments. I have no interest in or time for moderating the comments on this blog. I wish the more annoying elements, nasty and repetitive, would cease and desist. Say it once or twice, not twelve or fifty times. It isn't any smarter after repetition. And I don't understand the need for disrespect and reactions verging on paranoia. There are lots of smart people reading. If we could engage that talent for the greater benefit, we might get somewhere.

In the paper under discussion, the group from Sardinia seemed to think they were dealing with "virions" and that they could reliably measure viral load. I am on an iPhone so can't cite chapter and verse. There are more clues in the references from that same paper. That work was done years ago already. Not replicated or retracted. No dismissal as contamination. Just nothing. I guess MS doesn't rate all that much better than we do. The lack of curiosity on the part of a small community of scientists sitting on top of a powder keg is disturbing and difficult to explain.

I do not, and will not read ERV's blog, so please do not reference it. She wrote about me a long time ago in a way that made it clear that she is not only narrow minded, but completely lacking in compassion, as are many of the characters in this movie. No credibility as far as I am concerned. So if there is something you would like me to read, please give me the papers, not some graduate student's interpretation. So far, I've seen nothing to suggest that I'm wrong about anything of substance. I keep waiting for somebody to make me think harder. Do you have something better than, it isn't true, because it isn't in the literature? Do you have a better theory?

I was not implying that MSRV is the causative agent in our disease. I was making a case for the possibility of a similar endogenous retrovirus being involved. Or for one or more defective sequences to have been rescued by otherwise harmless simple animal retroviruses. Or, or...

As for gender disparities, the fact that more women are diagnosed with CFS and there are more males with ASD is not incompatible with their being related infectious diseases; the male brain may be susceptible earlier in life. Females are apparently more susceptible at puberty, post-partum and during perimenopause. All broad trends; male and female individuals can get sick at all ages. Vaccines implicated quite often (both live attenuated and killed), in both ASD and CFS, but not consistently, like everything that has been looked at.

The work of Andrew Mason on a beta retrovirus associated with Primary Biliary Cirrhosis and an antimitochondrial antibody suggests overlap with our disease. A mitochondrial defect is implicated in the pathogenesis of Parkinson's Disease and mtDNA mutations may be involved. One of the autoimmune markers that shows up commonly in ME/CFS is anticardiolipins; the inside of the mitochondrial membrane is rich in cardiolipins, a phospholipid common to mitochondria and bacterial membranes. If anyone would look at the epidemiology in a big way, I suspect a pattern of maternal inheritance will show. Lots of reasons to study our mitochondria.

Looking for it is a mess, because it is a mess. It isn't one thing. Lots of sequences recombining with lots of other sequences. Some replicative, some not. One group looks a bit different than another, but with notable similarities. Members of family groups can have symptom clusters that resemble each other but are distinct from symptoms of other family groups. I predict that it will not be as neat as the work on MSRV.

Virus, genetics, injury. We are the canaries. The tip of the iceberg.

Tunnel Vision

2011-12-26T17:37:00.005-07:00

If it looks like a duck, and quacks like a duck, we have at least to consider the possibility that we have a small aquatic bird of the family anatidae on our hands.
~ Douglas Adams

I have to hand it to Dr.'s Switzer et al for responding to the vaccine question. Even if it was a very literal response, the findings were imparted clearly and believably. They looked for mouse viruses in 8 vaccines currently on the market. None of the vaccines were grown in mouse cells and, not surprisingly, they didn't find any mouse viruses. No MLV's at all in vaccines produced from chick, macaque, guinea pig or hamster cells. However, they did find human, avian and porcine endogenous retroviruses that they already knew were there, plus a new hamster virus in the vaccine grown in hamster cells... but it was DNA only, not a speck of RNA, so no worries... No Evidence of Murine Leukemia Virus-Related Viruses in Live Attenuated Human Vaccines. Switzer. Their conclusion: "We found no evidence of XMRV and MLV in eight live attenuated human vaccines further supporting the safety of these vaccines..."

If it wasn't so sad, it'd be funny. Here is a paper from almost 30 years ago that says that a replication defective ERV can be rescued by mixing it up in culture with primate cells: Maturation of murine leukemia virus env proteins in the absence of other viral proteins. Schultz, derived from this work: Molecular properties of a gag- pol- env+ murine leukemia virus from cultured AKR lymphoma cells. Rein.

What a concept! Rescuable incompetent ERV's. They knew about it in the early 80's, and knew that there were infectious animal retroviruses in vaccines, but decided not to worry about it. And why can't these parenterally administered xenotropic and polytropic viruses infect humans? "Because they can't". "They are inactivated by human serum." Now that certainly is sound scientific reasoning. And they accuse patients of poor scientific discourse? Scientists please, take your blinders off. There is a whole generation in which 1 in 100 is autistic.

This is where the science is, if anyone cared enough to apply it to us: Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Macfarlan

Here are a few good ones:

Risks linked to endogenous retroviruses for vaccine production: a general overview. Dewannieux
Isolation of an Infectious Endogenous Retrovirus in a Proportion of Live Attenuated Vaccines for Pets. Miyazawa
Endogenous retroviruses as potential hazards for vaccines. Miyazawa
Divergent Patterns of Recent Retroviral Integrations in the Human and Chimpanzee Genomes: Probable Transmissions between Other Primates and Chimpanzees. Jern "According to the “breakout” hypothesis, copackaged RNA of partially defective ERV elements occasionally may recombine, thereby rescuing and optimizing retroviral function during reinfections from within."

Dr. Anon, PhD thinks I should do nothing for the next 10 years while I, my daughter and my patients deteriorate. We should all just wait while a bunch of jokers at the CDC try to figure out what the questions are. I know what the questions are. Anyone with critical thinking skills that has actually read what I have written on this blog (including the references) should know what the questions are. Whether or not one particular xenotropic MLV exists in humans or not is now quite besides the point. Not finding MLV's in 8 vaccines that never came near a mouse cell doesn't support the safety of anything. Even Switzer et al suggest that maybe they should look at batches of old vaccines, though my understanding is that they were mostly used up in the search for the origin of HIV. They also seem to think that maybe the monoclonal antibody folks should take a closer look into their products, e.g. rituximab, produced via an intentional fusion of mouse and human. They've been doing this since the '70's. Fooling Mother Nature. Would one of the scientists reading like to explain to us exactly how this is done? The literature is confusing.

But Dr. Anon, PhD, reading my blog, wants to "puke" because I am taking properly prescribed drugs for an off label indication? What a world! Tenofovir is prescribed for chronic Hepatitis B. Does that make you want to puke? We have non-HIV, non-HTLV AIDS, exactly analogous to non-A, non-B hepatitis before C was isolated. Wikipedia article: Off-label Use. The off-label prescribing of existing arv's is completely legal. The only reason to prohibit it is because of the enormous financial implications if it works. Only a very few people have tried it. No disasters yet attributable to it, unlike most of the pharmaceutical alternatives; and to the scientists reading, you wouldn't believe the dangerous crap my patients come to me taking, in combinations that have no research at all behind them to tell us about possible interactions. In my case, the only adverse effect of my experiment with arv's that I can point to is that my straight hair became curly; this happens occasionally with chemotherapy and other drugs.

Tenofovir treats Hepatitis B. Raltegravir inhibits Herpesviruses. AZT has been noted to impact Sjogren's, which seems to be overrepresented in our patient group. Protease inhibitors kill some parasites. I referenced a paper in the last blog in which it was reported that HAART brought about an impressive remission in a patient with advanced MS (and some of us, myself included, have MS light). Those "confounders" are good things about the drugs in clinical practice; all drugs have good things and bad things about them for a given individual. As a clinician, I love it when a drug hits two things in a patient, making it more likely that the cost/benefit ratio for that drug will be favorable for that person. However, the idea that my response to arv's is because they controlled my Herpesviruses is almost as ludicrous as the idea that Dr. Snyderman's cancer cells went down because of a placebo effect. Twice.

This seems like a good time to note that I have never had mono and am serologically negative for EBV. Since I was an ER doctor for 16 years and exposed to lots of mono, my body must be pretty good at keeping invaders out. Ali's EBV tests are consistent with prior infection, and we both have low titer IgG for HHV-6, like almost everybody. There is really nothing to suggest that we have activated Herpesviruses as part of our picture, opportunistically or otherwise. Ali falls squarely into the Lyme group, not the activated virus group, and opportunistic infectious are not really a part of my clinical picture at all. I catch almost nothing. It's the inflammatory effect of the physiological changes caused by the persistent immune shift to fight viruses so effectively that creates the subjective illness. Patients, and doctors, often confuse the symptoms of persistent inflammation with an active infection that needs to be killed or treated. There is also a subset of patients that catches everything and has ongoing problems with activated viruses. I have heard from people who have had mono and shingles numerous times.

Most novel uses of existing drugs are figured out serendipitously. Somebody with two things takes a drug for one thing and the other thing gets better. Occasionally, somebody actually connects some dots and tries something on purpose. If it gets reported, it is called a case study. In a sane world it would be followed with an open label trial and then a double blind placebo controlled study.

In response to the criticism that I've lead thousands of innocent patients down the garden path, please read what I've written, before jumping to conclusions. I have never said anyone should take arv's. My point is that it should not be prohibited, and most definitely, the decision should not be in the hands of a bunch of lab scientists that have never treated a patient. A retrovirologist has no basis for an opinion about treatment at all. That they would presume to comment is a sign of disordered thinking right there.

As I have said all along, ours was never a good experiment. What I have reported here is strictly clinical medicine. We were on an uphill course for about six months before starting arv's, after quitting Lyme treatment. I do think that antibiotics were making us worse and when we stopped them, we went uphill, though an LLMD might say our treatment had worked:). I believe that arv's helped us, though incompletely, not surprising for patients that have been sick for many years, who most likely have a high proviral load that continues to replicate mitotically. We still seem to be doing better than might be expected, but I have no way of knowing how we would be at this moment had we never taken them. The only marker we had to follow, TGF beta-1, initially very high has normalized for both of us over a year and a half (see numbers posted here; the pending results from 11/30 were normal TGF beta-1 and elevated C4a, for both of us). It is a very bad disease and we both feel lucky that our suffering is reduced. I wish that the science was keeping up so that we might have a better way of monitoring our therapy. We need a viral load measure or RT assay to follow, understanding full well that we might have more than one virus each and replication incompetent contributors. My biggest concern is the possibility of viral resistance, not toxicity of the drugs.

As far as the arv elist is concerned, I try to create a safe place for patients taking arv's to discuss their experiences. Occasionally, I answer a question, but mostly, it is patients talking to patients. Everyone on the list, thirty or so of them, decided to take arv's on their own, and all have their own prescribing doctors, except for a few that live outside of the US. In my practice, since I am willing to prescribe arv's for an extremely informed patient, I must not be pushing it very hard, since none of my private patients have yet swallowed an arv.

Unfortunately, it is still the patients least likely to respond who are trying it, people who have been sick for a very long time with advanced disease that feel like they have nothing to lose. Much scarier to contemplate, but with a much greater possible upside, is the question of what would happen if newly crashed ME/CFS or ASD patients were treated quickly after onset of symptoms. This obviously needs to be investigated, but in a controlled setting. It will be very expensive to do safely, so is unlikely to happen for either of these conditions (cancer more likely). People don't like to be wrong and there are lots of wrong, powerful people in this story.

My husband has been acting CFSy lately. When his symptoms flare, I am always impressed that it must be an infectious disease. All four members of my nuclear family have certain common symptoms, e.g. painless ocular migraine, which was a rare condition when I was an ER doctor 17 years ago, and orthostatic intolerance, of a form that nobody had ever heard of a few decades ago. Vascular instability and autonomic neuropathy in four members of a nuclear family, two sick, two not. Husband and wife not even distantly related. I thank God every day that my son isn't autistic. I vaccinated him selectively, for the wrong reasons, but I have heard from that woman out there who, like me, has CFS and a CFS daughter, plus an autistic son. Is it because I didn't give him the Hep B vaccine (which is not a live vaccine, but causes persistent immune activation over a long period of time)?

I get letters now and then suggesting that I do not know how horrible polio and other infectious diseases were before vaccines. That isn't true, I do know. But just because the vaccine program saved many people doesn't mean that we shouldn't look at problems that may have been caused by it, and modify our recommendations now for people at high risk, e.g. people with CFS and new offspring of ME/CFS women. We desperately need extensive epidemiological studies to find out what happened when. If you want to look at the bigger evolutionary picture, we have changed nature's culling process. If you take the starfish parable from a few blogs back to it's natural conclusion, throwing the starfish back is a mistake, because they are vicious predators that overbreed and damage the reef.

In the meantime, the backlash from the flash of illumination has started. The Mayo Clinic says SSRI's (which many ME/CFS patients don't tolerate), sleep meds, GET and 'therapy' are what we can have as far as treatment goes. That's the best they can do for a million sick people? On their website: "More than 3,300 physicians, scientists and researchers from Mayo Clinic share their expertise to empower you to manage your health." Shame on them. May the doctors that came up with this page never have to get sick, or have their child get sick, with a horrible debilitating disease and be faced with such options. May they find some shred of compassion in their hearts of stone before that fate can befall them.

I am writing to you today from the Louisiana bayou. My husband's 50th birthday present a couple of months ago was our first RV, and this is our first trip. We have always wanted to try the RV lifestyle, but now even more so, since we love to be in nature and it is the only way that I can still travel comfortably. Our son was just accepted to Tulane with a big scholarship, so we decided to take him to New Orleans to help him decide what he wants to do. Ali didn't come on this trip, but will come on the next one, shorter and closer to home. The trip has been exciting, to say the least. We survived the worst blizzard in 40 years in north Texas and a tornado warning in southern Louisiana.

I love the spontaneity and limitless possibility of seeing the world this way. Change is usually so difficult with this illness, but everything I need is close at hand and comes with us when we move. The pendulum of my disease continues to swing, as always, while I practice the art of transcending symptoms, living as many full moments as I can. Right now, my husband and son are fishing in the rain. We've had the worst luck with weather. Adversity is giving us all the opportunity to practice acceptance and work on our interactions in a close space. Like life, the difficulties have been punctuated by amazing moments; yesterday we watched from our canoe as a small otter caught and fought a huge fish, then defended it from a Great Blue Heron. This part of the country is very wild and alive. When I couldn't sleep for a while last night, I listened to wonderful, unfamiliar night noises.

And the breaking news? Lo et al just retracted, saying the work was perfect, but the conclusion must be wrong, since nobody has replicated it yet, except for one other lab. Therefore, enough money wasted. Now there's some ironclad logic for you.

Tonight's song: The Wild Goose

by Kate Rusby

Experiments In Vivo

2011-12-18T18:04:00.006-07:00

So here we are, two years after the scientific community was told which rock to look under, still arguing about whether two or three scientists can reproduce their work or not. In the meantime, a promising avenue of treatment, antiretrovirals, has been shut down like a prohibition, for the flimsiest of reasons. Too dangerous (compared to what?). Too expensive (for whom?). AIDS patients need their drugs (since they have a serious illness). How can we treat it if we don't know the precise agent we are treating? The way doctors treat people every day. Best guess. I actually think we have a better model than the rheumatologists are using to prescribe incredibly toxic drugs for patients with autoimmune diseases.

AIDS patients have to be treated forever, but we don't have any idea if that is true for us or not. Just think how much we'd know now if part of the money that was spent trying to find a virus that doesn't exist in nature could have been spent on very simple clinical trials of safe, existing drugs. It is becoming clear that at least some are concerned about lab contamination by viruses that are very good at infecting human cells in vitro. See Zhang and Sfanos on the side bar. It's about time somebody worried. Whatever works, and fear is a good motivator. It worked for HIV.

Here are a few excellent papers that have helped me to refine my working model, though I don't like it that it is going towards greater complexity, since I like grand unifying theories. But the level of complexity of the problem is intersecting with the state of the art. Cutting edge sequencing and analytics are required.

I still think it's simple retroviruses at the bottom of it, and maybe not just gammas. Simple retroviruses go for the germ line and become endogenous. Multiple assaults. Most end as ineffective sequences, with deletions, tamed by restriction factors that give an individual's offspring an evolutionary edge. ERV's can be defective and still cause disease. They can even become symbionts:

Defective sequences can be reconstituted by new incoming. It is not as simple as one sequence or one virus, or even five strains of one virus. Lots of viruses and pieces of viruses. Lots and lots of exposures, if it came from vaccines, grown in all kinds of cells, murine and avian, administered parenterally to most of the human race for decades, and subject to recombination. There were clearly waves when people got sick, but those may have been recombination events, when some necessary piece was supplied to reconstitute something that was there already. Or maybe there were waves of helper viruses that went out and turned on what was there. Or particular environmental toxins that activated one from an earlier invasion (from the Weiss paper above: "..we were able to show that treatment of normal chicken cells with a variety of activating agents such as ionizing radiation or carcinogens stimulated release of virus..").

This was probably part of the problem too; endless selective breeding of sick mice that produce retroviruses that they are resistant to, but the cells of other species may not be, hence putting lab workers at risk, especially those working directly with tissue culture and xenografts. The Mouse Trap: The dangers of using one lab animal to study every disease. Engber.

The younger women I am seeing, and who have written to me, often have symptoms consistent with PCOS (polycystic ovary syndrome). The few I have tested in my practice, have laboratory evidence of LH insensitivity, LH/FSH ratio greater than 2 in a menstruating woman with normal FSH. LH insensitivity interferes with the egg being released from the developing follicular cyst, so the corpus luteum doesn't form properly, progesterone isn't made normally, and estrogen dominance, with all its problems, ensues. The condition is also characterized by high androgens and a dysmetabolic syndrome causing central body fat distribution. Does progesterone deficiency favor the virus? Physiologic replacement is a powerful therapeutic option for women so affected. PCOS is a very common cause of reduced fertility, so if germline retroviral infection is involved, it isn't a very good strategy for a virus that is not spread horizontally. However from an evolutionary perspective, if the virus succeeds in most of its hosts, the few that become infertile and are a dead end, are just part of the evolutionary process. Remember that only a very small percentage of HTLV patients ever get sick and genetic factors are probably key.

Env proteins are strongly implicated in the neuropathogenicity of MLV's, and also recognized in the evolving retroviral model of RRMS (relapsing remitting multiple sclerosis).

Could antiretroviral drugs be effective in multiple sclerosis? A case report. Maruszak: This is a letter to the editor behind a paywall, but documents the resolution of significant neurologic impairments, including bladder and bowel incontinence, in an MS patient after being treated with HAART for HIV infection. The patient developed MS and was infected with HIV in '85. He was treated with HAART in '96, improved rapidly with resolution of many MS symptoms, including fatigue, within two years. It happened in the late '90's and it was just published... It is the only paper I could find where anyone has documented an effect of arv's on MS, despite the fact a retrovirus has been suspected for over a decade. How's that for blinders! What is it about this particular class of drugs that has everybody so spooked? Is it because AIDS patients have to take them forever? It may not be the case here. The best anecdote I've heard was 16, only sick for 8 months, responded quickly, stopped treatment after 6 months and has stayed well, as far as I know. And even if the drugs are for good, they are very clean drugs. HIV infected people have gotten very good research into their disease.

The literature suggests that the search for a sensitive enough reverse transcriptase assay was abandoned for HIV, as specific testing became highly sensitive. However, if you were looking for generic replication competent retroviruses that you could monitor, a clinically useful RT assay would seem to be indispensable. RT assays have been used in the lab since the late '60's, but seem to have been abandoned more recently, except for research purposes involving monitoring of retroviral vectors. Maybe one of the scientists reading can explain why this test isn't clinically available? Why wouldn't it be useful for MS, for example, given the suggestions of the papers above concerning that disease? Maybe some money to be made here, for any diagnostic test patent seekers who might be reading.

Ali remains on Viread/Isentress and continues to be surprised by greater than expected resilience, e.g. rapidly recovering from having her wisdom teeth extracted. I came off Isentress a couple of months ago and didn't notice much of anything. It didn't seem a good idea to stay on monotherapy and someone already committed to the experiment needs to give a protease inhibitor a try; therefore, I started Lexiva two weeks ago.

There was a recent paper showing that amprenavir inhibits XMRV in vitro (Li/Wlodawer on the side bar), but also, there are several clues in the literature that suggest that it might inhibit MLV proteases more broadly. HIV treatment wasn't truly effective until PI's were added. The first time I tried Lexiva, as a fourth drug then, still using an HIV model of HAART, it had the unexpected effect of CNS activation and it is doing that again. I describe it as "turning up the volume", a perceptual shift. I am more reactive, but that is dying down now. It doesn't do this with AIDS patients and I have no explanation, other than it moves the disease in some way, since I don't see how it is an adverse effect of the drug. The other arv's shook things up for me for a while too, but that felt like an inflammatory flare of usual symptoms. Physically, I think I feel a bit better, stronger in the last few days, but it could well be the swing of the pendulum. I will stay the course and report.

Here is a letter that I received a few days ago:

Dr. Deckoff-Jones,
I'm writing to you in the hope that by sharing a little of my medical history I can help. If XMRV is totally out of the picture it must in my case be a related retro-virus. I think if there were a place to pool ME/CFS patient information there might be something made obvious through comparative analysis.
I started on AZT about a year and a half ago On 3/6/10, my health seemed to gradually improve, by december I developed pain on the inside of both legs so at the end of december I stopped taking AZT. I declined rapidly and by the first of February I was worse than before I started on AZT. A few days into February I started taking Viread and Isentress and felt even worse for the next 10 days to two weeks (which I had read to expect this) I actually kept busy just to take my mind off how bad I felt.
Gradually I started to feel better and by the end of May of this year I thought I was well on my way to a normal existence. I think it was July and September I declined. Today I am definitely better than when I started but still far from my goal. I don't want to stop taking anti-retrovirals.
I'm wondering if I would have done better if I had included Emtricitabine and if I should start now. I will discuss it with my doctor. If a yet unknown retrovirus is the culprit, it's anybody's guess as to which drugs are most effective.
I think the best course of action would be to find the cohort who have responded to the three above mentioned drugs and divide them into groups to see how they respond to other (additional) anti-retrovirals.
I think everyone affected would be perfectly okay with finding the treatment before finding the cause. Even if it's a small subset of patients, we will have chipped away a little at this stumbling block we call ME/CFS.
I have had this for 18 and 1/2 years and I'm about to turn 64. So like everyone else I want answers now.

Sick patients trying to figure it out on their own, the ultimate failure of an ineffectual system. Scientists not only don't talk to patients or doctors, they don't even talk to each other, since somebody might steal their ideas. All closeted, each guy alone in a lab looking at a little piece of the elephant, writing in notebooks with pens?!! No copies? It seems even more dysfunctional than our broken medical system, that a dispute between a scientist and their employer can result in the hopes of an entire patient community being dashed on the shoals of intellectual property law and the criminal justice system.

I would like to thank Dr. Lipkin for being the voice of reason in an insane situation. He is positioned to help us. I hope he stays interested in our plight. We have very few friends, but maybe one new one who has the wherewithall to crack the case.

I maintain a confidential elist for patients taking antiretrovirals. Anyone reading who is taking arv's and who would like to be signed up, please contact me: jdeckoffjones@gmail.com

Today's song: If Not Now

by Tracy Chapman

Update From Michael Snyderman, MD

2011-12-15T21:37:00.008-07:00

To scientists and the CFS community:

I have updated my ongoing one person anti-retroviral treatment study of a patient with chronic lymphocytic leukemia and CFS. I have been on this treatment since 5/27/10. My first response to AZT and raltegravir lasted through March 7, 2011, 9.4 months. I collected relapse data until July to make sure I had enough parameters. I added tenofovir 7/18/11. My leukemia cell counts are about 25% of what I would have projected them to be by now. My last set of blood work was done December 12, 2011 although only the total lymphocyte count has returned, other parameters pending. It is now 4.5 months since I have added tenofovir. Before I started ARVs I was ill enough with the CFS that I thought I would have to retire. Since, I am not perfect, but I am improved and am functional, 17.8 months since I took my first dose.

I agree that XMRV is not the pathogen but indeed my results show that a retrovirus is part of the etiology of both the leukemia and the CFS. It is a one-person study, but my leukemia and CFS are quite typical and there is nothing at all unusual to suggest the results do not give an insight as to what is happening with us. The paper will be submitted for publication when my integration studies are available, hopefully in the next couple of months. I will add a title, abstract and methods at that point.

My conclusion is that further research is clearly indicated and it would be very reasonable to have the government fund this research.

Below is a FAQ that I believe will be helpful:

1. Is it unethical to treat myself with ARVs?: No

As an oncologist, I understand the value or lack of value of all standard treatment options for Chronic Lymphocytic Leukemia. I am not seeking reimbursement for the treatment from a third party payer and am not using illegal drugs. There is no associated financial gain.

2. Could my response have been due to selective toxicity of the ARVs? : No

Of the many anti-cancer agents developed over the last 50 years none has toxicity totally selective against cancer, toxicity is never seen in just the cancer. There was no toxicity associated with my treatment.

3. Could the effect of my ARVs be a chemotherapy effect?: No

There are no clinical studies claiming single-agent chemotherapy activity for AZT, raltegravir or tenofovir.

4. Could the effect be secondary to telomerase inhibition by the AZT and tenofovir?: No

The response of my leukemic cells within 4 weeks is too soon for depletion of telomeres and induction of apoptosis. The anti-telomerase compound imetelstat (GRN 163lL) has not shown single-agent activity in clinical trials and is thought at best to be a cytostatic compound.

5. Could the effect of the ARVs be really anti-herpesvirus activity?: No

DNA assays on my plasma for EBV and CMV DNA were negative. My lymphocytes were tested for active EBV infection at Mayo Clinic and were negative. A screening for active herpesvirus infection with CMV, EBV and HHV6 was negative at the WPI.

6. As this is done and reported by the same person, are the results reliable?: Yes

The results of the absolute lymphocyte count are on file at the Catholic Hospital System of Western NY and the other parameters are on file at Quest. I will give permission for anyone who wishes to get copies directly. Furthermore, as I am guided by the results to determine my treatment which in turn determines my health and survival, I want the results to be correct.

7. Is there any value in a one-person study?: Yes

Because of medical-legal concerns, a physician treating himself is the best starting point. My CFS and CLL are typical and the positive results indicate that further study is important and also give a rational starting place for a treatment protocol.

Michael Snyderman, MD

Eighteen Month Experience with Antiretrovirals in a Patient with CFS and Chronic Lymphocytic Leukemia

Introduction

In the 1970’s three independent laboratories reported the presence of a MLRV in sarcoma, leukemia and various lymphomas [1-6]. The MLRV was found only in neoplastic and not in normal cells and was similar to the Rauscher virus. The most recent nomenclature calls this type of virus an HGRV. Surprisingly, the 1970’s body of work was largely ignored for the next thirty years until 2006 when Urisman et al [7] reported a HGRV/MLRV which they named XMRV in some prostate cancer. In 2009, Lombardi et al [8] at the Whittemore Peterson Institute (WPI) found evidence of infection with HGRV/MLRVs similar to XMRV in most patients with the Chronic Fatigue Syndrome (CFS). At present, the Lombardi et al viral findings have been criticized because many laboratories have not been able to reproduce their results. Some retrovirologists have said unequivocally that HGRV/MLRVs do not cause CFS.

The diagnosis of CFS is objectified by using the Canadian Criteria for diagnosis of CFS and by demonstrating a typical elevation of cytokines and chemokines [9]. CFS patients are suspected to have an increased incidence of lymphoid malignancy and brain tumors compared to the normal population [10]. The implication of this is that HGRV/MLRVs may be etiological for both CFS and malignancy. Daniel Peterson’s CFS practice consisted of 300 patients from the 1984 Nevada CFS epidemic. Thirteen patients from this cohort developed various B-cell lymphoproliferative disorders and all that were tested were positive for a T-cell clonal expansion. They were also found to have evidence of infection with HGRV/MLRV at the WPI but this latter data is now in limbo. It was hypothesized that a HGRV/MLRV infection was responsible for the T-cell clonal expansion and that this clonal T-cell expansion might have promoted the development of CFS and malignancy.

Treatment of MLRV associated malignancy has not previously been reported. The retrovirus HTLV-1 associated T-cell lymphoma/leukemia does respond to AZT and IFNa [11, 12]. In addition, multiple human tumor cell lines including breast and ovarian cancers show growth inhibition and apoptosis when exposed to AZT [13, 14]. Several groups reported inhibition of XMRV by FDA approved antiretrovirals including AZT, raltegravir and tenofovir in cell culture [15, 16]. The response of a patient with CFS and a MLRV associated malignancy to anti-retroviral drug therapy would support a role of MLRV in both. We had the opportunity to study such a patient with both CFS and CLL who was positive for evidence of infection with MLRV and was also positive for a T-cell clonal expansion. He had cytokine and chemokine elevations consistent with the diagnosis of CFS. This patient was a Medical Oncologist who was well acquainted with the therapeutic options and guidelines for both disorders and decided to undergo anti-
retroviral therapy.

Results

A patient with B-cell CLL tested positive for antibodies to MLRV proteins. Integration studies are pending. Although not previously diagnosed as having CFS, his symptoms fulfilled the Canadian Criteria for diagnosis of CFS. His elevated cytokine and chemokine levels were consistent with the diagnosis of CFS. He was also positive for a clonal T-cell expansion by both quantitative and qualitative assays for the presence of a clonal TCRg gene rearrangement. He had average prognostic factors with the only potential adverse factor being a trisomy 12 clone. His testing for EBV, CMV, HHV6A and HHV6B was negative. He started treatment with AZT and raltegravir 571 days after diagnosis of CLL. By day 56 of treatment, his cytokine levels had improved (Figure 1). This coincided with improvement in symptoms of CFS which included fatigue, difficulty in concentration and neuropathic pain. His response continued for 9.4 months with no associated toxicity and he was able to work full time. His previously increasing absolute lymphocyte count (ALC), CD 19 cells and trisomy 12 cells trended downward during this period of time. At the start of treatment with AZT and raltegravir, his ALC was 16,348/cu mm and CD 19 cells 11,658/cu mm up from 3,303 at diagnosis. His trisomy 12 cells peaked at 8,490/cu mm day 117 of treatment up from 1,550 at diagnosis. After 285 days of treatment his ALC was down to 10,600/cu mm, CD 19 cells down to 6,015 and trisomy 12 down to 4,558. Subsequently, his counts relapsed despite continuation of AZT and raltegravir. Symptoms of CFS also worsened. Tenofovir was added and all parameters trended down again and symptoms of CFS improved (Figure 2). The ALC peaked at 16,194 at week 3 of treatment and by week 20 was down to 12,324. The baseline CD-19 count was 9,298, trisomy 12 cell count was 8,902 and the ZAP70 count was 3,068. By week 13 the CD-19 count was down to 6,570, the trisomy 12 count was down to 4,374 and the ZAP70 count was down to 591. Week 20 values of these last three parameters are pending. Quantitative data for clonal T-cells became available at the time of relapse and showed a rise in clonal T-cells that appeared to be more rapid than the increase in the CD-19 cells and after the addition of tenofovir both the clonal T-cells and the CD-19 cells trended down but the clonal T-cells appeared to decrease more rapidly (Figure 3).

Discussion

The development of B-cell lymphoid malignancies in 13 of 300 CFS patients suggests that CFS patients are at a several hundred fold increased risk for malignancy compared to generally quoted incidences for the general population. Of these 13 patients, all were positive for a clonal T-cell expansion. They were also positive for evidence of infection with HGRV/MLRVs but this data is now in question.

The greatly increased risk for B-cell malignancy in a potentially HGRV/MLRV infected population may be due to infection of the B-cell line by the HGRV/MLRVs. Retroviruses have been thought to cause cancer by insertional mutagenesis. 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 MLRVs 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” [17]. Spadafaro has shown that reverse transcriptase can cause gene activation and lead to the malignant phenotype [18]. In some retrovirus related cancers, Env [19] and Gag [20] may also be important in malignant transformation.

The finding that XMRV did not cause malignant transformation de novo in tissue culture [21] 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 block viral protein influence in a neoplastic cell line could make the neoplastic cell behave in a less malignant way.

A complementary hypothesis is that infection by HGRV/MLRVs results in a T-cell clonal expansion. The clonal T-cells produce elevated cytokine and chemokine levels which may be partially responsible for the CFS. Furthermore these cytokines and chemokines may have a paracrine activity that would stimulate a simultaneous neoplasm to behave in a more aggressive fashion [22].

One objection to considering HGRV/MLRVs to be pathogenic viruses is that there was previously no explanation as to how MLRVs could have entered the human population. However, early vaccines were prepared by passaging human virus through mice for the purposes of viral isolation and for attenuation. This would have allowed for contamination of vaccines with murine leukemia viruses [23]. The original Yellow Fever Vaccine was made in the early 1930’s by culturing the virus in mouse cerebral tissue [24]. Some patients received both the Yellow Fever virus and infected mouse cerebral tissue. The YF17D strain was used to immunize over 400 million people world-wide over the next 65 years [25]. The U.S. Armed Forces started to vaccinate service men for Yellow Fever during WWII and continued thereafter as per the branch of service and deployment status [26]. The polio vaccination trials in the United States started in 1952. The polio virus strains were initially serially transferred by Koprowski through many passages in mice, cotton rats and primates to achieve attenuation [27]. Olitsky with whom Sabin had a long-term collaboration adapted the type 2 (Lansing) polio strain to mice [28] and the Sabin vaccine contained this strain. Indeed, the patient studied here, received the live oral polio vaccine in the early 1960s, ten years later developed symptoms of CFS and forty years later developed CLL. He also received the Yellow Fever vaccine in the early 1970’s on entering the Armed Services.

In summary, a new patient with both CFS and B-cell CLL was identified. Infection with a HGRV/MLRV was suggested by the presence of antibodies to MLRV proteins. He also was positive for a T-cell clonal expansion and had elevated cytokine and chemokine levels typical of patients with CFS. With anti-retroviral therapy he showed improvement in his cytokine and chemokine levels, CFS symptoms and hematological parameters. Presumably his improvement was related to the anti-retroviral effects of treatment. The progressive improvement of his ALC, CD19 cells and trisomy 12 clone lasted 9.4 months. Despite continuation of AZT and raltegravir his leukemia relapsed. Interestingly, during relapse both the total B-cell count and the clonal T-cells increased with the rate of increase of the T-cells appearing more rapid. A second response was induced by the addition of the second reverse transcriptase inhibitor, tenofovir. Both the total lymphocyte count and the clonal T-cells fell with the rate of decrease of the clonal t-cells appearing more rapidly. At the time of this report the second response is ongoing at 14-20 weeks.

These findings are consistent with the importance of reverse transcriptase in the behavior of the patient’s leukemia and CFS and the potential influence of the clonal T-cells on both these processes. It is possible that inhibiting reverse transcriptase decreased proliferation of both the T and B-cell clones or the effect might be primarily on the clonal T-cells. The rise and fall of cytokines we have documented would be proportional to the absolute number of the clonal T-cells and secondarily could influence the proliferation of the B-cell clone.

Alternative explanations for the therapeutic effect of his anti-retroviral therapy have been considered. One of these is selective toxicity rather than an anti-retroviral effect. Selective toxicity has never before been seen with the hundreds of agents used as cancer therapeutics and seems an unlikely explanation for his improvement especially as the patient had no toxicity at all. AZT, raltegravir and tenofovir have never been shown to have single agent chemotherapy activity so a chemotherapy effect is unlikely to be an explanation. Anti-telomerase activity of the AZT has also been considered, but the rapid response to treatment does not fit the kinetics of depletion of telomeres and induction of apoptosis. Furthermore, an anti-telomerase agent did reach clinical trial and failed to induce remissions. Anti-herpesvirus activity of the antiretroviral regimen is not a tenable explanation of his response as an active herpesvirus infection was ruled out.

There is nothing unique about this patient’s clinical presentation to suggest that his case is any way unrepresentative. His response to anti-retroviral therapy implies that HGRV/MLRVs were etiological for both his CFS and CLL and that anti-retroviral therapy might help other patients with CFS and HGRV/MLRV associated malignancy. Many more patients need to be studied. Ultimately questions that should be answered are what neoplasms are associated with HGRV/MLRVs, will existing anti-retroviral drugs have activity in these neoplasms, will other anti-retroviral drugs such as a protease inhibitor be required and what would be the optimal combination of anti-retroviral drugs.

References

Kufe D, Hehlmann R, Spiegelman S: Human sarcomas contain RNA related to the RNA of a mouse leukemia virus. Science 1971, 175:182-185.
Hehlmann R, Kufe D, Spiegelman S: RNA in human leukemic cells related to the RNA of a mouse leukemia virus. Proc. Nat. Acad. Sci. USA 1972, 69:435-439.
Hehlmann R, Kufe D, Spiegelman S: Viral-related RNA in Hodgkins’ Disease and other human lymphomas. Proc. Nat. Acad. Sci. USA 1972, 69:1727-1731.
Kufe D, McGrath IT, Ziegler JL, Spiegelman S: Burkitt's tumors contain particles encapsulating RNA-instructed DNA polymerase and high molecular weight virus related RNA. Proc. Nat. Acad. Sci. USA 1973, 70:1737-741.
Baxt WG: Sequences present in both human leukemic cell nuclear DNA and Rauscher Leukemia Virus. Proc. Nat. Acad. Sci. USA 1974, 71:2853-2857.
Aulakh GS, Gallo RC: Rauscher-leukemia-virus-related sequences in human DNA: Presence in some tissues of some patients with hematopoietic neoplasias and absence in DNA from other tissues. Proc. Nati. Acad. Sci. USA 1977, 74:353-357.
Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi, K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL: Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2006, 2:e25.
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA: Detection of an infectious retrovirus, XMRV, in blood cells of patients with Chronic Fatigue Syndrome. Science 2009, 585-589.
Lombardi VC, Hagen KS, Hunter KW, Diamond JW, Smith-Gagen J, Yang W, Mikovits JA: Xenotropic Murine Leukemia Virus-related Virus-associated Chronic Fatigue Syndrome reveals a distinct inflammatory signature. In vivo 2011, 25: 307-314.
Levine PH, Fears T R, Cummings P, Hoover RN: Cancer and a fatiguing illness in Northern Nevada-A causal hypothesis. AEP 1998, 8:245-249.
Matutes E, Taylor GP, Cavenagh J, Pagliuca A, Bareford D, Domingo A, Hamblin M, Kelsey S, Mir N, Reilly JT: Interferon a and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. British J Hematology 2001, 113:779-784.
Bazarbachi A, Ghez D, Lepelletier Y, Nasr R, de The H, El-Sabban ME, Hermine O: New therapeutic approaches for adult T-cell leukaemia. The Lancet Oncology 2004, 5:664-672.
Melana SM, Holland JF, Pogo B G-T: Inhibition of cell growth and telomerase activity of breast cancer cells in vitro by 3’-Azido-3”-deoxythmidine. Clinical Cancer Research 1998, 4:693-696.
Li H, Song T, Xu W, Yu Y, Xin X, Hu D: Effect of 3’-azido-3’-deoxythymidine (AZT) on telomerase activity and proliferation of HO-8910 cell line of ovarian cancer. Int J Biomed Sci 2005, 2:35-41.
Singh IR, Gorzynski JE, Drobysheva D, Bassit L, Schinazi RF: Raltegravir is a potent inhibitor of XMRV, a virus implicated in prostate cancer and Chronic Fatigue Syndrome. PLoS Pathog 2010, 5:e9948.
Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu W-S, Pathak VK: Inhibition of Xenotropic Murine Leukemia Virus-Related virus by APOBEC3 proteins and antiviral drugs. J of Virology 2010, 84:5719-5729.
Lee M, Gusho E, Das Gupta J, Klein E, Silverman R: XMRV infection induces host genes that regulate inflammation and cellular physiology [abstract 280]. J Urology 2011, 185(suppl 4):e 113.
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: Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene 2005, 24:3923–3931.
Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, Ross SR,MonJG: MMTV env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. JEM 2005, 201:431-439.
Swanson I, Jude BJ, Zhang AR, Pucker A, Smith ZE, Golovkina TV: Sequences within the gag gene of mouse mammary tumor virus needed for mammary gland cell transformation. J Virology 2006, 80:3215–3224.
Metzger MJ, Holguin CJ, Mendoza R, Miller AD: The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells. J Virology 2010, 84: 1874-1880.
Erdman S., Poutahidis T: Roles for Inflammation and Regulatory T Cells in Colon Cancer. Toxicologic Pathology, 2010, 38: 76-87, 2010.
van der Kuyl AC, Cornelissen M, Berkhout B: Of mice and men: on the origin of XMRV. Frontiers in Microbiology 2011, 1:1-7.
Theiler M: Nobel Lecture, December 11, 1951. In Nobel Lectures, Physiology or Medicine 1942-1962, Elsevier Publishing Company; 1964: I:\yellow fever Max Theiler - Nobel Lecture.mht
Rockefeller University: Yellow Fever immunization statistics. In ScienceDaily www.sciencedaily.com/releases/2010/06/100611222839.htm
Millitary vaccinations. Air Force Joint Instruction 48-110, Army Regulation 40-52, BUMEDINST 6230.15, CGCOMTINST M6230.4E, dated 12 May 2004.
Koprowski H: Historical aspects of the development of live virus vaccine in poliomyelitis. Brit Med J 1960, 2:85-91.
Casals J, Olitsky PK, Anslow RO: Adaption of a Lansing strain of poliomyelitis virus to newborn mice. JEM 1951, 94:111-121.

Click figures to enlarge:

Figure 1

Figure 2

Figure 3

One Starfish At A Time

2011-12-06T12:27:00.021-07:00

The Parable of the Starfish

One morning an elderly man was walking on a nearly deserted beach after a big storm had washed up thousands and thousands of starfish. He came upon a boy who was picking them up and throwing them back into the ocean, as eagerly as he could.
Puzzled, the older man looked at the young boy and asked, "Little boy, what are you doing?"
The youth responded without looking up, "I'm trying to save these starfish, sir."
The old man chuckled aloud, and queried, "Son, there are thousands of starfish and only one of you. What difference can you make?"
Holding a starfish in his hand, the boy turned to the man and, gently tossing it into the water, said, "It will make a difference to that one!"

~ one of many variations, source unknown

As you might expect, the spectacle in Reno, has cost me some sleep. The WPI has fallen on its own sword in an agonizing display of poor judgement. Such a waste of promising research, money, energy, goodwill. Doors shutting tight all over the place. Tragic beyond belief. Judy Mikovits is my friend. I still do not know the details of what happened, as she is prevented from discussing the case by her attorneys. But whatever she did or didn't do with respect to the events since her firing, it is safe to say that she in no way deserves what is happening to her now. On this point, John Coffin and I agree.

It is all well and good to say that now that XMRV is dead, science can get back to its orderly, stepwise process; they even get to say, we told you so. And I say what I have said all along: millions of patients need treatment now. It is not a static situation. It is a progressive disease, slow, but lots of people are circling the drain. Many new cases that might be easier to treat sooner rather than later... that might respond more completely to arv's. New babies being born with it. Should we wait a decade to start to find out, in a systematic way, if existing treatments might not affect it? It is incumbent upon the medical and pharmaceutical industries to think about the disease in concept and find solutions, not sit there doing nothing until Virus X is found; that approach already hasn't worked for decades. It is quite likely that it won't turn out to be a one virus, one disease, one treatment paradigm. If it were that simple, it would have been found already. So I find myself sitting with real patients, in the here and now, framing the illness as I have outlined here over the last year and a half. I still find the model we are evolving useful in a clinical context.

In my last practice, my interest was peak performance with respect to brain function, no matter the degree of injury or illness. I worked with the things that I found useful, personally and for my patients, most of whom had already exhausted their medical options. I was undiagnosed at that time. I knew I was sick, but it wasn't too bad, and I knew that conventional medicine had nothing to offer me. It occurred to me now and then that I had some sort of less than MS. Other possibilities occurred as well. I tried to fit it into PTSD, but there were too many physical manifestations, hypertensive crises, arrhythmias, atypical migraines, malaise, this or that instability. I could exercise without problems for a decade. I used to say that whenever something went wrong with my body, it was undiagnosable. And I was CFIDS aware. That state of not knowing made me well suited to being a doctor of last resort. My armamentarium then was HBOT, neurofeedback, nootropics (cognitive enhancers), nutraceuticals, herbs and bioidentical hormones. I found discontinuing unnecessary drugs to be a powerful treatment modality. And I tried to create the space for the less tangible, but no less powerful healing that can happen in the context of connection and relationship.

So far, I am using pretty much the same gentle, yet powerful modalities that I used before, when I didn't know what I was doing:), and I'm having some beginner's luck. I am turning to these treatments first, because I know from experience, they work, and now I have a framework that gives me a better idea why. Pulsed, high dose normobaric oxygen is the most powerful and easy to deliver treatment that I have to offer. My patients so far are pretty uniformly impressed. Nobody that has rented a concentrator for a month has returned it, unless to buy one. Responses range from a little helpful to "wow". There is a short term effect and a long-term additive effect, as I observed with HBOT in practice. It seems one of the craziest things in all this that such a simple thing has been denied us. I wonder about why, and can't come up with much. It will never be studied, because it can't be patented. It might accelerate aging, but the longevity folks think it's the opposite. It needs to be more carefully dosed for patients with seizures and a few other things. Mostly, it's probably because doctors don't understand the gas laws, and so are uncomfortable with it. They can handle it when it comes out of a wall in a hospital, where it's use is sanctioned, and there's a respiratory therapist to hook things up. Otherwise, if you have COPD or are dying, you can have it. Sometimes insurance will cover it for cluster headaches, or migraines, common in our patient group. I am prescribing oxygen, for an hour a day and prn, at 10L/min by non-rebreather mask (has a reservoir and check valves), or 5-6L/min by simple mask for patients who bought lower flow concentrators (two are improving with this).

Here are a couple of references that address the oxygen paradox: Why might high dose oxygen be good for us, even though we have increased oxidative stress at baseline?

Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. Davies: Cells, tissues, organs, and organisms utilize multiple layers of antioxidant defenses and damage removal, and replacement or repair systems in order to cope with the remaining stress and damage that oxygen engenders. The enzymes comprising many of these protective systems are inducible under conditions of oxidative stress adaptation, in which the expression of over 40 mammalian genes is upregulated.
HIV: reactive oxygen species, enveloped viruses and hyperbaric oxygen. Baugh: ROIs repeatedly have been shown to be virucidal against enveloped-viruses, like the human immunodeficiency virus (HIV). Hyperbaric oxygen therapy (HBOT) increases the production of ROIs throughout the body, leaving no safe harbor for the virus to hide outside the genome. This technique already has been tried on acquired immune deficiency syndrome (AIDS) patients, with exciting results.

As I am finishing my first six months of practice, Ali is coming into her own, with great courage. She has enrolled for an online undergraduate program at U Mass, and will start next month. She has been dating, but still mostly staying home rather than venturing out. Right now, she is deep in the process of confronting that she is probably physically able to do more things away from home, but confined by habit and the limitations of the past. It is hugely more difficult for her than for me to emerge, without a former life to go back to.

Ali credits oxygen and modified Meyer's cocktail infusions with her slow but continued improvement. She tells me when she feels the need for an infusion. We are still tinkering with the best formula for her. She uses oxygen 4-5 times a week, according to her own instincts. She has come to use it prophylactically for PEM, when she knows she's overdone it. It is impossible to know what role antiretrovirals are playing in maintaining her gradual improvement which began with the cessation of Lyme treatment and was also obviously impacted by Deplin and treatment for PCOS (polycystic ovarian syndrome). Our concentrator has been broken for a couple of weeks and when the replacement came, she grabbed the mask, exclaiming "Oxygen! Mana of the Gods." For me too, oxygen is the most tangible thing I have. It impacts my sleep directly.

I asked Ali if she'd like to write something for the blog, and she said it has become too contentious for her to want to risk it. However, she said that if she was going to write, it would be about the things that she has gained from her illness. The silver lining. The wisdom that comes from living life with the toughest teacher always at your side. For one so young, she has become really good at making lemonade. I am very proud of her.

The markers we chose to follow when we started arv's, beyond what was going to be monitored at the WPI (NK cells and cytokines), were TGF beta-1 and C4a. Ali's were normal when checked a couple of months ago. The specimens require special handling, several were lost for both of us in 2011, as often happens with esoteric tests; we weren't motivated to go in for redraws, since they didn't seem exciting in terms of guiding treatment, and weren't needed for safety. Ali had no subjective inflammatory flare when she went on arv's, but most who have tried them, did, usually 6 weeks or so, shorter for tenofovir. Ali's numbers actually look like she did flare, though clinically she felt she was improving. My impression while I was watching these labs come in was that they were lagging behind the clinical picture. It looks like I flared in August 2010 and interestingly, I was about to leave for my first trip to Reno, first trip anywhere in years, when those were drawn.

click to enlarge

TGF beta-1 is a peptide involved in many cellular functions, including the control of cell growth, proliferation, differentiation and apoptosis. Here is a recent paper suggesting TGF beta-1 as a marker for CFS: Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Zhang. It is tempting to speculate that TGF beta-1 could be involved in the clonal expansion we are starting to think about with respect to the pathogenesis of ME/CFS and related leukemias; not forgetting that simple animal retroviruses replicate mitotically, by clonal expansion.

TGF beta-1 is implicated in the pathogenesis of Marfan's Syndrome, which my husband's uncle, husband and son have; in our family it appears to be more obviously expressed in each successive generation. Elevated TGF beta-1 is implicated in the pathophysiology of Marfan's. My husband and I both had different, subclinical manifestations of illness when we met, but most, though not all, of his were attributable to Marfan's. Marfan's is an autosomal dominant genetic condition where chromosome 15 encodes for a defective protein which is necessary to bind TGF beta-1 to keep it sequestered to normal levels (oversimplified model). Losartan, an ARB (angiotensin receptor blocker) has been shown in clinical trials of Marfan's patients to lower TGF beta-1 and slow the onset of the most serious consequence of the disease, aortic root dilatation. My biological father had a body habitus consistent with Marfan's and I may be an Ehlers Danlos variant, becoming more flexible with age and exacerbations of illness. I have minor features of both conditions. Both Marfan's and Ehlers Danlos seem to be over-expressed in the ME/CFS patient group, already showing up in my tiny practice. Here is an excellent article which considers related disorders with respect to abnormal TGF beta-1 signaling: Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. Jones/Ikonomidis.

A couple of weeks ago, I discontinued Actos for worsening dependent edema, mild, but not clearing overnight. The edema went away when I stopped the drug, but everything else flared. So it would appear that Actos was helping, but hurting too, as is often the case with pharmaceuticals. This little setback is making me take a look at my do as I say, not as I do tendencies. There are things I can do to help myself that I'm not doing, mostly having to do with consistency. So, my pre-New Year's resolution is to be more compliant with my own program, including pacing mental exertion, the hardest for me to accept the necessity for. Of course the most potent triggers are the ones we have no control over, though the response to one's predicament is always a choice.

Today's song: A Moment So Close

by Bela Fleck and the Flecktones

Down The Rabbit Hole

2011-11-25T21:45:00.002-07:00

I have about the same amount of mail from people who think I should never have said anything as from people who are angry that I waited too long. There is no way for me to win this one in the court of public opinion. The community is so fractious and reactive that no course of action I could take or not take could possibly leave me without disappointed, critical people. I am sorry for not disclosing my opinions sooner, but we are talking about 3 months, not the years some have claimed in the comments of the last blog. Shoot the messenger if you need to.

My blog was never about Judy Mikovits. It is about the hypothesis. That hypothesis is on the back shelf until this sordid mess plays itself out, which will now probably take years. Years of studying downstream effects, blinders on again, nobody looking for the source of the illness. Tragic.

Take a look at this, not a paper, a blurb on the bottom of a scientist's webpage. She is probably afraid to publish amidst all the controversy. Who in their right mind would want to jump into this cesspool? With the fishbowl of vitriol that comprise many of the comments on this blog?

Identification of a novel retrovirus in Benign Prostatic Hyperplasia (BPH)

BPH describes a benign condition experienced by most men as they age, and is a result of increased proliferation (growth) of fibroblast and epithelial cells surrounding the urethra, which over time can form “nodules” and result in compression of the urethra and subsequently obstruction of urinary flow. Symptoms of BPH include urinary hesitancy, frequent urination, dysuria (painful urination), increased risk of urinary tract infections, and urinary retention. Treatment includes surgery and pharmacologic options, although the cause of BPH is unknown. Using tissue from patients who have undergone surgical treatment to alleviate BPH, we discovered that the affected tissue appears to have altered gene expression patterns when compared to normal prostate tissue. This is not unexpected, as the tissue is clearly growing more quickly. However we identified what appears to be increased expression of genes related to an antiviral response. Given the recent findings of a novel virus, XMRV, found in some prostate tumors, we analyzed the BPH affected tissue for viral infection. We found that the majority of tissue from symptomatic BPH patients contained low levels of a virus not previously found in humans. Sequencing confirmed that the virus consists of 2 variants, is not XMRV, and likely produces a protein that has been related to inflammation in other species. Interestingly, the exact virus sequence differs among patients, suggesting that upon infection of the tissue, the virus undergoes replication. Furthermore, sequencing revealed that the virus is likely transcriptionally regulated by androgens, which is consistent with the fact that cell growth in BPH is androgen-dependent and the classic non surgical treatment for BPH is inhibition of DHT (an androgen) production. Both variants of the virus have submitted to the USPTO as a provisional patent, as they may be a therapeutic target for this disease. In addition, we are currently seeking funding to assist in the development of a vaccine, which could potentially eradicate BPH if this novel virus causes the disease, or even if it is just expressed (as a “bystander”) in BPH-affected tissue.

Denise O'Keefe, PhD webpage UPMC

Dr. O'Keefe's blog: So let's get this straight; CFS patients don't have XMRV or MLVs, but if they did, it would explain the neuromuscular pathology....

For everybody who has written that I need to admit that Judy fooled me, I still don't feel fooled. I could be fooled by a psychopath, like anyone. I have been before. I had a lawyer once that fooled me completely. I have reported my impressions of a person I know well, who is passionate and caring and stands up for what she believes. No signs of psychopathy at all. I hope I am right. In the fishbowl we now find ourselves, I'm sure we'll find out. Everything. It will be like a rape trial. Blame the victim is always a good strategy.

Annette was captain of the ship. In the ER, when a medical student kills someone in a back room, the attending physician is still responsible. Likewise the CEO of a "state of the art translational research institute". To me, it looked like Annette took a talented, but vulnerable scientist, and destroyed her. Judy functioned well and published regularly in Frank Ruscetti's lab for 20 years.

Here is the timeline, since people seem to be questioning what I did when. I read the paper on Oct 9, 2009. I wrote my angry email to the WPI on Oct 28. I was angry for a while, until I met Judy in January. I paid VIP Dx for 2 tests, for my daughter and myself, in early 2010. I couldn't afford to test my husband or son. I sent specimens to the WPI on a regular basis when we started arv's, but was never given any results. Some of our specimens were tested, but I don't know what those results were. It was never reported to me. I was told that some of our specimens were improperly handled by a research fellow who was subsequently fired. I started working as a volunteer for the WPI in the fall of 2010. I started working as an independent contractor in Jan 2011. I worked there for 6 months, mostly from Santa Fe. I made 5 trips to Reno from 3 days to a week. I was fired in early July of this year.

Finding oneself in the position of a whistle blower is a miserable experience. By writing I hope that I have put the WPI on notice of what I would say in court if dragged in. They don't need a subpoena to find out. They are behaving like thugs. Have they never heard of mediation? I am only sorry that I didn't say it all sooner. I have mail from people who are angry at me, because they gave money recently. I held hope for a good outcome for longer than I should have. For that I am so sorry.

I also have mail telling me that I should be afraid for my physical safety. That I should ask for witness protection. Witness to what? I wasn't there. That's how completely crazy this has become. I would laugh it off, but I would never have believed what has already happened. It is all so beyond the pale. SNR Denton, very expensive patent lawyers, are monitoring my blog again in the last couple of days from Chicago and Kansas City, including the tech department. It is creepy beyond belief. And the money being spent on all this? Where did it come from? Imagine what the tab is by now!

I feel like I stepped in dog shit and will never get it off. Everyone involved has been brought down by it. I don't know what to do, except keep telling the truth as I see it. As I said, I wish I had done it sooner, but I still held hope for a positive outcome somehow. I can't believe that all of this is happening. A year ago it was all so hopeful. I am heartsick.

Tonight's song: Trouble

Coming Clean

2011-11-23T17:35:00.004-07:00

Let me start by saying that I did not know where the notebooks were, or even that they were missing, until the lawsuit was filed. If Judy did this, she didn't tell me. I knew how concerned she was about them and I can tell you as Judy's friend, she believed that, as the PI (principle investigator), she had a right to them. She had no legal representation until the law suit and the legal issues are very complex. There are issues with not just who owns, but who can even see the notebooks. She said to me that the notebooks documented mistakes that others wouldn't want brought to light, something she had only realized recently. In our communications, her concern was always for the research and fulfilling her promises to patients. There didn't seem to be anything she wanted or needed to hide for herself. She was mostly concerned about the specimens, in the months leading up to this. She feared that they could be tampered with. Freezing and thawing destroys them. Her specimens were like her babies. So whatever she did, it was in that context. She and Max are very close, so he must have been very frightened to have signed that statement. Was he offered immunity or a reduced sentence? Did he have a lawyer? Max was missing for two days before Judy was arrested (and not listed on the Washoe County arrest list). My last text to Judy, around when she was being arrested was about Max, "Is it time to call the police?".

I still think what I thought. The Whittemore's have destroyed a very talented scientist, through the most incompetent management imaginable. And now Max. From my vantage point, the whole thing seems to have spiraled out of control after Dr. Lipkin's visit. My guess is that the patents and saving VIP Dx/Univex are at the bottom of it all. As Annette likes to say, "Follow the money". Or in this case, the lack thereof. As Harvey allowed me to say in the blog about VIP Dx, he doesn't have more money to pour into this, since the real estate market went south. Now I imagine they feel entitled to recoup their investment. VIP Dx brought them down. It all began with good intentions, but they have lost their way, in my opinion.

Here is the first email I ever wrote to the WPI, dated 10/28/09, after learning that commercial testing was being offered, before I met Judy in Jan 2010:

I am trying hard to think of WPI as a resource full of people who want to help, when nobody else has. But it has come to my attention that the lab that is doing the testing has a financial tie to a member of your board of directors. I am broke. I think four members of my immediate family will test positive for this or another similar virus. I pretty much know that anyway, without the test, but it might make a difference to my disabled daughter to be able to walk into a doctor's office and say, "I have Virus X". And I can't even give her that, at the moment, because her acute medical problems have to take precedence.

I know a conflict of interest when I smell one. Shame on you.

Jamie Deckoff-Jones, MD

Their PR person answered that Annette Whittemore would contact me directly, but she never did. And there you have it. It never changed. She is non-responsive. Doesn't answer email or phone calls. I'm sure lots of you out there can verify that statement. Her voicemail is often full. She disappears for long periods. Can't make a decision to save her life. And when she finally does, it was generally the wrong one, in my opinion. I never signed a contract; she spun her wheels about it for months, but never managed to actually give me one. Even so, I wrote nothing after I was fired, except that I'd gotten a "pink slip", until Judy was fired. Though I knew how terribly flawed it all was, my opinion at that time was that it was better for the patient community for them to exist. But without Judy, it is just a black hole.

With the implosion of the research, I no longer felt there was a reason to try to protect them. When they knew that they didn't have a reproducible assay, the sale of the XMRV test became fraud, in my opinion, and I advised Judy in the strongest terms that she should quit, since she apparently couldn't make them do the right thing. In response to my direct question, she told me that she demanded they stop testing on August 1 or earlier. I cautioned her that she might be an accessory to a crime if she remained silent. I advised her to give a press conference on more than one occasion. I didn't blog before the fund raiser because Judy asked me not to; she was still trying to figure out how she could save it at that point. She was desperate to keep her lab, to fulfill her promises to patients. I wasn't there, so I let it be her decision. For that, I owe the patient community an apology. I knew that the program was without substance and kept it to myself for several months.

I'm not sure exactly what went wrong with the BWG, but part of it was an attempt to validate their commercial assay at the same time. So again, they shot themselves in the foot over the commercial lab. When Lipkin came to dinner, Annette told him she had 19 people on the payroll. Judy had Max and Cassie, both without graduate degrees. And then just Max. Annette has a personal assistant.

Many have asked me what happened with me at the WPI. Here it is, and then I hope I am done writing about the WPI. I have good things to report from my practice, which is what I should be writing about. I can't tell you all how badly I would like to be done with this. My goal in writing this blog was to be of assistance, not be an energy suck, which is what this whole sordid affair has become.

I became involved with the WPI, because patients corresponding with Judy were sending me her answers to medical questions. I told her that answering those kinds of questions was a reflex for me, and since she was really bad at it, she should let me do it. She thought it was a great idea, but that I needed to have an official relationship with the institute. So I became ?; don't even remember the title, but it was an official, volunteer position that enabled me to respond to patient information questions.

Without reviewing our email for dates, in late 2010, since the clinic seemed dead in the water, I presented Annette with a model for structuring it, fashioned after emergency medicine groups, generally a contract held by the physician group. It's set up that way to protect the institution from medical liability. Annette loved the idea and asked me to make it so. An LLC was formed and we hired a physician recruiting company who started to send candidates. I wanted to set it up as a primary care clinic with specialty back-up. I was looking for competent doctors, not specifically CFS specialists. It is one very homogeneous disease after all (I can hear the gasps from here:). Annette expressed her relief to have me, saying that she knew she couldn't evaluate doctors. She acknowledged that she knew nothing about running a medical practice.

On 3/23/11, already in conflict, I sent this to Annette in an email:

A good administrator:
1. Knows what she doesn't know.
2. Knows how to delegate.
3. Protects the talent.

She said I was mean. I said I'm the best friend you have. You are paying me to be a consultant and I'm telling you what I think.

I provided a rough spreadsheet, with some numbers provided by the WPI accountant, that showed roughly a million dollars a year in profit with 10 doctors, which would be donated back to the institute for research. The budget asked for $100,000 up front, to be quickly repaid, which included my salary prior to opening. I even said that it was possible to get it open with no money, if I paid the doc's a percentage of gross, the way we did in the ER. I thought the distribution of expenses at the WPI seemed not in favor of producing any meaningful science, so I do admit to wanting to have a say in how the money was used. I expressed this to Judy, but not to Annette, though she probably sensed it. There was no evidence of a presence of a board of directors that I could detect at all when I was there.

I went to Reno to interview doctors in early spring. Two weren't right, but Chitra Bhakta was perfect. However, 15 minutes before Chitra arrived, Annette informed me that she had seen new lawyers in Las Vegas and had decided to employ the doctors rather than structure it as a separate corporation. I told her that I thought it a serious mistake for her to employ or try to manage doctors directly. Managing doctors is like herding cats, having done it before. Before my first crash, I was a 20% owner of an emergency medicine contract group and medical billing company in San Jose, CA. My 4 partners and I had 3 contracts and were responsible for 150,000 patient visits per year. I was vice president of human resources. I was responsible for recruiting, hiring, firing, knee-capping. We had 50 doctors and 20 PA's. I was, in fact, the right man for the job at the WPI. Though sick, I was willing to go down for it. I figured I could last at least long enough to get it up and running, find an onsite director. Getting fired saved me from myself, but I wanted to offer treatment to those 2000 people on the interest list. I wanted to develop a large database, so we could look at treatments in a systematic way. And Judy and I were planning the first clinical trial of tenofovir.

So Annette decided to employ the doctors, including me. I said, it's your baby, structure it however you like, but let me get to work. My attitude was that I owed her a debt of gratitude that could not be repaid and I would do what she needed me to. We agreed that Chitra should be the first hire. I told Chitra she was hired and that Annette would be in touch with a contract. Well, six weeks passed and no phone call to Chitra, no contract, nothing.

I was planning another recruiting trip. I had at least two interesting doctor candidates, as well as a nurse. I also had a couple of practice manager possibilities. Quite a few of the interested candidates for staff positions were a little sick, which Annette wasn't happy with, but as it was with me, that's what there was, except for training newbie primary care doctors. No famous CFS doctors were stepping up to the plate, except for Dr. Enlander who called me and offered to fly to Reno on a regular basis to teach. The other thing we locked horns about a bit was that my approach is non-invasive with respect to treatment choices. I have a strong bias against treatments that can kill, as well as unnecessary invasive procedures when there is plenty of necessary tissue harvesting happening in patients that would be happy to help. But it was always clear that I would not be determining protocol for other doctors. That was never the idea. I was actually thinking that with different doctors doing their own thing, the database would help us sort it out.

Shortly before that trip, Annette pulled the plug all together, deciding that there would be no clinic. Rather doctors would lease space and have their own practices. When I went to Reno for the Lipkin visit, I spoke to Dr. Fredericks and asked him if he would consider using Practice Fusion, free EMR, for the patients that he saw from the WPI wait list. I was still hoping to create the database somehow.

I also asked and received permission for Chitra to see patients under the same deal as Dr. Fredericks. After discussion with Chitra, Annette agreed, then, never got back to her, again. From what I could unravel after the fact, the WPI lawyer somehow decided there was something wrong with her credentials that would prevent her from getting a NV license. Chitra did her internship in NV and then her residency in California. Her NV license needed to be reactivated, but there shouldn't have been a problem with it. Precisely the kind of thing they needed an administrator for, but they fired me, so there was nobody bird dogging it that had a clue about the sytem. In the meantime, Chitra's father died and she had to go to India. By the time she got back, the WPI had decided that there was some problem with her. It seems they have even damaged her reputation with this nonsense. In the midst of all this, I was fired, "because we don't need a clinical director", but asked to still volunteer, to write for their website or something. I think it happened because Annette is a control freak and couldn't stand the thought of not calling the shots for the clinic. She did pretty much the same thing with the research, as far as I can tell.

The Whittemore's went public saying that Andrea takes a pill that makes her well enough to work and exercise, but wouldn't say what it is. So patients, sending in their $10/month from their social security checks can't even know, let alone hope to access what Andrea has. I expressed my opinion on multiple occasions that this was wrong and an exceedingly poor decision on many levels. It would have been fine to say nothing, but to use it to bolster the reputation of the institute, without disclosing what that treatment is was disgusting. And then Annette lying on the news about all the miracles happening. Using another patient similarly. We got her out of a wheel chair, but won't disclose her treatment... Fairy dust. My loyalty is to the patient community and I am feeling guilt about saying too little, not too much. People have a right to medical privacy and certainly saying nothing was an option. Many, many people have asked me, but it is not my place to disclose anyone else's treatment. I never have and I never will. However, as I said to the Whittemore's, being a public figure has it's responsibilities and this went down with typical ineptitude.

I am not going to guess what happened with respect to the notebooks before speaking to Judy. The black and white thinking displayed here and on FaceBook is telling. Even poor Lilly Meehan, the sweetest woman on earth, is collateral damage. If Judy isn't a saint, then Annette must again be one, and Judy now has to be the sinner. All black and white. The reality is all shades of gray, imperfect people in an imperfect world. Epic fail. And that includes me, since I was briefly on the payroll. No matter what just happened with the latest chapter of this disaster, it was very unfortunate that Judy was hogtied by incompetence the entire time. Annette should have stuck to her fund raising activities. But she doesn't know what she doesn't know. It was like Keystone Kops. Amateurs. And who are the biggest losers? As usual, it's the patients.

Today's song: All My Tears

by Julie Miller

China Syndrome At The WPI

2011-11-19T18:51:00.005-07:00

My friend Judy is in jail. It defies explanation. Nine policeman appeared at the home of Lilly Meehan yesterday with a warrant and searched her house, finding nothing of course. At the same time, Judy's house was searched and she was arrested for being a "fugitive". She was fired unexpectedly and went home to her husband. That's being a fugitive? Only legal machinations, misuse of the system, could define her as a fugitive. If it wasn't so horrible, it would be laughable. What she was "fleeing" was a veritable looney bin, having made every attempt to remain on the inside. And now they have taken her freedom. Turning her into not just a fraud, but a criminal, a thief? Come on. She is incarcerated and anything can happen. It is critical that the patient community find ways to let the authorities know that we are watching. If anyone harms a hair on her head, it will be noticed.

Dr. Mikovits was due in New York for the Mt. Sinai conference tomorrow, so would have had to leave the state in any event. And they knew very well she had been invited to that conference; it was no secret and they could have warned her that they thought that a violation of the injunction. What were they going to do if she had just gone to New York? Would she have been hauled off to jail for attending an important ME conference at which she was slated to be on a panel?

My blog is being monitored by the same law firm that sued Dr. Mikovits in the last few days. From Chicago and Kansas City. There are even 3 hits from the tech department in Kansas City. It would appear that they are actually paying really expensive lawyers to think about my blog! Are they going to spend money on a libel suit? To win a libel suit, you have to prove an untruth. I have told the truth and nothing but the truth. Everything I've said is my opinion and my own experience. I have nothing to hide and stand behind everything I've said. The only blog I regret is the one Harvey fed me about VIP Dx. I believed what he told me implicitly at the time, but now? Anything they told me is suspect. Who are these people? The sweet well-intentioned parents of a sick young woman? They must have used a very long, very strong arm to have made that happen yesterday. An intensive police effort in another state for a non-violent crime? How many cops involved? 20? You'd think she was a serial killer.

For the record, and lawyers at SNR Denton please take note, when I said that the WPI was spending money that patients donated on lawyers, I was stating my opinion, based on my assumption that the WPI's income comes from grants and donations, and that they aren't using grant money to pay lawyers. However, I was never privy to the books or finances at the WPI. I did not mean that there are line items in the books showing patient donations going to lawyers. The lack of accountability is part of the problem. What did happen to all that money, since there was lots of it, and apparently still enough left to burn up a bunch on lawyers? I wanted to write a blog before the annual fundraiser, but Judy stopped me. And now they have all that money, to pay lawyers to destroy Judy and go over my blog with a fine tooth comb. Very ugly.

Personally, I think it was Professor Plum in the library with the candlestick. The materials in question document a failed experiment. I have no idea where the notebooks are, but the value being put on them is smoke and mirrors, in my estimate. Their only real value would seem to be to someone with something to hide, which could be a number of people, Judy being the least likely. Any value the notebooks might have had is destroyed with this crazy maneuver. They are in the process of completing the destruction of the only scientist in the world who cares enough to have laid it all on the line. The scientist that helped their daughter by finally conceptualizing what was wrong with her, even if she didn't have the resources, human and financial, to prove it. The damage to patients, to my daughter, is inestimable. The Whittemore's are throwing us back into darkness. Complete meltdown for the patients. They held themselves out as our best hope, but have managed to snatch defeat from the jaws of victory. Beyond tragic. They have now ensured their own place in the community as a pariah, it seems to me. The saddest thing of all is that they are fighting about the past, and ensuring that nothing at all will happen going forward, while our hearts get dissected in the courts.

I had to cancel my trip to NYC. I have been pushing to see patients for a couple of weeks and was too close to the edge to throw myself off a cliff and hope to fly. And now this. I will be in LA on Tuesday for Judy's arraignment. I hope that as many of you as possible will attend. Let the authorities know that we are watching. Let her know that we are with her.

A hearing for Dr. Mikovits will take place on Tuesday, November 22 at the Ventura County Government Center, Hall of Justice, Room 13, at 1:30 p.m. The government center is on Victoria Avenue in East Ventura.

County of Ventura Government Center
800 S. Victoria Avenue
Ventura, California 93009

See Click here: Maps Map of the Ventura County Government Center

Parking for the Hall of Justice is accessible from Lots B & C, entering from Victoria Avenue, and from lots E & F, entering from Hill Road. Even with handicapped parking, there is considerable distance to walk from the parking lot to the Hall of Justice, so bring a wheelchair if needed.

Ventura is a coastal Southern California town between Santa Barbara and Malibu. Travel to Ventura County by car is accessible by freeway. The Ventura County Government Center is bordered by the 126 Freeway and Victoria Avenue and is close to the 101 freeway as well.

Amtrac has stops at both Oxnard and Ventura. The Metrolink train station in Montalvo is much closer to the government center than the Amtrac stations, so if possible to use Metrolink, that is the best.

Tonight's song: For What It's Worth

A Game With No Winner

2011-11-12T00:11:00.000-07:00

Let the lawyer games begin. My blog "Square One", of October 1, was unfortunately prophetic. The WPI is in fact using money donated by patients to pay lawyers to sue Dr. Mikovits. One more in a very long line of horrible decisions. I am truly incredulous. This entire fiasco is doing great harm to the patient community, the extent of which is unknowable at this time. The research is destroyed. The notebooks and specimens are potentially compromised.

As I finished that last paragraph, a friend sent me Annette Whittemore's blog just posted. I really don't know how she keeps a straight face. She's suing her chief scientist and the principle investigator on the institute's grants, after termination without cause, to obtain notebooks and flash drives that Dr. Mikovits apparently does not have, since she was locked out of her lab suddenly and unexpectedly. I would say that as the "the guardian of this property", Mrs. Whittemore has failed pretty miserably. And now she is using a little of the millions of unaccounted for dollars to sue Dr. Mikovits. I thought I understood the depth of the incompetence, but it just keeps getting worse. She thinks the patient community is going to be OK with this? Business as usual? Wait for the WPI to figure out a cure, without a chief scientist, and oh, please send more money? Who is she kidding? Sorry Annette, now we have to think about a legal defense fund for Judy!

I was going to write some good news, to follow the bad news, but I think I'll write that when I'm not feeling like I've been slimed.

Tonight's song: Highway To Hell

Are We Crazy?

2011-11-04T18:44:00.009-06:00

My mail this morning bears witness to the routine abuse of ME/CFS patients by their doctors, especially when forced to seek care in a hospital. Here is one:

Do you have any survival advice for M.E. patients who are admitted to the hospital? I had a very negative experience when I was admitted to the hospital a few months ago for an inflamed appendix and severe stomach pain (no surgery done). Besides the complete lack of sleep for three days, neglect, and bungling of care, there was the underlying disbelief that there is a real illness. I know now to try to avoid hospitals, as it was perilous to my health and overall condition, setting me back perhaps in permanent ways.

Because of my negative experience, I requested some of my hospital records, and found that the doctors wrote things that are just not true, were written with sarcasm, and seemingly to protect themselves. I can’t believe how simply asking for my normal sleep prescription the first night led to the surgeon on call (who denied me my sleep Rx) writing in my records that “she may need psychotropic drugs. She did ask for Ambien.” He also falsely stated that I was taking Librax for anxiety, which was not true. I have never been prescribed anything for anxiety. The next doctor I saw, a GI specialist, read what the previous doctor wrote, and wrote that I have an anxiety disorder. My husband was there the whole time and said he noticed no evidence of anxiety, and that these statements seemed to come out of the blue. I have to wonder how much of this is due to there being a medical history at the hospital with a diagnosis of CFS (from diagnosis codes on outpatient x-rays, etc.?), and perhaps gender bias. On my last day in the hospital, just prior to an endoscopy, the same G.I. doctor (who was now in charge of my care) was very impatient, rude, and verbally abusive (shouting at me). Then after this reprehensible behavior he had the nerve to write in my diagnosis, along with stomach and esophagus findings, “severe anxiety disorder as well.” There was no basis for this. Again, my husband was also present. I did mention having episodes of fainting that follow a squeezing stomach pain. But I don’t think anxiety is causing it. I have never been diagnosed with an anxiety disorder, he did not prescribe anything for it, nor did he mention it to me in person. I am asking for your insight – what can I, or should I do about my records? I am concerned it will affect future care. In fact, I think it already has – I had a follow-up with a different surgeon who had received my records. At the time of this appointment, I had not yet seen what was written in my records. While this surgeon was very pleasant with me, when I mentioned to him the stomach squeezing and fainting spells, he said he didn’t think it was anything to worry about. I thought that was odd. When I had the phone consultation with you, I think you said it was probably due to autonomic dysfunction, but other causes should be ruled out. How can the doctors be educated about the autonomic dysfunction?

I advised her to complain to the hospital administration about the behavior of it's staff physicians and to demand that any inappropriate references to "anxiety" by expunged from her record. She should demand an apology. We all should. Regularly. This patient's account is a good example of why CFS patients get better care if they don't mention the underlying diagnosis. If this patient had presented as a healthy woman with abdominal pain, they would have been all over it.

From one of my patients, who has the common complication of palpitations from various benign dysrrhythmias, related to her dysautonomia. She was sent for an ablation a couple of years back:

They took me to the operating room looking for an arrthymia. They could not find one. I was being medically abused by doctors giving me benzodiazapenes [which she does not tolerate] which were contributing to the heart issue yet they kept giving me more. I didn't know that the benzodiazapenes were joining forces with the disease making me sick and catapulting me into hell. They took my gown off and put me on a freezing table I was begging for my parents screaming and sobbing uncontrollably. In a room full of men and women nurses and techs they proceded to shave my whole pubic area. They were not kind, gentle, or discreet. They were harsh. Then they cut into my artery. I kept telling them I didn't feel relaxed or calm and the medication wasn't helping. They told me they would give me some more benzodiazapenes! I was wide awake. When they got to my heart they injected some adrenaline to induce an arrythmia. I now began screaming for them to stop. I thought this was the end for me. They told me to be still or I'd mess it up. They had men hold me down. I don't think terror is a sufficient word to describe the horror taking place in my mind and body. After he could not reproduce an arrhythmia they wheeled me out a shaking mess and I remember the doctor told me I must be producing too much of my own adrenaline and that was causing this. I asked him how. He said by worrying and because of my anxiety.

Then they wheeled the bed to the next chamber of hell. The emergency room. The world renowned hospital had nowhere to put me so they stuck me there next to dying men in heart failure. They told me not to move for 6 hrs or I would risk bleeding to death. But the best was yet to come. When I started having cardiac episodes and more adverse reactions as the benzodiazapenes they had pumped in me began to wear off they called in the psychiatrist. He sat by my bed and told me he would give me the drug Seroquel to put me to sleep, confirming what had yet to be uttered outloud thus far. I was deemed mentally ill to this facility. Labeled, stamped, sealed, delivered. Somewhere during that sickening day I had earned my title. I am not and have never been psychotic. How dare they put such drugs into a young innocent suffering body. After administering this powerful medication to me I fell into some delusional form of sleep with vivid dreams and illusions taking place all the while still half awake. I was awake enough to hear the man just besides me, only a curtain between us, have cardiac arrest, and die. I hope everyone who was involved in my care in that facility that day rots in hell. That memory haunts me and always will. I don't think terror is a sufficient enough word to describe the damage that took place to my mind and body.

But I think the one that takes the cake. was my experience at the Mayo Clinic! When I became sick the 2nd time around with unexplained total body shutdown, as I've come to call it, I headed to the Mayo Clinic. This was the place everyone said to go when no one else could figure you out. So with my doctor's help I got in. We ventured across the country to Minnesota. I could barely walk. I spent two weeks there being examined from my toenails to my ponytail. I was sent to see a psychologist everyday when I was there so they could be a part of "the team". I was told that the cardiology department there wrote the book on POTS, they discovered it. And the CFS center was the best of the best. I will not recount the abuses taking place during my two week stay but I will share two noteworthy final encounters. On my last days there I went to the cardiology department to get my final report. I was brought into a room where I waited for an arrogant dapper South African cardiologist to make his grand entrance. The whole meeting went like this and I kid you not. "Young lady you do not have POTS. Not even close. You have no autonomic problems at all. Anyone who tells you different is a fool. I wrote the book on POTS. In addition a girl with your symptoms of depression will not get any beta (he pronounced this BEETA blockers) from me." He then walked out of the room as abruptly as he entered.

The next day I was met by a team of psychiatrists and psychologists for my final report. They prepared a huge file on me which they handed out to everyone in the meeting. It said I have a mental illness not a physical one. The psychiatrist wouldn't let me speak at this meeting. He told me any attempts would be ignored. All the evidence pointed to a mental illness where people believe they are really medically ill. He then told me I would need to be started on Effexor an SNRI as it would save my life. He closed by telling me that I could find quacks down the block. (he had their names and numbers) who would tell me I had such things as chronic Lyme or CFS but they were just quacks and I'd be going down a dangerous path by getting involved with that.

I will never forget where this illness can take us and I will never allow such negligence to bring me to hell again.

This patient had a 36 beat per minute increase in her pulse rate, 72 to 108 upon going from lying to standing, with a BP of 90/70 in both positions, and runs of what were probably PSVT, in my office. I wonder how the Mayo Clinic doctor thinks she performed that trick with her anxiety. The only thing he got right was that beta blockers and depression are not good together, though this patient isn't clinically depressed.

And in the UK, patients get "sectioned" so they can be talked out of being ill. Even the comfort of good therapy is denied to patients with a diagnosis that is a pejorative. CBT might in fact be useful if it were about helping patients cope with the reality of their disease, rather than talk them out of their "false illness beliefs" and being so overly focused on their symptoms. Symptoms like being unable to sit up or lift their arms. Or using up a day's allotment of ATP to go to the bathroom.

The association between ME/CFS and autonomic dysfunction is unrecognized by the medical profession at large. Even cardiologists who know enough to diagnose POTS are unaware and fail to see it in it's larger context. There is a whole department dedicated to autonomic dysfunction at Vanderbilt that seems to see CFS as an overlapping confounder to the real work. This condition was largely unknown 30 years ago, except as a fatal genetic disease (Familial Dysautonomia). The first paper in the literature appears in 1993, Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Schondorf, and "neurally mediated syncope" first appears in 1989. Why doesn't anyone wonder what's going on that a significant percentage of the non-diabetic population has an autonomic neuropathy that was unheard of a couple decades ago? Any epidemiologists want to ponder this one?

In reviewing the paltry literature on the subject, the work of Julian Stewart, at New York Medical College's Center for Hypotension, stands out. He has an NIH grant to study "whether circulatory problems explain the symptoms and signs of the chronic fatigue syndrome in teenagers". Next best to figuring out what caused the circulatory problems in the first place.

Dr. Stewart was the lead author on this paper documenting that CFS patients hyperventilate during what I call a mini tilt test, which I include in the physical exam when evaluating a new patient. Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome. Natelson. This study documents that there is a problem with hypoxia, stimulating increased minute ventilation (though apparently not increased respiratory rate, at least in this study), despite the fact that oxygen saturation in the blood is normal. Sad that we need to turn ourselves into lab rats, and be subjected to barbaric studies like being strapped to a tilt table to prove what we know full well, that we actually have OI from an organic illness.

And what is the clinical armamentarium? Florinef, licorice, IV saline, electrolyte drinks, maybe DDAVP, beta blockers, midodrine, all imperfect bandaids. Hawthorne, a vascular toner, is a magic herb for some. Ali's POTS has resolved in recent months with high dose normobaric oxygen ad lib and modified Meyer's cocktail infusions every week or two. The most bare bones infusion seems effective for her, containing MgCl 400mg, Ascorbic acid 500mg, B-100, pyridoxine 100mg, dexpanthanol 250mg and hydroxocobalamin 5mg. I am not sure that the glutathione push adds anything for her, but we will continue to explore it. After her initial response to the cocktail containing Leukovorin 10mg, she tried oral folinic acid. It had a positive effect initially, but then she thought it might be contributing to sleep disruption and went down, then off. Coincidentally, she felt the need to reduce her Deplin from 15mg to 7.5mg. Her requirement for folic acid derivatives appears to be decreasing with time, as her health improves.

I was interviewed yesterday by a graduate student in communications who is researching gender bias with respect to CFS. We discussed the ignorance and disbelief to which patients, especially female patients, are routinely subjected. I recounted this story to him. In the summer of '06, I was hospitalized three times for abdominal pain and an inability to eat. I required TPN (total parenteral nutrition) and eventually needed a transfusion and emergency surgery. At one point, as I was near death, Ali was in a different hospital, because she woke up one morning with a paralyzed arm. We were both subjected to involuntary psychiatric evaluations. Why was that necessary? Because we had Lyme Disease? It makes my blood boil to think of it even five years later. If I'm crazy, my doctors drove me to it. There were times that seeking treatment was like signing into a veritable looney bin. With this disease, we must all learn to fly over the cuckoo's nest.

Boulevard of Broken Dreams

Rituximab: The Big Guns For ME/CFS

2011-10-26T13:52:00.018-06:00

I appreciate all the good wishes I've received from readers. I want to assure everyone that the anonymous personal attacks don't really bother me. It comes with the territory for hanging it out there as I have. I chose controversy consciously. This type of harassment is what happens when you step out of line and threaten the status quo. I actually kind of like the free-for-all in some ways. It lets us know what we are up against. Too much agreement makes for complacency. To people who have written that it makes you sick, please don't internalize it. I don't. I suspect the harassment is in fact a very few individuals. Don't let it get you down. I do think things will calm down a bit now naturally, since I don't foresee a great deal of retrovirology forthcoming on our behalf in the near future. I anticipate the discussion will now turn to treatment and how best to live with the disease. We should be on much more stable ground, since it is much harder to take pot shots at my medicine than my retrovirology. I'm sure someone will try though; wouldn't it be wonderful if the criticism was considered rather than knee jerk?

The little mystery play we just witnessed, courtesy of Jason, exemplified the pitfalls of science as a religion unto itself. Operating under the guise of "science" creates a safety net for its practitioners, satisfying the need for self-aggrandizement, simultaneously providing excuses for not going the extra distance to look outside the box. Very much the same as the medical profession. The Health Director of Norway just apologized to patients for decades of neglect and abuse. I'd like to see a similar apology from the Surgeon General of the USA. An apology tied to some serious restitution.

Personally, I was abused in every way possible due to CDC/NIH incompetence, from being unable to find adequate care to being denied entitlements, private disability to the SSDI system, all compounded by incompetent doctors, lawyers and now scientists. When I was first disabled in 1995, I had occupation specific disability insurance through Provident, meaning, if I couldn't be an ER doctor, they had to pay, even if I could be some other kind of doctor, $6000/month for life. They harassed me with IME's and other invasions into my life, literally forced me into psychiatric treatment I didn't want, until I settled with them. For the sake of entertainment and telling the whole story, though it has no bearing on the discussion, my lawyer stole the money; he went to jail, after I spent a bunch more money to expose him, but I never recovered what he stole. When I was disabled the second time, I didn't apply for SSDI right away, because I couldn't believe I wasn't going back to work. I applied after my first near death experience at our local Santa Fe hospital, with a thousand pages of records. But it turns out my last "date of insurability" was before that, so it was over before I knew I needed to build a case. Since I didn't have a correct diagnosis for 15 years, I'm completely screwed, case sitting in appeal for 2 years as I write this. All because I didn't have a diagnosis. And the new ICC wouldn't have helped. It is coming to light now, that although I didn't know what was wrong with me, Provident, in fact, did know. There is a class action suit about those policies, sold before so many yuppies were becoming disabled early in life, but since I settled, I can't participate. A cluster fuck, as they say in the military.

The observations that my behavior is not in line with what is considered "professional" has me thinking about what professionalism means to me now that I am reinventing myself yet again. According to Wikipedia, the criteria for a professional are:

Expert and specialized knowledge in field which one is practicing professionally.
Excellent manual/practical and literary skills in relation to profession.
High quality work in (examples): creations, products, services, presentations, consultancy, primary/other research, administrative, marketing, photography or other work endeavors.
A high standard of professional ethics, behavior and work activities while carrying out one's profession (as an employee, self-employed person, career, enterprise, business, company, or partnership/associate/colleague, etc.). The professional owes a higher duty to a client, often a privilege of confidentiality, as well as a duty not to abandon the client just because he or she may not be able to pay or remunerate the professional. Often the professional is required to put the interest of the client ahead of his own interests.
Participating for gain or livelihood in an activity or field of endeavor often engaged in by amateurs b : having a particular profession as a permanent career c : engaged in by persons receiving financial return.
Reasonable work morale and motivation. Having interest and desire to do a job well as holding positive attitude towards the profession are important elements in attaining a high level of professionalism.
Appropriate treatment of relationships with colleagues. Special respect should be demonstrated to special people and interns. An example must be set to perpetuate the attitude of one's business without doing it harm.A professional is an expert who is master in a specific field.

I admit to difficulty with the last two at this point in my career. My disgust with most physicians and 'the profession' is profound and being 'appropriate' is low on my list of priorities. But I certainly can live by the rest of it. Personally, I would have been better off with a good village witch doctor than any of the so-called professionals who 'took care' of me for the first 15 years of my disease, all of whom did great harm to my mind, body and spirit. In fact, one of my goals in life is not to need a doctor or a lawyer:).

In general, CFS patients get better care if they don't tell doctors what they have. Many patients have told me this. Have chest pain or a belly ache and need to go to the ER? You will get better care if you just talk about the chief complaint. Sad, but true. Maybe it is finally changing? XMRV, however it plays out, has brought us into the spotlight at last. We are finally worthy of study, not only because of numbers of affected people, but because maybe, just maybe, we are sick. And not because of our wrong thoughts. We don't tolerate stress, because we have diffuse hormone receptor insensitivity and depletion, including stress hormones. The response to stress is abnormal, and not because of distorted thinking. Viruses hi-jack cellular machinery, and retroviruses do it on an evolutionary level, using the organism's own DNA to replicate, either by reverse transcription and assembly of new viral particles or mitotically. Stress is an inevitable consequence of life, and some retroviruses have evolved a strategy to take advantage of this, hormone receptor elements that, when activated, turn on virus: Glucocorticoid Regulation of Murine Leukemia Virus Transcription Elements Is Specified by Determinants within the Viral Enhancer Region. Celander. Note interesting evidence that steroid responsiveness of MLV's may be competitively inhibited by progesterone.

And now we have the Rituxan study from Norway:

An unintended effect of treating a patient for cancer was remission of CFS symptoms and the patient's doctor actually noticed. The entire CFS community owes the doctors who pursued and published their study a debt of gratitude. Whether Rituxan pans out for CFS or not, Drs. Fluge et al gave CFS patients big guns, and reported scientifically (though blinding doesn't seem possible since the patients could probably mostly tell who got the drug).

Rituximab is not the only chemotherapeutic drug to result in temporary remission of CFS symptoms. The question is why and who might be helped by it enough to justify the risk. Given that it is possible to die from a trial of the drug, it isn't an academic question, or mostly about money and politics, as with arv's. If you want to look at the disease as an immune disorder of unknown etiology, rituximab, might help a subset of patients by depleting CD20 expressing B cells. However, even for rheumatoid arthritis patients, 40% or so don't respond to B cell depletion, even though B cells are clearly involved in the pathogenesis of that disease. Rituximab also selectively depletes certain T cell and NK cell populations. Most cytokines/chemokines are made by T-cells, but under certain circumstances, B cells make proinflammatory cytokines also. Here are some hints:

And the argument against: The drug cripples immunologically on purpose and we may be more at risk than rheumatoid arthritis patients for the worst possible outcome:

Functional Energetics of CD4+-Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune Disorders. Haghikia "For a resting T-cell to become an activated immune effector cell it must experience a phenotypic and functional shift that requires an enhanced supply of ATP-generating metabolites to meet the increased bioenergetic demands of the activated cell state. The ability of lymphocytes to import energy-carrying metabolites and to upregulate oxidative phosphorylation appears to be critical in the maintenance of effective immune responses."

Take a look at this paper, addressing the question of why some RA patients respond to B cell depletion and some don't: New Insight in the Mechanism of Action of Rituximab: The Interferon Signature Towards Personalized Medicine. Verweij. It suggests that particular levels of gene expression, disease phenotype, low IFN signature, predicts response to treatment. This paper also talks about the effect of the drug on macrophages, shifting them to a more mature, less proinflammatory stage, possibly suggesting some mechanistic overlap with the positive clinical effect observed in some patients with GcMAF. Since a course of treatment, 2 infusions 2 weeks apart, costs $9000, generally needs to be repeated every 6 months, and includes significant risk of morbidity/mortality to the patient, it is important to predict response to treatment. There are over 8000 papers on PubMed about rituximab (a search for 'chronic fatigue syndrome' brings up 5430 papers). The arthritis literature seems to find the risk acceptable. The risk of hypotension, anaphylaxis from the infusion itself, can be ameliorated with skilled administration and/or concurrent treatment. The increased risk of infection, deemed mild to moderate, in the arthritis literature, is anecdotally significant, according to doctor friends of mine who have treated complications of the drug. There is a small risk of sepsis, fulminant hepatitis B reactivation and PML (progressive multifocal leukoencephalopathy). It does appear that the risks decrease for a particular patient with time, though the longest patients have only been followed for 5, to at most 10, years. Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials. Vollenhoven.

Although I am enthusiastic that someone is talking about big guns for CFS, my initial reaction was, I'll sit this one out until we know a lot more. It scares me. But when I answered Ali's questions about why I'm not more interested, she said, "I'd take a small risk of death every 6 months for a complete remission." So Russian Roulette. I have a patient with a high Rheumatoid Arthritis Factor, degenerative arthritic changes on MRI and clinical synovitis. She could probably get it covered, a problem for most CFS patients. Though I wouldn't prescribe it at this time, this patient could seek treatment from any number of rheumatologists who have vast experience with the drug.

Dr. Michael Snyderman's comments of this morning:

In my practice, rituximab at 375mg/m2 causes hypotension in most patients, about 60% need downward adjustment of their infusion rates and about 25% the hypotension is severe enough to be symptomatic. I would expect the hypotensive reactions to be more severe and frequent at the dose of 500mg/m2 used in the CFS protocol. If the patients signed a proper consent form they would have been warned that hypotension would be a risk, therefore most patients would be aware that they had received rituximab rather than placebo. The physicians who administered the rituximab would have to be adjusting the infusion rate in most patients and would also be aware that they had given the active drug rather than the placebo.

Therefore the statement that the study was double blinded is incorrect; it is not possible to double blind rituximab for the above reasons. Furthermore, the results are based on subjective, "how do I feel" criteria which could be influenced by the patients knowledge that they had received rituximab. We have not proven that there is an expansion or clonal component of B-lymphocytes in CFS. There may be but it has to be proved and we have just started looking on a small scale. I believe that the MLRVs (I know this is politically incorrect nomenclature) probably integrate into a number of cell types. I and other people with CFS and cancer have clonal gamma delta T-cell expansions. Gamma delta T-cells are a more likely source of the well-known and accepted elevation of cytokines/chemokines in CFS than B-cells. I could find very little about cytokine/chemokine production by B-cells, certainly with respect to those elevated in CFS. I did a search as to the origin of IL8 and could only find that neutrophils and "macrophages" which would be derived from monocytes could make IL8. I could not find any article saying that B- or T-lymphocytes made IL8 but maybe they do, the area needs more research.

With respect to the present preoccupation with B-cells in CFS all I have seen were nebulous references to autoantibodies. What are the autoantibodies that cause CFS? This is too much of a leap of faith for me. Finally, rituximab would have no activity against the T-cells that are responsible for elevated cytokines found in many patients with CFS.

It maybe that CFS patients have a veritable zoo of clonal cell lines that interact with each other. I would not be surprised at all if there was a clonal expansion of cells derived from monocytes in CFS. Monocytes are the source of macrophages and microglial cells. This would fit Dr. Sandra Ruscetti's belief that microglial cells are part of the problem with CFS. So, MLRV would integrate into monocytes, increased levels of IL8 would be made and rogue microglial cells would cause problems in the CNS. Rituximab would have no activity against monocytes or microglial cells.

Rituximab is very immunosuppressive and patients who receive it are at risk for opportunistic infections including the dreaded progressive multifocal leukoencephalopathy which is caused by the JC polyoma virus. I hope to soon prove that I have a unique MLRV (not “XMRV”) and it therefore doesn’t make sense to me to take an immunosuppressive drug. In conclusion, we need new treatment for CFS but for many reasons I don’t think that rituximab will be useful.

Occam's Razor, as applied to medicine, advocates looking for diagnostic parsimony, though patients may of course have more than one disease; the subsets of patients I think related, e.g. treatment refractory Lyme Disease and ME/CFS, may in fact have different diseases. In any case, it is a big step up to have an immune disorder rather than a psych disorder. But with respect to an explanation for all the manifestations of the disease, plus the epidemiology, I still think a retroviral hypothesis fits best. Clonality contributing to pathogenesis fits. MLV's replicate mitotically, by clonal expansion, in addition to conventionally (as does HTLV). This is a likely explanation for the incomplete response to arv's in people with advanced disease. The little bit of information that we have about this in CFS suggests that clonal expansion can happen with various cell lines, so B cells might be implicated in some patients, but T cell clonality more important in others. LabCorp has testing to look at both T cell and B cell clonality (southern blot and PCR).

Epigenetic factors are clearly a very important piece of the clinical picture, likely impacting who gets sick and who doesn't. Here is an excellent article to start the discussion, illustrating where the environmental piece comes into play. As I've said before, I think environmental and retroviral illness are two peas in a pod, not in any way mutually exclusive hypotheses. Why Your DNA Isn't Your Destiny. Cloud.

Silverman found that XMRV induces 30 genes in vitro within 24-48 post infection. This is the kind of quality work that isn't being done on our behalf, because XMRV is dead. For posterity, please reread Lee/Silverman. Journal or Urology. Vol 185, No. 4S, Supplement, May 15, 2011 :

EPIGENETIC REGULATION IN INHIBITION OF PROSTATE-DERIVED ETS FACTOR, A TUMOR METASTASIS SUPPRESSOR, IN ADVANCED PROSTATE CANCER A TUMOR METASTASIS SUPPRESSOR, IN ADVANCED PROSTATE CANCER Joshua Steffan, Sweaty Koul, Randall B. Meacham, Hari Koul*, Aurora, CO INTRODUCTION AND OBJECTIVES: There is, at present, no effective treatment for intervention in metastatic prostate cancer. In our recent studies we demonstrated that Prostate-derived Ets factor (PDEF) expression is decreased, and even lost in high grade prostate cancer. Using in vitro assays we show that reintroduction of PDEF results in phenotypic reversal from aggressive to a less morbid pheno- type in prostate cancer cells. Since a common mechanism of tumor suppressor inactivation is by promoter hyper-methylation, the objective of this study was to determine if and how PDEF is regulated epigeneti- cally through promoter methylation. METHODS: LNCaP cells (Androgen dependent), LNCaP C4-2B (Androgen un-responsive) and PC3 (Androgen independent) prostate cancer cell lines were maintained in their respective growth media supplemented with 10% Fetal Bovine Serum and antibiotics. PDEF was over-expressed using bicistronic vectors and delivered by retroviral transfection. Where indicated cells were pretreated with 5-aza cytidine (5-azaC) for various time points prior to measurement of PDEF expression by RTPCR method. Cellular RNA was isolated, reverse- transcribed into cDNA, and PCR was performed using PDEF-specific primers. Migration (scratch assays and Boyden chambers without Matrigel) and invasion (Boyden chambers with Matrigel) were per- formed on cells treated with or without 5-azza-2’-deoxycytidine. RESULTS: We observed decreased PDEF expression in pros- tate cancer cell lines correlated with increased aggressive phenotype, and complete loss of PDEF protein in metastatic prostate cancer cell lines. Treatment of prostate cancer cells (PC3 cells) that do not show any PDEF expression with DNA methyl transferase inhibitor, 5-azaC, led to expression of PDEF in a time dependent fashion, suggesting epigenetic mechanisms in suppression of PDEF in advanced prostate cancer. Our studies suggest that treatment with 5-azaC results in decreased cell migration and invasion, concordant with an increase in PDEF expression. CONCLUSIONS: These studies demonstrate for the first time that inhibition of PDEF expression in aggressive prostate cancer cells is modulated by epigenetic mechanisms. Based on these exciting results, we propose that epigenetic regulations are critical for progres- sion of prostate cancer to aggressive phenotype and that demethylating agents like 5-azaC may serve as effective agents to prevent prostate cancer progression.

Since XMRV is dead as a human pathogen it makes no sense for the Lipkin study to use precious specimens collected at a cost to the taxpayers of $450,000 ($1500/specimen to the doctors for each patient and control, 150 of each) to allow WPI to try to prove that they can do what they already proved they couldn't do, and now without a chief scientist. It seems to me that the patient community should object to that vociferously. Rather, the rest of the money should be spent on deep sequencing, looking for the actual cause of the disease. Why not allow Dr. Lipkin to look? He said in Reno that if someone gave him a million dollars he'd look. Let the virus hunter hunt look for it, not Unevx. What if they don't find it? Then it's really dead. It is most definitely not in our best interest to give them another shot. They should sink or swim on their own, not spending the very few tax dollars earmarked for investigating causation in our disease. We should certainly not be willing to have the WPI be our last best hope at this point.

I thought this article particularly interesting while we consider where our disease came from: Canadian researcher traces AIDS to single bush hunter from 1921. The scientific community is showing a stunning lack of concern with respect to live vaccines and other medical technology known to be contaminated with animal retroviruses. The case is growing. Too many clues. The burden of proof is on the folks selling the stuff. A little humility, in short supply in the past, is certainly in order now. The band is playing on again.

Today's song: I Won't Back Down

With A Little Help From My Friends

2011-10-18T16:50:00.004-06:00

Somebody posted on FaceBook a few days ago: I love my computer, because my friends live in it. For no one has that been more true than for me, despite the trolls. I started to write, because I was so excited about what was happening and thought sharing my experiences would be useful. My selfish motivation was to move it along as quickly as possible, so we could all get on with it. I thought the anecdotal clinical responses might drive it, along with fear of a contaminated blood supply and the lure of money for the drug companies. I actually felt a twinge of regret that by the time I was ready to work, it would be all figured out. Ha!

I wrote because it was all I could do at the time, and it didn't matter what anyone thought about me. Work was an impossibility, a fantasy. Now I'm working part time and taking care of a very small number of patients. I am caring for them in a very hands on way, like they are all Ali:). I will be max'ed out very quickly. I am not selling a protocol or seeking patients on this blog. That will take care of itself word of mouth, as it did in my last practice. I am writing to share with people who could never get to me. Many readers are on the other side of the world. My approach to treatment is very moderate and non-invasive, having learned from the mistakes of the past. Primum non nocere. Why should that threaten anyone? Unless you disagree with my question authority point of view. Honestly, the idea that what I've been saying has ignited such a firestorm is a puzzle. You would think that people would be happy that a doctor is willing to share openly, not to mention hearing that someone is making progress. Instead the whole thing has spun into some weird parallel universe where the critters all have big, sharp teeth. That's what has me scratching my head. The response is so off kilter to the message.

My interaction with Jason was a personification of the problem. After insulting me on my own blog to the point that I thought he was a troll, he sent me a request to review the science and post his thoughts. I responded as warmly as I knew how. The only thing I asked was that he learn something about the disease. I offered to share with him, so that the time he put into it would be meaningful. He said he would review the literature. Period. End of discussion. If it isn't in the literature, it doesn't exist. Below is my second letter to Jason.

Dear Jason,

I deeply appreciate your coming forward as yourself, and not an anonymous poster. I will publish what you write without editing. I will only state that it is opinion, not fact, and that I think you were brave and generous to do it. If I disagree, I'll blog my thoughts after. The only way I wouldn't post is if it was clearly written from a place of needing to prove me wrong. I am asking you to come to this project with a "beginner's mind".

"In the beginner's mind there are many possibilities, but in the expert's mind there are few."
~ Shunryu Suzuki

In your quest for objectivity, please don't forget that there are real people with a horrible disease, many trapped in their beds with no medical care and no hope. I am the CFS suicide hotline. The shoulder to cry on. I take calls and email regularly. I am not exaggerating the importance of what you write. Please take that responsibility very seriously, even if it makes you somewhat less "objective". Think about why the hypothesis might be right, not just why it's wrong. Don't decide going into it what the answer is, even though I have attacked some of your heroes, you think unfairly, but I think they have shown an incredible lack of compassion, cruelty to oppressed people.

I don't think that you can fully consider the hypothesis without understanding the pathophysiology of CFS, autism, Gulf War Illness, Lyme Disease. Also human and animal retroviral disease. The veterinary literature is very telling. What you will find when you start to look into viral etiology of CFS is literature proving it isn't EBV or HHV-6. There is nothing but the recent furor to connect CFS to retroviruses. Other than Michael Snyderman's data, published as a poster presentation. So the only choice is to start with a hypothesis and work backwards. Please bear in mind, I am a doctor, not a scientist. I sit in a room with people who want to die because they have lost everything, are suffering unbelievably and are laughed at by doctors and scientists. Imagine having the worst day of flu of your life and having it never go away (not the way I got sick btw). Then maybe a hundred other horrible symptoms, pain, nausea, intractable headache, chronic cramps and diarrhea, sleep deprivation. Then your doctor sends you to a psychiatrist who says you are too focused on your symptoms. Cowboy up. Only you can't even sit up. Then your kids and husband start getting sick too, and nobody cares.

I have never claimed to be 'objective'. It was an ah-ha for me. A 15 year mystery, that almost cost me my life (transfusion, emergency surgery, small bowel resection at midnight, TPN), beginning to give up its secrets. A mystery that ended any chance for a normal life for my beloved daughter at 13. I am tearing up as I write this, thinking of what she was like when she was the size of your precious baby. Not that she isn't wonderful now, but her life is so diminished compared to the one she could have had. I was 41 and a successful doctor, so I had something to fall back on each time I've recovered enough to do something, but the kids who get sick in adolescence never get to live at all. The second generation is sicker. The youngest person I've heard of with CFS is 4, not autism, CFS, 3rd generation. Grandma is very sick. Mother, a doctor, a little sick. Doctors and nurses are over represented in the patient group. Also vets. You should be able to share in my outrage at the lack of epidemiological studies, since it doesn't impact your field, once you start to hear what the patients are saying about their families (some on my blog). I am looking forward to your figuring out how little money has been spent on a disease that affects so many and causes so much disability. You wouldn't believe the untapped talent in my mail.

Judy Mikovits heard the pain of the patients. Too much for her own good. She took all the desperate mail and was terribly affected by it. She visited horribly ill patients in the UK and Norway, who are being abused by their doctors and governments. Patients lying in dark rooms with ear protection and feeding tubes, for years; too weak to roll over, begging to be let out of their bodies. I kid you not. I got involved with the WPI because Judy was answering all this mail, from people who were writing to me also, and she was really bad at it, while it was a reflex for me. Judy Mikovits is a gifted scientist, with human frailties. She was working in an impossibly toxic environment with no help and the entire old boys network coming down on her. She did lots of things wrong from a PR point of view. What she did or didn't do right scientifically will all come out in the wash. It is the finding the novel pathogen, or more likely pathogens, the theory that matters now and that must be investigated. Even though you prefer deductive reasoning, genius requires induction. There is an enormous opportunity here for you, both as a scientist and as a humanitarian. It is possible to be both.

I have brainstormed with Frank Ruscetti. He thinks it's real. Sandy Ruscetti thinks it's real and she understands the murine retrovirology better than almost anyone. I had dinner with Ian Lipkin. He said "it smells viral". He was clearly very interested. It isn't one of the known pathogens...

I know you are in the lion's den and need not to get eaten. But always question authority:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1182327/?tool=pubmed

The 'souless freak',
Jamie

PS. I didn't send any letters.
PPS. Another Suzuki Roshi quote:

If you want to enjoy the movie, you should know that it is the combination of film and light and white screen, and that the most important thing is to have a plain, white screen.
~ Shunryu Suzuki

Jason

Jamie

I sent our correspondence to five trusted friends for reality testing, two of whom are well known advocates, before I answered Jason's response to my letter. Complete consensus. One of them called him a 'snot' and I did pass it on to him, I confess. If the shoe fits. I suggested he start his own blog. I'm sure, in fact, Jason is a very nice young man, with a young family, trying to get by, like all of us. He doesn't even really know what hit him, removed as he is, working in an ivory tower environment. He was unwilling to take off the blinders and my readers don't need any more negativity. Plenty of that to go around. Patients, with no medical help, have to decide what to do, in real time, with incomplete information, in a very imperfect world. And I have to treat patients in the here and now.

The attacks are an energy suck. Not just my energy, but readers' precious energy. Any suggestions about how to deal with it are greatly appreciated. It is very strange to be judged by anonymous people. It's not just me that they are judging, but the uppity patients who agree with me. If nobody was reading, they wouldn't bother with me. It is the growing sense of community that is spooking them, not lil ol me. Being forced to defend myself again and again, to prove I'm right, when I've never said that I am, serves no one. Being right is the booby prize.

I want to get better. I want my daughter, my patients and my readers to improve. If somebody has better ideas, please share them. The name of the blog is X Rx. I think it is still appropriate. Virologists call an unknown pathogen X. Elaine De Freitas called her virus X. I concede the URL is obsolete. But the point is, it does me no good to be right if it doesn't result in treatment, at least an approach to the illness. We can start to look at our NK cells, number and function, as well as cytokines. There are many things that can be done for AIDS, in the alternative medicine world, in addition to HAART. Let's look at those. One of the reasons we are better is the excellent help we've had from our FP, Russ Canfield, a smart, young doctor in Santa Fe, who has a profound understanding of the functional medicine piece, which I didn't find cost effective when I was in practice last time, but which, he is slowly convincing me, has made progress since then. I have a longstanding interest in herbs. Trying to put it all together, like everyone else. The blog is an assist, bilaterally, except for anonymous attacks and gratuitous insults. I will persevere, as the vast majority of the feedback I get is positive, even from people who disagree with me.

Today's song: With A Little Help From My Friends

by Joe Cocker

Null Result

2011-10-14T14:07:00.007-06:00

"Appeal to ignorance – the claim that whatever has not been proved false must be true, and vice versa (e.g., there is no compelling evidence that UFOs are not visiting the Earth; therefore UFOs exist – and there is intelligent life elsewhere in the Universe. Or: there may be seventy kazillion other worlds, but not one is known to have the moral advancement of the Earth, so we're still central to the Universe.) This impatience with ambiguity can be criticized in the phrase: absence of evidence is not evidence of absence." ~ Carl Sagan. The Demon-Haunted World: Chapter 12 – The Fine Art of Baloney Detection.

I am feeling subdued. Jason contacted me back channel after our conversation in the comments of the last blog. We said what we each perceived to be a reach across the divide, but it quickly became clear that the distance was too great. I am deeply saddened by this state of affairs. 'Scientific community' is an oxymoron. Everybody in their own labs doing their little absence of evidence experiments, knowing nothing of the disease in question. Argumentum ad ignorantium. A false dichotomy. I own that I am one half of the dichotomy, though unlike the other side, I don't fail to consider alternatives. The obvious third alternative here is there has been insufficient investigation to reach a conclusion. Unfortunately, it's the folks with the above 'vice versa' view that we need to do the work in order to have enough information to know what is true and what is false. Deductive reasoning leads to blinders and inductive reasoning can go to religion; I acknowledge that. All valid alternatives must be considered. Hume’s Problem of Induction puts the current conundrum in a larger philosophical context.

Taking heart in the belief that regardless of the tone or outcome of our interchange, progress has been made with Jason. He will never, ever forget this and it will inform his life, even if it's not conscious. Now he gets to decide if he is willing to see and be responsible for his assumptions and motivations. He's just found out that there are consequences for those, even the ones you aren't paying attention to. Especially the ones you aren't paying attention to. It's only a seed right now and who knows what fruit it may bear. Somewhere, somehow. Even if the only person he feels sorry for is himself, that's a start. I articulated the ground he was standing on and he didn't want to see it. And when it got handed to him plainly and clearly it hurt. Rightfully so, because I held up a mirror.

I didn't even see a possibility for mediation. No common ground at all. It felt like a microcosm of the entire situation. The emperor has no clothes, but he is sighing with relief, because nobody is going to know. They aren't going to have to deal with us. XMRV is going away.

The divide that I was unable to bridge was our hope for reaching the promised land anytime soon. I don't see it coming in the near future, unless it is from 'left field'. Chronix? Andrew Mason's lab? We can hope there are some others quietly going about their work, waiting for the dust to settle. I thought I detected real interest in Ian Lipkin when I met him. Here are Kent Heckenlively's always incisive observations: The Wakefield Rehabilitation in Age of Autism.

I feel like a lightening rod, a lot of anger going to ground through me. Making people squirm isn't my first choice, but I guess it's better than being ignored. I'd rather be a lover than a fighter, but it seems it isn't to be. I am propelled by the 'atta girl's I get from people who have had no voice for a very long time. It seems more important than who is pissed off or hurt.

More mail from Dr. Peterson's patients. The jist is, he is really sad, but can't say anything because of Annette Whittemore. And Annette Whittemore has never been willing to clear it up publicly either. These people are holding themselves out as our best hope. A little transparency is in order. I repeat. I have never met Dr. Peterson. Everything I know about him and what happened at the WPI came from the people there. Not one person, a bunch of people, but all hearsay and I plan never to repeat any of it. I believe patients first and foremost, so I apologize to Dr. Peterson. I don't understand the apparent fixation with HHV-6 though. It seems so much less plausible than a retroviral etiology. I do admire his persistence above all else. Anyone dealing with CFS for 27 years without going insane deserves huge gratitude and congratulation for unusual survival skills and fortitude.

Like everybody, I hope the CFI gets somewhere. I've had a hard time getting past the name though. Seems kind of like the tee-shirt. I wish the 'Initiative' was not coming from the CAA, given their track record. I can't find much in what's been made public to suggest that resources will be spent looking for novel pathogens. We need more than a better definition of the problems, not that that isn't important. Whether you like the CAA or not, it has managed to completely divide the patient community. Two different forums and never the twain shall meet! Very sad. Even we, the marginalized, can't come together because so many see the powers that be at the CAA to be in bed with our captors. So ugly.

Transmission questions have been the hardest to answer, since I placed myself in the position of trying to answer questions. At this point, the scientific community has essentially alleviated you of any responsibility for transmitting a retrovirus. If my hypothesis is correct, pretty much everybody has something by now. It would appear, without the benefit of real epidemiological studies, that bad things went out horizontally at certain points, suggesting a few viruses with higher pathogenicity, or ones that combined in bad ways with what was already there; but by now, it's pretty much of a mish mosh. What this means practically speaking for PWC's is, sexual contact with healthy people may be more dangerous for you than them. I don't hear that prior sexual partners of brief duration get sick, even many years later. I've heard occasional reports of spouses getting sick fairly quickly, but it seems to be rare. HIV precautions seem good enough for us too.

From an internet friend who is helping me to stay positive:

Emotions run high because there is a huge reservoir of feelings and thoughts that has had no outlet for years and years. So many have suffered silently, trying to be good so they could be believed, much less helped. It's one thing to ask for help and another to become a supplicant and plead and beg. Unfortunately pleading and begging is what we've been reduced to. Seems like birthing a new paradigm is just like any other birth, difficult and messy, but oh, the results matter so much. We have the old paradigm fighting tooth and nail to stop an unstoppable process. Progress will be made in strange, uncomfortable ways, but move forward we will.

Today's song: World on Fire

Some answers...

2011-10-10T16:08:00.014-06:00

Although the personal questions in the comments of the last blog were asked very rudely, I will try to answer them anyway. I have represented myself as an open book, and I truly am, even though it gets me in trouble, as witnessed by the tone of the questions. Most of this has been said before, but things have changed, and perhaps it needs to be said again, from our current vantage point. So, I'll give it a go.

I am not trying to persuade anyone to take anything. I share my reasoning, with references, within the limits of my writing ability. I intentionally report before I know the outcome so that it won't be seen as my pushing a particular protocol. I am in the same boat as everyone else. I don't know what to do to fix it. I don't believe that anyone else does either. Arv's are only one of the treatments I have written about here. I am sharing my thoughts and experiences in real time.

This is a blog. Opinion. If you read it carefully, there are inconsistencies. I even reserve the right to change my opinion from time to time. I try to summarize occasionally, but yes, a "casual" reader might come away with something I didn't intend. I am not sure what to do about that. I cannot recapitulate the entire blog each time I write. It is an ongoing discussion, not "the truth" at a moment in time. Almost everybody gets that, I think.

I am endlessly surprised that my opinions are so controversial and can evoke such ire. Most of it seems common sense to me. It is incredible, and very telling, that there are actually people that want to restrict my freedom of speech! Why does anyone care if others find my musings useful? I am not telling anyone else what to think. I have said repeatedly that I could be wrong about anything. If I were to say nothing until everything is scientifically validated and I was positive, I would never say anything at all. I am learning as I go, as is everyone. For some peculiar reason, I seem to need to write, and some people find it helpful. The blog is the best I can do, with the limited energy and time I have left, and I am grateful for it. When Ali suggested I write a blog, I didn't know what a blog was:). The patients who comment and write are very sophisticated and opinionated all on their own, not needing me to tell them what to think. They ask for my thoughts so they can put the information into their own equations, not take it as some kind of truth written in stone. The reflex to restrict what I say so that the poor gullible patients won't hear it is patronizing. And to the conventional physicians who might be reading, why the sudden concern for our well being? There are many useless things that you are willing to prescribe that are much more dangerous than arv's.

I have never claimed to be anywhere near "well" and I have said all along that there were confounders with respect to our treatment with arv's. As noted in the comments, gamma retroviruses replicate by clonal expansion, so we need specific drugs, but transcription of viral proteins and the assembly of new viral particles may be involved in pathogenesis, if the hypothesis is correct. I am endlessly reevaluating everything with new information as it becomes available. I am not in fact a "true believer". I would love to hear any alternative hypothesis that fits close to as well. Anything at all that might suggest a direction to turn for efficacious treatment. I am dismayed that we are back to having an idiopathic immune disorder, albeit repackaged to sound like good news. Redefining it as a syndrome, yet again.

There is no way to know if arv's are helping us at this time, as I have said several times. I expected viral load measures and other ways to monitor that didn't pan out. I did monitor several likely parameters which showed trends, but not convincingly enough to be useful. There are specimens sitting at the WPI that might contain valuable information. I certainly hoped it would be less ambiguous than it turned out to be. But there are others that experienced what we did, apparent cause and effect improvement from starting arv's (often after an initial mild symptom flare). Some of them have written on this blog. I am NOT saying anyone should take arv's, and never have, only that they shouldn't be forbidden. The main problem I have recommending it as an option now, is that because it isn't being studied, anyone starting will likely find themselves where we are, not knowing what to do for the long haul, and no help coming anytime soon. I actually think it is probably mostly a moot point now; the forces against have essentially won, shut it down for all practical purposes. The important thing isn't really even arv's, which at best only help incompletely, but our inability to get any help at all due to the attitude displayed in the reaction we have seen to the idea.

There are many drugs that are used because they work, even though the mechanism is unknown. One would think that for a debilitating disease which affects millions of people, for which there is no meaningful treatment, somebody would want to find out if that might be the case here. The usual way that happens is somebody has a good case, publishes it and then it gets studied. I have reported our experience. The burden of proof is not on me. What if it was a serendipitous discovery for the wrong reasons? The reaction of the medical community to trying arv's is irrational, as the reactions of the medical community often are, especially when it comes to anything to do with this disease. The reaction of the scientific community is a joke, with no basis for an opinion at all; practicing medicine without a license, understanding nothing of the disease about which they are so opinionated.

Take a look at this paper: Zidovudine in primary Sjögren's syndrome. Steinfeld. Rheumatology (Oxford). 1999 Sep;38(9):814-7. Did everyone get up in arms about this small clinical trial? Were the authors discredited for trying it? It doesn't look like anyone followed up on it.

I have shared many personal details here, both physical and emotional. I have been very forthcoming, approaching undressing in public at times, so it is strange to be accused of "hiding". The problem is that my sharing a list of symptoms that are "better" than before isn't terribly illuminating, since some things are better or gone and some things aren't. I even have a couple of new things. Like most ME/CFS patients, my condition changes from day to day and tweeting my moment to moment condition would benefit no one. However, I will try to define the big things.

The most tangible thing that happened to me, seemingly from arv's, was the near resolution of my chronic malaise. I had it much of the time for 15 years. It went away shortly after starting AZT/Isentress and I almost never have it now. So 90% of the time before, 10% or less now. That alone was life changing for me.

My down periods used to last for 5 days to a week at a time, and now, rarely more than part of a day. The worst moments happen less often.

When I started arv's, I never slept more than two hours without awakening, and I didn't dream at all. I now often sleep all night with one or two awakenings and I dream normally. My day to day wellness is linked to the quality of my sleep in a chicken or egg fashion, so this improvement is key.

Painless migraines (scintillating scotoma without headache) and hypertensive crises are much reduced in frequency.

Another "big thing" that happened: I experienced a definite decrease in my peripheral neuropathy pain at one point early into arv's. However, trying to explain one's pain to anyone else is an exercise in futility. The pain I have now is worse than pain that almost drove me insane at the beginning of my illness, but my coping skills are very different. Still when the reduction happened, it seemed definite. I am not pain free, but my pain is quite tolerable and does not require pain medicine. Others have also reported less pain on arv's. Again, I am reporting, not selling. For everyone who thinks they were helped, somebody else thinks they weren't, but the risks of trying it are pretty minimal with proper monitoring.

I acknowledge that it is possible that all these things happened in spite of, and not because of, arv's.

A big disappointment for me has been that the abnormal response to big time stressors remains, though it may be attenuated. Impossible to tell.

As for my daily functioning? I am able to work long days, most days, electronically (phone, Skype, email). I don't have brain fog, but do sometimes have more symptoms after mental exertion. I am limited physically, more so in Santa Fe than Hawaii. I can climb a couple of flights of stairs with some dyspnea, more if needed, if I go slowly. I can usually walk several blocks, but might have some mild PEM if I overdo it, though my exercise tolerance is very variable. I don't need handicap parking. I have no difficulty lifting groceries, etc. Resistance exercise is easier than anything aerobic. Swimming is easier than walking. Standing still is the hardest. The most physically challenging thing I have to do is negotiating airports and I use the airport wheelchair service for that. Gentle yoga is helpful. Pretty much all of the above is better than before I started arv's, though as a commenter said, and, as I have said all along, other things happened too, before, during and after. Also my illness historically follows my state of mind (knowing full well how unPC it is to say that out loud). I am also much more tolerant of symptoms than I used to be, and not a very compliant patient, more confounders.

I can only work part-time face to face, a couple of hours at a time, but I'm OK for many successive days. I could fake it for longer hours than that, but don't want to do that. My patients travel a long way to see me, and I want it to be useful and special. I am seeing new patients for 4-5 hours on two different days, which is working out well for all concerned. It is a unique, collaborative endeavor. Sick doctor and sick patient. I am limited, but can function fairly reliably, though there are days when it's tough; however, there are more days when it isn't.

When I started arv's, I was unable to speak on the phone, because of auditory processing disturbance. I also had to lie down most of the day, only sitting or standing for a very short time, and I now sit up most of the day. Standing is more difficult some days than others, but there is never a time when I can't if I need to; that was not always true.

So huge functional change in the last 20 months on arv's, but improvement started about 6 months before that, with cessation of Lyme and symptom-based treatment. From housebound to functional, but not at all "well". I have written about the reasons why I abandoned the use of rating scales to evaluate our experiment and don't want to rehash it again. It is sad that it's all we have. I am collecting them on my patients, but don't expect them to be as useful as patients' subjective reports. Yes, I do believe what my patients tell me.

My illness certainly isn't gone, though it has lifted, lessened, but it is a relapsing, remitting illness all on its own, making it extremely difficult to assess cause and effect. I have said this over and over again. I am fully aware that many ineffective or harmful treatments have been perpetuated because of this feature of the illness (see my prior blog entries about Lyme Disease treatment). Whenever anyone gets better, they think it's because of whatever they were doing at the time. I received an email recently from a patient who was housebound for fourteen years and suddenly improved enough to get a life, having changed nothing. I was of course influenced by the fact that there were two of us sharing the same experience; Ali and I had similar experiences with respect to the timing of improvement, though she had no side effects and I did experience a flare of symptoms initially. And for the record, neither of us has a history of placebo responses.

Ali went uphill during her first 6 months or so on arv's, but had more therapeutic interventions concurrently than I did. The goal was always to get her better, not demonstrate something scientific to others. Her treatments did not prevent her crash when she tried to engage life again a year ago. She is doing well again now, but it is impossible to say if this level of wellness is the same, above or below her last remission. The "crash" didn't become as serious as prior crashes have been for her. The important thing to her now, I think, is that she is better at this moment, and seems still to be slowly improving. Will it last? She is savoring it while it does.

My baseline was better prior to the events of early July than it is now, though I am not "crashed". I have been under a great deal of stress, though I am hoping things will calm down a little now, so I can regain what I have lost. There is no way to know if I tolerated the crisis better than I would have without arv's. I suffered the kinds of losses and persistent stress that have historically set me back in a major way. I stopped Isentress a while back, and am worse. Cause and effect? Who knows, but I don't want to stay on monotherapy and am afraid to stop Viread, since a couple of patients who were forced to go off have lost gains. I may go back on Isentress. Also thinking about Lexiva (see Li on the sidebar).

I have received several demands for an apology from me to Dr. Peterson. As I said when I mentioned his name for the first time, I have never met him. Making enemies was never my intention, just the inevitable consequence of stating one's opinions openly and publicly in such a contentious arena. My frustration feels overwhelming sometimes and it comes out in my writing. I hear from patients that love Dr. Peterson, and that does make a difference to me, but it still seems inconceivable that he abandoned the pursuit of a retroviral etiology when he jettisoned the WPI, knowing what he knows about the science and the disease. His teaming up with Konstance Knox to sink the WPI still seems really sleazy to me and his claim that it was to protect patients disingenuous. He could not have known there were problems with the VIP Dx test, or questions of contamination, at the time that he left, so how could he have been "right". His agenda appears to go beyond figuring out how to treat the disease and help patients. I am not saying that I know precisely what that agenda is. It would seem that everyone who was involved with the WPI was hurt, likely including Dr. Peterson. I only wish that he hadn't thrown the baby out with the bath water.

I regret any pain that I have caused, but some truths are painful. For me, it is painful to acknowledge how few friends there are worth having in the medical or scientific communities. My referral list for mainland doctors is a very short list. When I think back over the people I have mentioned by name in an angry or personal way, it is a select few that had it coming. My lack of professional decorum, or whatever you want to call it, comes from outrage, and mostly justified. I challenge anyone who has been sick with this disease for any length of time to write their truth and not say some angry things. My writing is also full of hope for the future. It's just that it is the hope of learning to live well with the disease, rather than to truly vanquish it any time soon.

I really think many have too much confidence in "science", especially retrovirology, which seems to have an unusual number of landmines scattered across its landscape. Even if Dr. Lipkin were to say tomorrow that he agrees that there are gamma retroviruses infecting ME/CFS patients, it will be a long time before that translates into specific treatment. Compassionate use of existing drugs should be tried and available, especially for the sickest patients. There are possibilities besides arv's. Lenolidamide? Pentoxyfyllin? Nexavir? Existing drugs. What others? I recently heard of a big time response to Copaxone. Is anyone looking in a systematic way? Really looking? Why does it feel almost subversive to talk about it? The idea that these patients should, or can, wait is indecent. Again, I am not trying to convince anyone to do anything other than consider my ideas. I continue to write because some find it helpful, and I have made many friends, but I have made enemies too, and that gives me pause. I do grow weary of the personal attacks, on top of everything else that has happened recently. I need to focus on my patients, but want to continue to reach out to readers; there is so little information with respect to how and what to consider for treatment in the here and now. Five or ten more years is too late for many of us.

OK. Now I have some actual work to do:).

Aloha,

Jamie

Today's song: Can't Find My Way Home

When One Door Closes...

2011-10-09T17:34:00.017-06:00

I believe this demonstrates a social 'immune system' in science which is remarkable for its ability to distinguish 'self' from 'other'. ~ From my email

I feel like we are post-op. The patient got opened, the problem identified and resected, but the smallest movement produces a wince of pain. Still, it is becoming clear, there will in fact be a future. The dilettantes, fair weather friends, have all gone home, closed the shutters, locked their doors, and minds. Nothing more to think about. We have been easy to ignore for a long time. Now, it's even worse than that. The scientific community is actually making fun of us in their ignorance, as is the CAA, our supposed representatives, who in 20 years have never managed to sound the alarm. If XMRV wasted some money, what about the CAA? If these scientists were truly objective, they wouldn't all be so happy about the outcome. Mikovits, Ruscetti and Hanson, a very few others, are the only scientists in the world who know anything at all about the disease. And the fact that they care about us, doesn't make them wrong. The rest of the scientists in this story are completely ignorant of the pathophysiology. Clueless, and not interested. Racaniello, ERV, commenter Jason, et al have not an iota of understanding about why simple retroviral disease is such a good fit. To them, it's all about a test, not a disease. Money, glory, fame. Most certainly not about patients. They seem shocked to find out there are real people impacted.

The idea that it is better for the patient community if research into gamma retroviruses stops now, so that all the money can be spent on investigating the same old downstream effects and known pathogens, is a cruel joke.

From the limited anecdotal evidence we have, I'm pretty sure the response to antiretrovirals, even without specific drugs and without a PI, is better than placebo. The AIDS community doesn't want to share their drugs, even though they are available to healthy partners and prostitutes for prophylaxis. Doctors who have already prescribed antiretrovirals are now, on the heels of the BWG results, refusing to refill prescriptions for their own patients who have improved on them! What could this be but politics and money? Why is the scientific community invested in creating a prohibition against these particular, not very dangerous, drugs? Why so much resistance to the idea of a retroviral etiology that they are gloating as the hypothesis takes a hit. Let's have a party and burn Judy Mikovits at the stake. Glee. At our expense. Like psychopathic children who enjoy pulling the wings off insects. This, while babies are born with it, new cases are occurring every day and huge numbers of patients, already sick for decades, circle the drain.

The question of whether antiretrovirals are helpful or not and for whom, is a question that hasn't even been asked, let alone answered. It is politics, not medicine, that prevents it from even being considered. The clinical piece still strongly suggests a retrovirus, or retroviruses. It is possible that it isn't only gamma retroviruses. ALV's, alpha retroviruses, do pretty much the same things as MLV's. Although it is likely that ALV's would be less infectious to human cells than MLV's, because of phylogenetic distance from mammals, there is evidence in the literature, by none other than John Coffin, that suggests, under some circumstances, it is possible for ALV's to infect human cells. But he didn't think we should worry about it: Science Fiction? and Pure Speculation (I can see and hear the virologists, rolling their eyes and snorting, all the way from here). So what's the motivation for making sure this hypothesis is found wrong? If it is right, it's responsible for bringing down the health of the species, so some might be a little invested. But it's so big, that saying it out loud makes you sound crazy. We have a possible source of infection: parenterally administered simple endogenous animal retroviruses. What else causes both neurological disease and cancer? Methylation issues, multiple gene activation in the same patient, persistent immune activation, multi-generational neuro endocrine immune disease. Think top down. What else does that? The fact that not everybody gets sick, that there are various opportunistic infections, that it goes in different directions in different people, that it is of variable onset shouldn't be so bewildering. There is obviously a greatly increased risk of ME/CFS in the partners, children and parents of patients. Too much autism found in the same families. IT IS AN INFECTIOUS DISEASE. Where are the epidemiologists?

There have been lots of questions, people asking for clarification of the last two blogs I wrote. For the most part, if it was ambiguous, it is ambiguous to me, at least I wouldn't personally testify to it, especially anything about who did what for the BWG. I don't think there are any villains in this story. Only people who lost their way, sailing into open ocean in a dense fog without a navigator. People are fallible, and we are where we are because they never had a chance. Much of what ensued was like middle school more than anything else. Nothing sinister. No malice and absolutely no aforethought. It still has a middle school flavor to it, all the way to bullying in order to cover-up.

What I meant by saying that the XMRV testing that was done at VIP Dx is now null and void is that there were likely many false negatives and false positives; therefore it had no clinical utility. It cannot be interpreted. However, everyone knew that it was experimental. At the time, we were grateful to have it. Dr. Mikovits stands by the testing done at the WPI research lab. My understanding of her position is that she was not responsible for quality control or precisely which assays were used at VIP Dx, after the initial release of the test, when Cooperative Diagnostics made their bid for the market. If contamination occurred, it sounds like it wasn't necessarily with VP62, but with the cultures from hot patients (like us). Apparently, what has been learned through all this is that the labs need to be using precautions required for Mycoplasma. Retroviruses have not been thought to be aerosolized previously, but now it seems, some probably are. There are two papers that show rapid spread through a clean lab in a couple of days, Zhang and Sfanos, linked on the sidebar. The serology is picking up proteins that are, if not actually to HGRV's, at least very similar to MLV proteins. It has nothing to do with XMRV per se, and cross reactivity has not been ruled out. At least this is how it's been explained to me, though I know very little about the technicalities of lab testing; more than I used to, but still not much. Therein lies a key problem, little sharing between doctors and scientists.

The slide issue seems like a tempest in a teapot to me, part of the same insanity that requires Judy Mikovits to be a perfect human being or all is lost. There is now an investigation, so in the end, we will find out what the designated judge says. What I would like to know is, how did Dr. Mikovits's firing go from 'insolence' to 'fraud' from Thursday to Monday? Dr. Mikovits was fired on September 29 and ERV blogged her over the top accusations on September 30, I've been told, though I still have not been to her blog (thousands have visited mine from her site). Who fed it to her? The editors at the Chicago Tribune should be ashamed that Tsouderos was taken in. Nothing more than tabloid journalism. For the record, I waited three days after Dr. Mikovits was fired, before I wrote anything. By then, it was clear to me that it had been decided that Dr. Mikovits' reputation was the price of the WPI's survival and my inbox was full of unanswerable letters. I said nothing for a very long time, hoping for a different outcome. Also for the record, I did not send any letters to the press. Trine Tsouderos wrote to me and asked me what I meant by lock-down. I told her "The personnel was locked out of the lab." (proof of which is on my computer). Nothing else came from me.

Obviously, something went very wrong. Most likely lots of things did. I know Dr. Mikovits would like to have the chance to figure out what. I think the probability that what went wrong was a 'fraud' committed by Judy Mikovits is at the very bottom of my list of possibilities. I know her personally and it seems beyond improbable. Inevitably mistakes were made and everyone on the planet has something to hide, so, poor Judy, and poor everyone else involved.

I hope to never be an insider again. Two people have asked me how I could have forgotten what the Whittemore's did for me. I have not forgotten, but they seem to have forgotten what Dr. Mikovits did for them. I was videotaped for the WPI saying they had saved my life, and it was true. I said nothing, except that I had been fired; I said that because I wanted to distance myself from the decisions being made there. But then Dr. Mikovits was fired. If I hadn't written anything, Trine and ERV would have had the only say. But I am not going to engage in any further mudslinging going forward. I am now supposed to apologize to this one and that one, who was right because the interloper has fallen; the WPI was wrong and I stood behind them. I was a starry eyed kid then, believing that the cavalry was actually coming over the hill. I am a battle weary soldier now, having taken a few arrows in the heart. I no longer think the cavalry is coming at all, any time soon. Also, I still think that all the people I mentioned at one time or another on this blog in a negative context have behaved very badly, even if everything the WPI ever did is wrong. It's not black or white. It never was and it never will be. The patients are the ones that get screwed, over and over again. CAA, the most divisive force in our community, HHV-6 Foundation, WPI, it doesn't matter. Loss and more loss.

So, "Cheshire Puss... Would you tell me, please, which way I ought to go from here?", said Alice to the Cheshire Cat.

Since I am feeling like my change the world phase is over, as Kita said, what next? My job now is to interpret the events in terms of their clinical significance, one on one. Primum non nocere is my guiding principle, as it was for my first 25 years of practice. When possible, I include the pocket book in that. It is curious what insurance will and won't pay for, having very little to do with what might produce results with the least risk of harm. In my practice, I am using only LabCorp and Quest for labs. I am no longer interested in results from labs that have a stake in the results.

My attention is on my daughter, as it has been all along. She was "Harvard material", as my step-father, a Yale/Harvard educated surgeon, said before he died of the late effects of treatment of his Gleason 9 prostate cancer. Ali still might succeed at having a life with the right physical and social support. For a long time I have envisioned a collective with the goal of creating a supportive, assisted living environment for young people with CFS. It is clear to me that I will be dead before there is treatment that approaches a functional cure. Whether you think arv's are a good or bad idea, we are both doing well on them. Ali is engaging her life again, dating, going out, shmoozing with her illness. Not suffering much at all. Last time she was at this point, she did too much too soon. She is wiser now.

She is very responsive to the right treatments, now that we know what we are treating (not a specific pathogen, but still a context and approach to the illness). Folinic acid is hot stuff for her, Leucovorin 10mg IV weekly for a while, and now she is playing with the oral form, finding some of the same side effects as with Deplin. It appears to build up over a period of time, days to weeks, and cause dose dependent sleep disruption. But some amount helps the overall picture. I am hearing similar things about Deplin from patients. Important initial response, then dose related insomnia, sometimes still with improvement in other things. For Ali, the amount of folic acid derivatives required for positive effect without sleep disruption seems to be decreasing with improved wellness. So she's tinkering. Next stop, 5-MTHF. I'm starting to order MTHFR mutation testing on my patients (MTHFR Thermolabile Variant DNA Analysis at LapCorp and MTHFR DNA Mutation Analysis at Quest).

She continues to use oxygen with great regularity. We both find it useful for rescue, as well as believing that it supports our recovery, which seems steady and real, but slow. There was a single comment a while back that oxygen had been bad for someone, but without specifics. I want to hear about any problems, since I've been advocating its use. I have a lot of experience prescribing oxygen as a hyperbaricist and the risks, without adding pressure, are so minimal as to be almost non-existant. You can always turn it off, after all. Long term, there may be a risk of accelerating aging. That's all I can think of. I can't really come up with another reason not to try it, but I certainly want to hear it, if someone has something to add to the discussion. So far, practically speaking, my patients are liking oxygen. It is representative of the insanity in all this that patients can have Fentanyl patches for years and years, but can't try an oxygen concentrator.

My illness is pretty much refractory to everything, except being positively engaged. For me, helping helps the most. I do best when I don't mess with it much. I was the sickest when I was taking the most drugs. Antiretrovirals are one of the few things that actually seemed to move me. I sent specimens to the WPI regularly during first year of our experiment. Dr. Mikovits had evidence of our positive response to antiretrovirals, at least initially. I wonder where those specimens are now? I've tolerated 5 trips to Reno and 3 to Hawaii in the last 13 months. Pretty good for an ME/CFS patient who had been desperately ill twice in the previous few years. It is becoming clearer and clearer that I do feel better in Hawaii than Santa Fe. I think for me it is the elevation, because Santa Fe is one of the cleanest cities in the country, Los Alamos aside. However I'm hearing from lots of people that say they felt better in Hawaii but who live at sea level (and others who didn't get better there of course). Some of those people live in really polluted places, like LA and NYC, so that may be the greater factor for them.

I am in complete and total agreement with the mold warriors that environment is critical to success, defining success as the patient's maximum possible wellness within the context of an incurable, but remittable disease, though my idea of environment is much broader, not just avoidance, but feeding the positive, including strengthening the spirit. Stress makes us sick. My fantasy kibbutz would be organic, as chemical free as possible, MCS friendly, and of course as mold free as achievable. But as important, would be an opportunity to be alone, with necessary help, or to be able to with others who understand and support. To be able to go out, but not fear ruining it for everyone else, if assistance is needed. To not have to apologize for existing. I see the mold warriors insistence that I am the enemy as a microcosm of what anybody with this disease who finds a way out feels. Huge frustration that they aren't being heard in the face of immense unnecessary suffering. It's just that from my perspective, hearing from people from the full spectrum of the ME/CFS community, it's one of many factors, most important for some, but not so much for others.

Almost the most important thing that didn't happen at the WPI clinic was the use of an electronic EMR by multiple clinicians, so that a large database would be created, which would ultimately be searchable by any parameter chosen. I am using Practice Fusion, free cloud based EMR. It is brilliant. It can only improve patient care for doctors using it. Converting from another method of documentation is difficult, but it's not insurmountable. It's possible that physicians might be able to contribute to the creation of a large patient database anyway, even though they are not physically in the same place. I mentioned a particular test above; it is beyond time that clinical research (pardon the oxymoron) was happening in a broader context than one physician's practice. Thinking about this, and what might be still be possible...

Tonight's song: Closer To Fine

What Next? by Kita Rael

2011-10-07T15:04:00.001-06:00

Time to stop feeding the beast that is intent on eating us. I believe that until some sort of money making model is invented to reap CFS/ME, our community will be the target of and subject to parties and people whose job it is to keep us divided, traumatized and so focused on that trauma that we are rendered as politically disabled as many of us are physically disabled.

Can you see how this takes us off the playing field? The one we just really stepped on with so much hope not too long ago? We finally found our voices. The thing to remember is that these are OUR voices and they weren’t given to us by research, they were inspired by research. And research/government/science/(whatever) cannot take them away unless we give them away.

Yes, there is howling pain when there is a setback. What looks like a huge crash right now may well prove to be a really big speed bump, on the order of what I once encountered while driving around in Mexico. The dreaded “tope” (pronounced toe-pay). It’s about three times the size of our American speed bumps with sharp corners. If you’re not paying attention they can be lethal to your tires. So one person was appointed to watch and would sing out “TOPE!” in order to avoid more problems than were required on this particular trip.

I vote to call these latest events a pretty big tope. Everyone had their eyes on the horizon and were speeding up. Then bang. Now we are on the other side of it, maybe sitting on the side of the road. Damage is being assessed. There are some of us in fistfights in the back seat and it’s taking all of the attention off of the road. Yes, we’re still on the road, it was just a tope.

Pay no attention to the onlookers who are trying to tell you that the damage is so terrible that they will have to help tow your car off to the repair shop, (there to “try” to repair it and possibly even causing more problems than you arrived with in order to make that tope into such a disaster that you can’t continue on your way) even though, with careful inspection, you can see that you’ll probably be okay. It’s worth getting back in the car, quelling the uproar in the back seat, turning the key and easing back onto the road and heading further towards your destination.

We still have our voices. We’re still moving forward, even if we took a bigger hit than we thought possible to sustain. There will always be outbreaks of fighting in the back seat even after periods of relative quiet and harmony. An elbow will be thrown, someone will feel crowded, someone else really enjoys a tussle. The car keeps moving. Now and then it’s time to switch drivers. Either a driver got tired or their stop came along, a different destination than the majority in the car. We just saw a designated driver pitched out, but who says there can’t be a way to circle around and pick her back up, dust her off and cheer her amazing driving skills once again?

But guess what? We patients OWN the car and we actually do have a say in where it goes and how it gets there. Every time research/government/science/(whatever) throws a wall in front of us we can go around! What will we do when it’s actually a wall and not a tope? I say this was a terrific exercise in preparedness and courage and fortitude. Our community is diverse and filled with inventive and capable people, sick or not. A great example of that was the write-in campaign that morphed into such creative forms that it was stunning. Who knew? Who knew what we could be and do until it got started? We have deep resources in the people around us who DO care. That’s a proven thing.

I don’t know about you, but I still feel excitement in the air and movement with our community and also with investigations on the part of researchers. This is so different from the 25 years of stagnation that preceded the Science paper. Like it or not, the dam was breached and here comes a flood. I do not believe it can be stopped because there is the weight of aware and passionate people pushing ahead.

Again I say that I hold with this: he of the highest light wins.

No Good Deed Goes Unpunished

2011-10-04T09:50:00.003-06:00

Yesterday made clear that it is going to be a circus. All that's needed is cotton candy and clowns. Annette Whittemore is still selling fairy dust and the fate of humanity depends on whether Judy Mikovits was perfect or not. It's more exciting than a high wire act. The CAA, the folks at the CDC, most of the scientific community are all gleeful. They wanted to turn the iconoclast into Joan of Arc. Since she isn't a saint, the Salem Witch Trials is a better metaphor. If the scientific community had actually been impartial, they wouldn't be so happy. They say it needs to be about the science, not the scientist, but in fact, it was, and is, very personal, not about the science at all.

I am not a lab scientist and cannot evaluate the slides written about in yesterday's Chicago Tribune. I refuse to read ERV's blog on general principles. Trine Tsouderos seems to be slumming for sources. And Annette Whittemore, who has no viable option but to blame Dr. Mikovits for everything that ever happened at the WPI, has turned to the journalist with an agenda. The debunker. Necessity makes strange bedfellows. Even discounting my own experience of Dr. Mikovits, which makes fraud as an explanation for an error extremely unlikely, it makes no sense that she would intentionally subject herself to the possibility of that fraud being detected by using the same slide again on purpose. The only person who has a reason right now to characterize a mistake, if one was made, as fraud, is the person trying to save the WPI. And maybe ERV and her ilk. Now all that money that was just raised at Vivant and the WPI annual fund raiser can be spent on lawyers to go after Dr. Mikovits, as they try to continue to lure patients down the yellow brick road. The baby in this divorce? The grants. An institute without a chief scientist and a scientist without a lab.

What's left? A lab running a bunch of tests that I can order from Quest and LabCorp, for which insurance will pay. A CEO who, when I was there, had six people working for her, including a personal assistant, while Dr. Mikovits had two, and then one. A doctor working for himself. An awful lot of empty space. Less than no respect at the medical school. A post doc. A paper which looks like, one way or another, it will be completely discredited soon with everybody calling everybody a liar. Some GenBank sequences and related patents, which I know very little about, but which I imagine are enough to muddy the waters for everyone else, and therefore prevent work from seeing the light of day. Why would anyone want to get into this mess now? My fear is that the WPI will try to exist without substance to preserve their intellectual property. At this point, the counter on the top of the side bar is counting more lost time.

All this in the context of: I still think a gamma retroviral hypothesis is the best one we have.

Today's song: Stuck In The Middle With You

Square One

2011-10-02T21:12:00.001-06:00

Breaking news. The entire WPI research program has been closed by the institute's CEO, and the facility is now locked down. It's former principle investigator, Dr. Judy Mikovits, is in active discussions concerning institutions to which she may move to continue her grant-funded research. The institutions must remain unidentified, for obvious reasons, but it’s important for patients to know that she remains committed to continuing this critical work.

So now, on top of everything else, a divorce at the WPI. Yet to come are all the things that can happen in such messy situations. Meanwhile, there is no Mikovits-led research at the WPI or any research institution at the moment. An enormous loss of possibility. I've done a lot of soul searching about whether to write this blog or not. My motivation for writing all along has been to make things better, to inform, alleviate isolation, share ideas that I hoped would be useful. This is different. Writing this entry, I feel like I'll be taking away hope, which is anathema to me. But at this time, withholding the information I have would be dishonest. I don't know what else to do, except tell it the way I see it.

Here is the reality and the context for why I write this particular blog entry: My email inbox is filled with so much pain and confusion, as patients try to figure out what the BWG study means to them. I feel it is my obligation to both these patients and the larger community to share my opinions. I think what the BWG results mean is that all the XMRV/HGRV testing done at VIP Dx has been and is now null and void. Keep in mind that Dr. Mikovits works at the WPI research lab, which is a separate lab from the clinical, commercially-oriented VIP Dx lab. She believes that she has reproduced her original work many times and found evidence of infection in the patients who were previously found XMRV positive. But she never found any single patient positive on every date tested by every assay. So there has been an assumption that there were false negatives in the WPI research lab for some time. Another important thing to keep in mind is that WPI routinely used several tests on each sample, whereas VIP Dx used different, more limited testing, on the samples they received, testing that apparently was never truly validated against WPI methods or performed with appropriate controls. I personally don't know why this was the case or how it happened. Obviously the decision to sell a test was a very poor one, hindsight being 20/20. It left the institute with a difficult conflict of interest.

I have watched this whole thing unfold and kept quiet because I hoped that management at the WPI would come to their senses, before it was too late. They have not, so I now feel obligated to share what I know.

Dr. Mikovits is a personal friend of mine. We've spent time together in Reno. We were excited about our collaboration. We still speak and email regularly. Because I know her so well, I can tell you first hand that she never thinks of or spares herself, and instead gives her all to the research and the patients who need it so badly. She has been criticized for the unorthodox step she took of allowing patients to gain access to her, a step that was life-saving for some, though it turned her into the ME/CFS hotline.

In terms of the BWG: I was told that the BWG specimens were being run in both the WPI research lab and the VIP Dx clinical lab. Though the labs were kept separate, and cooperation between the two labs was already very troubled, Dr. Mikovits believed that VIP Dx would succeed, and everything would be doubly validated.

When the results of the BWG were uncoded and revealed to all nine labs (but not yet made public), in early August, WPI was left in a bad place. Dr. Mikovits says that at that time she asked WPI management to stop offering the XMRV test at VIP Dx. But the testing was not stopped. Why?

Then, when the BWG results were finally made public on September 22, Dr. Mikovits was quoted as saying, "VIPdx lab will NOT continue XMRV-testing because it hasn't been shown to be reproducible in [the] BloodWorkingGroup". Shortly after she said this, cooperation between the two labs ceased completely and the research lab was closed. Why?

It is important to know that Dr. Mikovits stands by her work at the WPI research lab, which is all she can vouch for. She cannot account for what happened at VIP Dx. It was in a different location, under different leadership: Dr. Lombardi was in charge at VIP Dx.

Now it appears the WPI research program is getting thrown under the bus, but VIP Dx is still up and running, now minus XMRV testing. None of this means that we don't have HGRV's, or that some of the work that came out of the Mikovits-led research lab wasn't correct. What it does mean is that there is no validated test for clinical, commercial use. And it means we are now at risk of losing all the gains we've made because of poor managerial decisions.

My next blog will be to repost Dr. Mikovits' slides from Ottawa, this time with her comments and a summary from me, making the case for HGRV's. Culture contamination with VP62 doesn't explain away her findings. She was finding variants of XMRV. The serology test used in the BWG and published in Lombardi et al is picking up something that is at least very close to, if not antibodies to, MLV proteins. Someone needs to find out what those proteins are. There were electron micrographs from patients showing retroviruses. Pictures. Frank Ruscetti has been studying retroviruses since the beginning of the field and he believes he has been looking at something real. And there have been clinical responses to antiretrovirals, including ours, that are hard to explain away, other than that they are doing what they are supposed to do, inhibiting the replication of retroviruses. Please read Dr. Snyderman's posts and comments again: A Reason For Hope.

As sometimes happens with divorce, we now find ourselves in a position where we have to take sides. The science, not the institution, is the child that must be protected somehow in the ensuing custody fight.

For the record. As we descend back into darkness... I wrote the below text a few weeks ago, but didn't post it. I have confronted these issues directly with WPI management and not gotten an adequate response.

Untitled blog:

If you tell the truth, you don't have to remember anything.
~ Mark Twain

I've been quiet about my own personal experiences at the WPI, figuring things would unfold on their own, without disclosure from me. But something is happening that I can't just let pass, It is this belief patients have that, could they only get to Reno and be treated at WPI, it would all be better. This dynamic is too painful to watch in silence. It hits a nerve. When my daughter got sick with "Chronic Lyme Disease," I felt that there was information other doctors had that might help her. The memory of that feeling, of being unable to help my child, thinking that there was something to know that I didn't know, and the poor decisions that desperate feeling led to, is driving this next disclosure of mine. Keep in mind that most of what I know about that is happening on the clinical side at the WPI now is hearsay. He said, she said. Eventually, it will all come out in the wash. But as a physician, I feel the medical carrot being dangled before the public needs comment.

I recently watched Annette Whittemore on Nevada Newsmakers imply that there is new treatment available at the WPI that is producing miraculous results. Due to patient confidences, I can only impart my reaction, not prove my case with details. But her comments were over the top, an advertisement, cobbled together from little pieces of reality, but not reality. There is one doctor working independently in the clinic space, downstairs from the WPI. He is a lovely doctor, an experienced endocrinologist with an interest in CFS. He would have made a wonderful addition to a multidisciplinary team. Does he know something that nobody else knows regarding how to treat CFS? No. There is no treatment being offered in Reno that isn't mentioned on my blog. No secret knowledge. Nothing you need to be an insider to find out.

It has been really tough for me to decide what, if anything, to say about this next topic. Given that I promised to be truthful here, saying nothing seems almost a lie of omission. If I say something, I sound bitter, which maybe I am. And if I say nothing, I sound incompetent, which I am not. A no win situation. But the truth is, I was well on my way to getting the WPI clinic going as envisioned from day one: A team of like-minded doctors sharing ideas and generating a large patient database, an integral part of a WPI translational research institute. It would have generated enough income to support the research program. But the plug was pulled, inexplicably. A very poor decision.

The ways in which I was mismanaged and completely constrained by ineffective micromanaging when I was working at the WPI, and now this insanity, shutting down the research program, establishes a pattern of behavior. Although it is sad, the party is over, and needs to be. They were, and are, in over their heads. They started with the best of intentions. We will always owe them a debt of gratitude for the spark of genius and the increased awareness they have brought to our disease. But now, the work needs to be done by someone with the resources to do it right. They have risen to their level of incompetence. It doesn't matter to us who wins, gets the money or what their personalities are like, as long as the research continues. We need it to happen. The WPI is now an obstacle to progress.

Tonight's song: Square One by Tom Petty

The IgNobel Prize

2011-09-28T14:23:00.004-06:00

I opened an email from Dr. Racaniello's virology blog, in my wheelchair, at the Phoenix airport Monday morning, after the redeye from Kona:

It was like opening my door and finding a burning cross in the front yard. I was so angry, I was shaking by the time I got on the plane to Albuquerque. Anyone who would engage in such a tasteless joke in order to gloat, at the expense of millions of sick people, has zero credibility as far as I'm concerned. Closed mind. Closed heart. A little man, and I am not referring to his height.

I am writing to the president of Columbia University demanding a public apology to the patient community for this obscenity. I hope you will too.

Office of the President
Lee C. Bollinger

Office of the President
202 Low Library
535 West 116th Street, Mail Code 4309
New York, NY 10027
General Inquiries or To Contact the President

Phone: (212) 854-9970
Fax: (212) 854-9973
Email: officeofthepresident@columbia.edu

When The Going Gets Tough...

2011-09-23T14:53:00.000-06:00

The intrepid Dr. Mikovits went up against Darth Vader today in Ottawa. In the face of incredible adversity, she took the heat. For us. And she points the way to the next step. Next Generation Sequencing. Here are her slides. Click each to enlarge. May the force be with her. Brava!

A Reason For Hope

2011-09-22T17:03:00.000-06:00

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.

click to enlarge

The parameters are:

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.
CD-19. Total B-cell count. CD19 percentages were determined by flow cytometry and the total count was measured directly.
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.
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.
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

2011-09-20T19:26:00.000-06:00

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?

2011-08-19T21:57:00.007-06:00

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...

2011-08-18T22:11:00.002-06:00

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

2011-08-13T22:09:00.015-06:00

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

2011-08-05T09:16:00.005-06:00

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

2011-07-31T14:17:00.017-06:00

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

2011-07-17T18:57:00.009-06:00

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

2011-07-02T15:19:00.039-06:00

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

2011-06-20T21:27:00.003-06:00

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.

New Beginnings

2011-06-17T10:19:00.000-06:00

As the battle is waged on the scientific front, it is with great joy that I am able to announce that we will begin to see patients at the WPI on August 1. It will close the circle necessary to be a true translational research center with synergy between disciplines.

Dr. Chitra Bhakta is a Family Practitioner with a private practice in Orange County where she treats ME/CFS and autism. She brings medical insight, scientific literacy and compassion for the patients. Dr. Bhakta will continue to be available to her Orange County patients during this transition.

Dr. Robert Fredericks is an Endocrinologist in private practice in Reno. His special interests include the endocrinology of neuroimmune illnesses and he is an expert in bone metabolism. He has decided to join us and is in the process of moving his practice into the clinic, thus providing us with our first specialist.

There are a very large number of patients asking to be seen. We will only be able to accommodate a few in the beginning. We have other interested doctors, but Nevada's licensure process for new physicians coming into the state is long and can be convoluted. Dr. Bhakta has had a Nevada license since her residency at the University of Nevada, allowing her to begin without a delay. Our goal is to create a group of like-minded physicians. I tried active recruiting hoping to accommodate the volume of patients at the outset, but it will have to happen more organically, as we find the right doctors with passion for the project.

It's a start. The need is enormous. We will get our systems in place, fill in the gaps with respect to pathophysiology, and approach treatment with the benefit of the perspective of our scientists. The seeds are sown. We will water and care for this unique garden, growing our knowledge for the day when we can harvest in the form of clinical results.

A journey of a thousand miles begins with a single step.
~ Lao-tzu

Whodunit?

2011-06-11T16:08:00.000-06:00

Where large sums of money are concerned, it is advisable to trust nobody. ~ Agatha Christie

Thank you to Kristin Loomis, for contributing her comment and for the additional information she provided privately. I have a better understanding of the HHV-6 Foundation's policies and interests. I understand that retroviruses really aren't on the foundation's radar these days. I apologize for any inaccuracies, this time, and anytime; I do my best to fact check before publishing, and to limit any criticism that is directed at an individual to what can be verified on the internet, not gossip. I write each blog with the information at hand at that moment, intending to stimulate discussion. It is personal opinion, reaction to the events, public and private, not investigative journalism, though I wish a good investigative journalist would take it on. I'm getting mail suggesting that I interview people before posting blogs, but I have a day job again:). In any case, the information circulating that HHV-6 Foundation funded Knox et al is apparently incorrect. I invite anyone who feels they have been criticized unfairly to join us. Everyone needs to know the truth.

In your comment, Kristin, you said that you believe that Abbott funded Knox et al. I guess it's logical to conclude that if Abbott appears on a paper, there is money involved, either because they funded the study and/or there is a patent and potential lucrative test involved. This raises a number of questions. I hope that anyone with information to answer these questions will contribute to the discussion as you did. I have never thought that there is a conspiracy in the sense that Peterson, Knox, Coffin, Stoye, Vernon, McCleary, the editors at Science, et al are having conference calls plotting our destruction. Each individual has their own reasons for doing and saying the things they have.

In my opinion, whoever funded their study, Knox et al have some pretty unsavory stuff to explain to the patient community. If I put the best spin on it possible, then the patients have been harmed by misguided acts. The publication of their shoddy work was unethical and immoral, in my opinion. The collection of the specimens in the first place for this purpose is inexplicable to me. Even if Peterson woke up one morning and said OMG, XMRV is all a big mistake, it is inconceivable to me that he no longer believes it is a retrovirus. So his desire to bury XMRV has to be about being right, ego and revenge, or money. Roche funding Valcyte? Hemispherx funding Ampligen? As I've said, he is welcome to respond. I will be happy to post anything he'd care to share. I would like to point out here that although I've had a lot of questions about Dr. Peterson for a long time, and have heard many stories, from protagonists and patients (always my most important source), I didn't mention his name on this blog until the publication of Knox et al, which I took as a declaration of war on the patient community.

Abbott turns up all over the place, e.g. link; see Industry Relationships at the bottom of the page. They are clearly interested in XMRV. Their employees appeared as co-authors on negative and positive papers in Belgium, the positive paper being about a test for XMRV in prostate cancer tissue, not blood. When someone does a study, they know what they want to find; then they blind it to make it convincing, keep it honest. It makes no sense to do a study knowing at the outset that your test detects nothing, unless that is what you were trying to show in the first place.

From where I sit, there are many unanswered questions. It would be lovely to have no need of considering anything but the unfolding science, answering all of our questions in logical sequence, so everyone could take the high road; but that isn't what happened. Thus my questions of the moment. Why and when did Abbott approach Konstance Knox to do a study on XMRV, when she had never published on anything but HHV-6 and owns a commercial lab dedicated to it's detection? Why is Abbott's funding of Knox et al not disclosed? Why would Abbott want to publish a negative detection study? Who is Graham Simmons and what is his stake, as he appears on negative, equivocal and positive papers? He works for a business entity involved in transfusion science and has a teaching appointment at UCSF, as does Jay Levy. Where do Roche, manufacturer of Valcyte, and Hemispherx, manufacturer of Ampligen, fit in to all this, since it seems likely they are a piece of the puzzle as well? What else do these people/companies have waiting in the wings? Intellectual property laws support a unique patent. Who put pressure on Science to rush Knox and their EEC to press when they did? When did Dr. Peterson collect the specimens for Knox, and what was his relationship to the WPI at the time? Did he inform everyone of what he was doing? You can't get into anyone's head. In the end, only the Shadow knows. But facts, actions, dates can be verified.

Nobody wants to have anything to do with CFS, except the WPI (and the CAA, with their peculiar spin). It's common to hear that this or that researcher is sorry they got involved in CFS, because the advocacy community is becoming so strident. I'm not sure what the answer is. Polite hasn't gotten us anywhere, as witnessed by the useless money that's been spent on the CAA over the years in their pitiful attempt to validate the illness scientifically. If that had worked we wouldn't be confronted with the psychiatric community wanting to label us with "CSSD". The CAA too is free to respond in any way they like; the comments on this blog aren't moderated.

ME/CFS is of retroviral origin, as is ASD, in my opinion. Read the HIV and animal retrovirology literature, much of which is referenced in previous blogs. It's all there, plus the methylation defect and mitochondrial issues, covered to a large degree in the HIV literature, that were making up the bulk of my reading until the recent salvo was fired. The parallels are obvious. Nothing we've ever had to work with as physicians comes even close as a workable model to provide us with an approach to treatment, with a chance of healing the patients, forgetting about whether XMRV is the major player or not. For an individual to take any action at this time which has the effect of shutting down research into the retroviral origin of the disease is a crime against humanity.

Nobody is saying that the associated, opportunistic infections seen in ME/CFS aren't important, anymore than Pneumocystis is unimportant in AIDS. It is exactly analogous. In this case, there may be interaction between viruses. Activation of latent viruses may benefit the underlying retroviral process, turn it on if you will. Another possibility is that any persistent infection causes downstream inflammatory changes that favor activation of provirus. The research into how retroviral etiology explains CFS pathophysiology needs to proceed, even before everything is sequenced and proven, even while XMRV's defendants are being raked over the coals. Everyone involved knows it's much bigger than whether individuals get discredited or laughed at. Scientists and doctors are much the same when it comes to fear of ridicule restricting their abilities to fulfill their prime directives.

In the end, science will tell us who is right, irrespective of personalities, unless the work isn't done at all. Although I look forward to the results of Dr. Lipkin's study, and from what I have read and heard, he is worthy of the respect he has been proferred by being put in charge of such crucial work, it seems wrong to me that it all rests on one man's conclusions, or the ability of a couple of scientists to flawlessly reproduce their work, though they will certainly try. Maldarelli, Lipkin, XMRV Blood Working Group. That's not much for a million sick people. When John Coffin declared XMRV dead, he said it could be another retrovirus. Is he looking for it? Why is the federal government going to let this go another year, waiting for a ruling on one virus, before considering the bigger questions? It needs to be studied as an enormous health crisis, whatever the outcome of the work on XMRV. If it were anything other than a kangaroo court in session on a federal level, the work would be a priority, with our Center for Disease Control finally trying to do some controlling of our disease.

Once more unto the breach, dear friends

2011-06-08T15:19:00.007-06:00

From Shakespeare's King Henry V, Act III, Scene I

King Henry V:
Once more unto the breach, dear friends, once more;
Or close the wall up with our English dead.
In peace there's nothing so becomes a man
As modest stillness and humility:
But when the blast of war blows in our ears,
Then imitate the action of the tiger;

Responding to the flurry of concern for my feelings and irritation from readers about negative comments left by angry Anonymous people, personally, I welcome the discussion, even if expressed without courtesy. There is much to be learned by considering the things the opposition is thinking. Their need for anonymity is amusing and speaks for itself. Don't let them get you down. Keep your friends close and your enemies closer. It's all grist for the mill.

As far as I know, the WPI, which is a non-profit, has no conflict of interest. The mission is clear and the people dedicated to the cause. The individuals at the WPI have waived their IP (intellectual property) rights in favor of the institute. Should VIP Dx ever make a profit, it all goes to the institute also. I challenge the other characters in this story to say the same.

As for everyone using their inside voices until the science runs it's proper course, that's just naive. That's like saying that our newspaper reporters are only reporting the truth. People are people. They ask the questions they want answered, and they frame those questions in such a way that the answers will spin it the way they like. That's why blinding is necessary for the scientific method.

I received an email this morning from Michael Snyderman that I am copying here with his permission:

There is a conflict interest here. A major player is a very wealthy woman by the name of Kristin Loomis who with Annette Whittemore founded the HHV-6 Foundation. Loomis is a great believer that Herpes 6 causes CFS and a lot of other disease. Both women had children with CFS.

Whittemore later set up the WPI with Daniel Peterson who gave the WPI its original CFS samples. Initially the WPI was going to further the cause of Herpes 6. They had a scientist, Konnie Knox and Peterson who were from the HHV-6 Foundation and continued to get money from the HHV-6 Foundation. Knox was fired from the WPI. About this time Lombardi et al. found XMRV (arguably a poor name). Peterson was disturbed because he was a believer in Herpes 6. He left soon after the Lombardi et al. report came out. The position of the HHV-6 Foundation is that Herpes 6 is the cause of CFS and not XMRV and indeed that XMRV does not exist. Peterson then gave Knox the samples from his patients that she reported as negative in the new Science article. She did not declare any conflict of interest over her funds from the HHV-6 Foundation or the fact that she had been fired from the WPI.

There is more. The other article in Science is by John Coffin from Tufts. He first reported that XMRV was a contaminant in 2010. His colleague at Tufts is Brigitte Huber and she was a coauthor on this paper.

On the Tufts website Huber is listed as getting a grant from the HHV-6 Foundation:
Huber, Brigitte HHV-6, EBV and Endogenous Retrovirus in Patients with CFS HHV-
6 Foundation 11/1/09 – 4/30/10

This grant was received right after the Lombardi et al. Science report in 2009. Coffin also did not declare any conflict of interest in his Science article although he had collaborated closely with Huber and was a colleague with her at Tufts.

The bottom line is that drug companies will not develop drugs that will help us if they believe that XMRV and related MLRVs do not exist. Lives could be saved with just one type of drug, a protease inhibitor - the one for HIV doesn't work for XMRV and is a key category of drug for treatment of MLRV-related disorders as proteins such as env are not countered by raltegravir and the RT inhibitors.

Michael Snyderman, MD

Also from my morning mail:

My dr. and I have mostly contact by email because I am bedbound and cannot get to the office as much as I should. This morning I received an email from him ... he made the remark that it is very interesting to him that WPI was asked to retreat their paper. Than he proceeded to tell me that he ran some test in his office and that WPI was mistaken to tell me I am XMRV positive because his test came out negative from the other...

How can that be? I feel like the ground has been pulled from under me. The hope I had to finding a solution for my 30 years of suffering is gone! How is it possible that a regular physician who specializes in ME/CFS and Fibromyalgia can do a test like this? I'm gobsmacked and feel myself tunneling in a deep depression. Everything I believed in he took away from me with just one sentence, I just can not stop crying and am so upset.

WPI tested me positive and I have been holding on to that, because I didn't have much hope elsewhere. I don't know what to do now. There isn't any hope left for me.

One of the many sad things happening is that the only testing available may not yet be sensitive enough. Or it may be sensitive enough, but some of us have different viruses that cause clinically indistinguishable disease from the XMRV positive patients. The current VIP Dx serology is aimed at xenotropic and polytropic MLV's and is not positive in everyone one would expect if the test picks up every infected patient or if XMRV was the only cause of CFS. VIP Dx has a test. It comes out positive or negative. But like many tests, it's not that black and white. Like all lab tests, it must be interpreted by a doctor within the context of a complete clinical picture, and an understanding of the state of the testing with respect to a particular disease. At this point in time, it's that test or nothing. Nothing is a valid choice. It is a personal matter. But why the invective? Nobody has to use VIP Dx that doesn't want to.

As I've said before. I could be wrong about anything. Like everyone, I interpret what comes my way from my own perspective. I am not a retrovirologist or even a scientist. I'm a doctor who is fluent with the literature. I also have the disease and my daughter has the disease. Why does my sharing my opinions and experiences make some people so angry, when the vast majority seem to benefit from hearing my thoughts? I challenge any of the people I've criticized to come forward as themselves and tell us what happened from your perspective. My mind can change. I'd love to think that everyone involved has integrity and is motivated by the right things, but human beings being what they are, that isn't likely. As I keep saying, I am wedded to nothing but the truth. And time is of the essence.

This abstract by Prosperi et al may be of importance and I look forward to the paper. It seems confirmation in concept of what I suspect, that 22Rv1 isn't the one in a trillion recombination event described in Paprotka et al. Interestingly the et al includes William Switzer who published a 0/0 study with Satterfield, as discussed in a previous blog here.
Murine leukemia viruses (MuLV) and Xenotropic MuLV-related viruses exhibit inter-tropic complex recombination patterns. Prosperi/Salemi

Given the evidence of inter-tropic recombination in MuLV, detection and classification of recombination in XMRV using different MuLV tropism prototypes should be interpreted with caution. Despite using a small dataset, a strong phylogenetic signal in the alignments and highly resolved phylogenies inferred both by full-length and sliding-window approaches, different recombination programs reported conflicting results. These results suggest that identification of parental strains of the potential recombinants is difficult and that recombination in the highly genetically related MuLV have been occurring for some time.

The hysteria in the media about the thousands of patients taking AIDS drugs is a joke. If that had happened, we'd have learned a lot, but they shut it down pretty effectively. I still don't understand the inordinate fear of these particular drugs. All drugs have side effects. Every prescription has a potential cost/benefit ratio that has to be considered by the doctor and the patient at a particular moment. All options should be considered for a disease with no cure that produces such tremendous suffering. This was a prohibition from the beginning, such that taking antiretrovirals feels almost like a form of civil disobedience. As I said at the beginning, what if it works? Why does the scientific community not want to know, irrespective of the detection problems and their horror at skipping beyond their deductive reasoning process, clutched to their breasts like a religious totem? I know of about 50 patients taking arv's, one to three drugs, for varying lengths of time. All have been sick for a long time. About a third feel they are improved. The rate of change is slow. I don't know of anyone who has been seriously harmed, other than self-limited adverse reactions in the very early part of treatment. Some people who haven't done well have gone off. As far as I know, everyone is getting proper monitoring. The interference in the physician patient relationship, happening on a grand scale with respect to restricting this particular treatment, is a travesty.

I have gone from sofa bound to very high functioning in 15 months, while taking antiretrovirals. It was not a good experiment however, nor have I ever claimed otherwise. I am more of an atypical MS picture than classic ME/CFS (like Ali), and I was already on an upswing since quitting lots of Lyme and symptom based treatment six months prior, but still very sick and essentially non-functional. I have also started other medication since, Deplin and Actos. I feel safe in saying that arv's haven't hurt me, including a year of AZT. In no way am I suggesting that anyone should do what I did, but everyone should have the right to consider it. The scariest potential risk is renal failure from tenofovir, a very rare event in the HIV world, seen primarily in people with preexisting renal problems. There are some long term consequences of AZT that need consideration. Proper monitoring is necessary.

I've returned to practice on the Big Island in Hawaii, because that's where my active license is, and because I love it there. I trained in Honolulu, after medical school in the Bronx, and had my first job there. I've been licensed since 1980, always hoping to return. My family has recently grown to include my eldest daughter (who is adopted and very healthy) and my two small grandchildren. My son has a year of high school to go in Santa Fe. Moving everybody right now is out of the question. And I'm still traveling to Reno also. My husband and I are adapting to the fact that we will be spending a lot of time apart, after 23 years of marriage without separation. I am profoundly grateful to be able to contribute again. When I was practicing in Great Barrington, I was at 90% and it was all about the 10%. Now 90% feels like 110%. When pain goes away, it's better than if you'd never experienced pain in your life. So round 3 for me. The comeback kid. Who better to treat it? I know the enemy intimately.

I wish it were Ali and not me that was better enough to reenter. I have tremendous survivor's guilt writing this. My impression is that the second generation is sicker. Simple retroviruses can endogenize or maybe it's just worst to get it before your immune system is developed. I have heard of very small children who sound like they have full-blown CFS (Beethoven's 9th symphony?), 4 being the youngest. Not autistic. ME/CFS. 3rd generation.

The Fire Smolders

2011-06-07T19:59:00.005-06:00

Here are more abstracts about XMRV from Belgium which strongly suggest that it is more than a contaminant:

Restricted infection of xenotropic murine leukemia virus-related virus in human lymphoid tissue
Marta Curriu, Jorge Carrillo, Marta Massanella, Elisabet Garcia, Bonaventura Clotet, Julian Blanco, Cecilia Cabrera
http://www.retrovirology.com/content/8/S1/A208

Heme oxygenase-1 activation inhibits XMRV pathogenesis and carcinogenesis in prostate cancer cells
Subhash Dhawan
http://www.retrovirology.com/content/8/S1/A218

A prototype RT-PCR assay for detection of XMRV in multiple human sample types
Ning Tang, Andrea Frank, Robert Kowal, Gregor Leckie, John Hackett Jr, Graham Simmons, Michael Busch and Klara Abravaya
http://www.retrovirology.com/content/8/S1/A220

Dr. De Meirleir's presentation was listed in the Poster Section of the agenda and was called "Serological evidence of XMRV in CFS and blood donors in Belgium". I don't believe it's available online, but certainly look forward to his report.

The take home message from this conference and the recent publications from the point of view of what does it all mean to a patient? If you have prostate cancer, you may be allowed to have it, but if you have CFS, you aren't. But there are a few fighting for us, Mikovits, Russcetti, Lombardi, Hanson, Snyderman, Bell and co-authors.

If you look at the conflicting papers of which Graham Simmons is a co-author, assuming that you believe that Knox et al is worthy of consideration in light of the various potential conflicts of interest of its authors, the combined findings suggest that blood isn't the best place to look for XMRV by PCR. The Tang et al paper referenced above is co-authored by more people who work for Abbott. The author's of the paper looking for XMRV in blood donors (#3 last blog) also work for Abbott; they concluded the positives were due to cross-reactivity with HTLV sequences.

Simmons and Busch work for Blood Systems Research Institute, an institute dedicated to transfusion safety, primarily funded by NIH grants according to their website, apparently a for profit organization; they are also part of the Blood XMRV Scientific Research Working Group, whose abstract (#4 last blog) states they found enough going on with Phase II to keep going, even though it was inconclusive. More evidence that something's going on, but we don't know how to look for it yet. The clinical evidence and the first paper above, suggest that lymphoid tissue would be a good place to look. Gut is another likely reservoir, not too difficult to get tissue. The Tang paper looked at paraffin embedded tissue. There's lots of that to go around, some small intestine of mine in paraffin at the hospital down the street.

#6, 7 and 8 in the last blog represent the kind of work we need to be seeing, to begin to figure out the nuts and bolts. Fascinating how they are going about producing a mouse that expresses XPR1 receptors in prostate tissue. Exploring receptor physiology, and tissue tropism.

Pointing out the connections between various authors and potential conflicts is not coming from some kind of inside information. Everything I've noted is readily available on the internet. I don't claim to know exactly what's at the bottom of it. Only that it doesn't add up, the Knox paper being especially suspect, and the people involved suspect by association. The work isn't going as well or as quickly as it should be, as we need it to, and there seem to be certain entities and individuals coming up with studies which seem designed to fail. There are an awful lot of people parroting negative studies without looking at the totality of the evidence. People attached to HHV-6 as The Cause come up a lot. People attached to it not being a retrovirus. Different individuals have different stakes I'm sure. There's too much at stake not to bring out the worst in human nature.

If anybody feels the need to write in the comments that I am biased, don't bother. I am biased. I believe that ME/CFS and related neuroimmune disorders are caused by retroviruses, of which XMRV is likely only one. The other organisms that turn up with regularity are opportunists and copathogens. There are patients that are both culture and serology positive. Contaminant and cross-reacting antibodies with HTLV? My working hypothesis is that we are infected with simple retroviruses that jumped from mice, probably naturally, but then assisted tremendously by the use of animal cells and gene manipulation in tissue culture and nude mice, for various purposes including vaccine production. That starting point for considering my illness has gotten me very far from where I was when I didn't have that understanding.

At the bottom of this blog are links and excerpts from the NIH online project reporter that are of interest to us. Sandra Ruscetti giving us clues as to why VIP Dx is getting different serology results than those using tests derived from infected monkeys.

Also Ila Singh's contention that it is present not only in prostate cancer tumors, but in 6% of controls. And she didn't wonder why she couldn't find it in anybody's blood in her new study, including controls? And that didn't bother her because? It makes me shake my head in disbelief every time I think of it. Scientists like Singh, Knox and Coffin telling people they don't have the right to treatment based on such flimsy evidence and faulty logic? It's disgusting.

Maribeth Eiden is an expert in GALV, the only other gammaretrovirus found in a primate. "In addition to being a horizontally transmitted infectious agent, xmrv is a threat to the human genome."

A clinical trial of IV saline for POTS found its way into my inbox today: http://clinicaltrials.gov/ct2/show/NCT01000350?term=NCT01000350&rank=1. It's fascinating that doctors in an academic setting taking care of a condition that used to be very rare, but now isn't, haven't noticed that it occurs mostly in ME/CFS patients, and seem unaware of XMRV as even a possibility. In any case this approach has had some success anecdotally for keeping ME/CFS patients on their feet, but isn't practical for most, and like everything, it doesn't help everyone, including me. It helps Ali a little, but, in general, not enough for the stick, and she doesn't have enough veins for daily access, nor does she tolerate indwelling lines or FB's of any kind.

The infusions so far seem very helpful to Ali: more energy, less reactive. I had an adverse reaction to the first one, generalized over-activation, sleep disruption, PVC's, GI hypermotility, etc. The only thing in the infusion I haven't had before was Leukovorin, and too much Deplin can cause a similar, though less severe, reaction. It took almost 5 days to resolve and was yet another reminder that sometimes it's best to leave well enough alone. I did an infusion of glutathione alone about 10 days after the first one and didn't notice anything. I haven't been too excited about sticking myself again, since I'm doing amazingly well (knock on wood).

The mild hyperbaric treatments are wonderful for me. I feel great in the chamber, a little slowed after, then really good later on. Ali continues to be sensitive to odors and has stayed away from the chamber because of the new plastic smell. However, the fire burning in Arizona has made the air quality very poor here (in Santa Fe). The horizon is obscured by smoke and there is ash on the ground, though the fire is hundreds of miles away. It burns your eyes, nose and lungs. Yesterday she became short of breath and decided to use the concentrator with a well aired non-rebreather mask at 10L/min. After 20 minutes she felt much better. She repeated that treatment again last night before bed and slept much better than usual, something I notice after each treatment (I'm going in about 3 times/week). Since she tolerates the mask, she can wear it in the chamber and will be protected from any other smells inside the chamber itself. We are both grateful for something so safe that helps in such an immediate way.

Ongoing NIH projects:

Sandra Ruscetti
http://projectreporter.nih.gov/project_info_description.cfm?aid=8157190&icde=8392424
In collaboration with the laboratories of Judy Mikovits and Frank Ruscetti, we were able to use antibodies developed against the envelope protein of SFFV to detect infectious xmrv in the blood cells and plasma of patients suffering from the neuroimmune disease chronic fatigue syndrome (CFS). We were further able to develop a seroconversion assay using cells expressing the SFFV envelope protein to detect antibodies against the virus in the plasma of CFS patients. We now plan to apply our knowledge of the pathogenesis of mouse retroviruses that cause cancer and neurological disease in rodents to study the molecular basis for similar diseases associated with xmrv. We are in the process of developing rodent models for determining the biological effects of xmrv in vivo, which if successful will provide a small animal model for preclinical testing of potential anti-xmrv drugs. In addition, we are testing both in vitro and in vivo the biological effects of the envelope protein of xmrv, which like its related SFFV counterpart may be responsible for the pathogenicity of xmrv.

Ila Singh
http://projectreporter.nih.gov/project_info_description.cfm?aid=8040941&icde=8392424
Narrative: xmrv is a new retrovirus that was recently identified from human prostate cancers. This study will attempt to understand the replication of this virus in vitro and its association with cancer. We will explore mechanisms of oncogenesis in cells, in tumors, as well as in animal models, and carry out epidemiological studies to estimate prevalence of viral infection in the general population.

Maribeth Eiden
http://projectreporter.nih.gov/project_info_description.cfm?aid=8158079&icde=8392424
Our lab is recognized for our research on a similar gammaretrovirus isolated from nonhuman primates, gibbon ape leukemia virus (GALV). GALV is the only gammaretrovirus other than xmrv found in primates. In collaboration with Frank Ruscetti at the NCI, Bill Switzer at the CDC and Suzan Winfield and Jessica Siegal-Willcot at the National Zoo, we are investigating the source animal for xmrv, and screening gibbon apes in US zoos for the presence of GALV and xmrv. We have obtained samples from the CDC and the Biological Research Steering Committee that provide us with materials permitting us to determine that many gibbon apes at various zoos have been infected with an xmrv-like virus. We have determined the cell tropism of xmrv using an engineered biologically active xmrv virus with a GFP reporter gene and are identifying cellular factors that restrict xmrv infection of receptor bearing cells. These factors that can restrict xmrv infection will be used as a means of developing xmrv antiviral drugs. In addition to being a horizontally transmitted infectious agent, xmrv is a threat to the human genome. We are in the process of isolating rat germ line cells and exposing these cells to engineered biologically active xmrv virus with a GFP reporter. Sperm obtained from these cells are being assessed. Positive results of sperm expressing GFP indicate that xmrv can be transmitted from infected individuals horizontally (i.e., to offspring as a mendelian trait) as well as vertically through the more traditionally route of viral infection. We used cysteine scanning mutagenesis (SCAM) methods to assess the topology of the GALV receptor and intend to identify extracellular domains of the xmrv receptor using similar methods. These studies will lead to the identification of the xmrv-binding domain. Finally the spread of most retroviruses is mediated not by direct virus infection but by cell-cell transmission from an infected cell to an uninfected cell. We have developed a model system to assess blocks to cell-cell virus transmission using spinning-disc confocal microscopy to visualized individual budding of fluorescently labeled virus particles into adjacent cells in three dimensional space over time.

Frank Maldarelli
http://projectreporter.nih.gov/project_info_description.cfm?aid=8157762&icde=8392424
We have established useful collaborations with Drs. W. Marston Linehan and Peter Pinto (Urologic Oncology Branch, CCR) to study samples from patients with prostate cancer, and with Drs. Frank Ruscetti and Kathryn Jones (Laboratory of Experimental Immunology, CCR) and Dr. Judy Mikovits (Whittemore Peterson Institute) to study patients with severe CFS. As immune deficiency may contribute to infection by xmrv, we have also established collaborations with NIAID to obtain samples from study individuals with immune deficiency, including HIV-infected patients and patients with both HIV infection and prostate cancer. In addition, we are collaborating with Dr. Vinay Pathak (HIV Drug Resistance Program, CCR) in a study of xmrv pathogenesis and prostate cancer as part of a Bench to Bedside Award to Dr. Pathak. Reports of xmrv infection in individuals with chronic fatigue and in otherwise healthy individuals raised concerns regarding new health risks. Within a year of these reports, we have optimized a series of detection and analytical assays with excellent performance characteristics. In the next year, we will apply these approaches to shed new light on the potential role of mouse-related viruses in human disease.

Arthur Horowitz
http://projectreporter.nih.gov/project_info_description.cfm?aid=8157670&icde=8392424
In a related and collaborative project, we have joined Dr, Frank Ruscetti in his studies of the link between prostate cancer and xmrv, a recently-identified retrovirus associated with prostate cancer. Together, we are testing the hypothesis that inflammatory cells serve as a viral reservoir or infection route. We are characterizing the susceptibility of prostate-infiltrating myeloid cells (macrophages and dendritic cells) to xmrv infection. A long-term goal is to identify murine models to study the link between xmrv pathogenesis and prostate carcinogenesis.

Susan Swedo
http://projectreporter.nih.gov/project_info_description.cfm?aid=8158154&icde=8392424
D. Vargas et al (Johns Hopkins) demonstrated that individuals with autism and a history of neurodevelopmental regression had evidence of chronic brain neuroinflammation, as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokine and growth factors assayed in both tissue samples and CSF. The authors remarked that chronic microglia activation appeared to be responsible for a sustained neuroinflammatory response that facilitated the production of a number of neurotoxic mediators. Alternatively, neuroglial activation could occur in response to a secondary neurotoxic factor(s) and thus represent the result, rather than the cause, of the injury. Neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. A small pilot study of minocycline, an antibiotic with known effects on NF-kappaB was undertaken in an effort to determine if the drug might have an effect on autistic behaviors or change patterns of distribution for the CSF or serum cytokines or chemokines. At the doses used in the pilot investigation, no clinically meaningful improvements were seen in behavior nor in the pattern of distribution of the CSF or serum cytokines or chemokines. Thus, no further investigations are planned for minocycline, but the search for novel therapeutic agents continues through the phenotyping study, where longitudinal assessments provide the opportunity to identify biomarkers of neuroinflammation in serial CSF and serum samples and to correlate the results of the assays with clinical symptomatology.

Christine Kozak
http://projectreporter.nih.gov/project_info_description.cfm?aid=8156820&icde=8392424
We are also interested in determining the extent to which virus resistance is mediated by polymorphisms of the cell surface receptor. We seek to analyze the XPR1 receptor for the xenotropic/polytropic gammaretroviruses and for xmrv, a xenotropic virus-like virus isolated from humans with prostate cancer or chronic fatigue syndrome.

Some interesting abstracts from the conference in Belgium about HTLV:

HERV's and MS
http://www.retrovirology.com/content/8/S1/A210

Stem cells for HTLV
http://www.retrovirology.com/content/8/S1/A32
http://www.retrovirology.com/content/8/S1/A33

Raltegravir inhibitis HTLV
http://www.retrovirology.com/content/8/S1/A34

AZT/IFN for ATL
http://www.retrovirology.com/content/8/S1/A37
http://www.retrovirology.com/content/8/S1/A53

Arsenic trioxyde for ATLL
http://www.retrovirology.com/content/8/S1/A59

Ascorbic acid and HTLV
http://www.retrovirology.com/content/8/S1/A61

Risk of vertical transmission of HTLV correlates with maternal proviral load.
http://www.retrovirology.com/content/8/S1/A72

γδ T cell immunotherapy for HTLV ???
http://www.retrovirology.com/content/8/S1/A109

Estradiol and HTLV
http://www.retrovirology.com/content/8/S1/A196

XMRV-related abstracts from 15th International Conference on Human Retroviruses

2011-06-06T16:08:00.028-06:00

For easier reading and sharing XMRV Global Action has compiled the XMRV related abstracts from the 15th International Conference on Human Retroviruses: HTLV and Related Viruses, Leuven and Gembloux, Belgium. 5-8 June 2011

1. XMRV replicates preferentially in mucosal sites in vivo: Relevance to XMRV transmission?

http://www.retrovirology.com/content/8/S1/A219

Francois Villinger1,2*, Jaydip Das Gupta3, Nattawat Onlamoon4, Ross Molinaro1,2, Suganthi Suppiah1,2, Prachi Sharma5, Kenneth Rogers5, Christina Gaughan3, Eric Klein3, Xiaoxing Qiu6, Gerald Schochetman6, John Hackett Jr6, Robert H Silverman3

"In fact, a single atraumatic mucosal exposure with a high dose of XMRV virus into the urethra resulted in infection of 1 out of 4 macaques providing proof of concept that such transmission is possible. However, additional work is needed to fully investigate potential modes of XMRV infection."

2. Development of XMRV producing B Cell lines from lymphomas from patients with Chronic Fatigue Syndrome

http://www.retrovirology.com/content/8/S1/A230

Francis Ruscetti1*, Vincent C Lombardi2, Michael Snyderman3, Dan Bertolette4, Kathryn S Jones1, Judy A Mikovits1

"Therefore XMRV infection may accelerate the development of B cell malignancies by either indirect chronic stimulation of the immune system and/or by direct infection of the B-cell lineage . Since viral load in peripheral blood is low, these data suggest that B cells in tissues such as spleen and lymph nodes could be an in vivo reservoir for XMRV."

3. Prevalence of XMRV in blood donors, HTLV and HIV cohorts

http://www.retrovirology.com/content/8/S1/A222

Xiaoxing Qiu1*, Priscilla Swanson1, Ning Tang2, Gregor W Leckie2, Sushil Devare1, Gerald Schochetman1, John Hackett Jr1

"XMRV seroprevalence ranged from 0 - 0.6% in US blood donors, HIV-1 infected and HTLV uninfected subjects. Notably, 4.1% of Japanese HTLV-I infected individuals were p15E reactive. Inspection of sequence homology between HTLV and XMRV revealed a high level of conservation within the immunodominant region of HTLV gp21 suggesting increased seroreactivity is due to cross-reactive antibodies."

4. Multi-laboratory evaluations of XMRV nucleic acid detection assays

http://www.retrovirology.com/content/8/S1/A231

Graham Simmons1,2*, John M Coffin3,4, Indira K Hewlett5, Shyh-Ching Lo6, Judy A Mikovits7,8, William M Switzer9, Jeffrey M Linnen10, Francis Ruscetti11, Simone A Glynn12, Michael P Busch1,2

"The Blood XMRV Scientific Research Working Group was formed to facilitate collaborative studies into the impact of XMRV in blood donors. Studies will evaluate XMRV detection assays in terms of sensitivity, specificity and reproducibility; assess performance on specimens represented in existing blood donor repositories, and determine the prevalence of XMRV in donors." Phase III results expected soon. Phase IV will test a blinded panel of 300 blood donor samples.

5. Immune correlates of XMRV infection

http://www.retrovirology.com/content/8/S1/A221

Vincent Lombardi1, Deborah Goetz2, Max Pfost1, Cassandra Puccinelli1, Judy Mikovits1*

"XMRV infection results in dysregulation of the immune response, either directly by infection of specific leukocyte subsets or indirectly through cytokine modulation."

6. The effects of XMRV gene expression on the mouse prostate

http://www.retrovirology.com/content/8/S1/A223

Daniel Rauch, Sirosh Bokhari, John Harding, Lee Ratner*

"Breeding PRO-XMRV mice with PRO-XPR1 mice will allow us to test whether XMRV integration or gene expression can cause more advanced prostate pathology in vivo. With these XMRV mouse models we seek to address the question that remains unanswered to date as to whether XMRV is capable of causing prostate dysplasia or cancer in vivo."

7. XMRV: usage of receptors and potential co-receptors

http://www.retrovirology.com/content/8/S1/A224

Mohan K H G Setty*, Krishnakumar Devadas, Ragupathy Viswanath, Veeraswamy Ravichandran, Shixing Tang, Owen Wood, Durga S Gaddam, Sherwin Lee, Indira K Hewlett

"XMRV replication was observed in GHOST cells that express CD4, and each of the chemokine receptors ranging from CCR1- CCR8 and Bob suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors. Infection of Lung epithelial cell A549 lacking XPR1 expression clearly indicates usage of other receptors by XMRV for entry into susceptible cells."

8. Cell line tropism and replication of XMRV

http://www.retrovirology.com/content/8/S1/A225

Krishnakumar Devadas, Mohan K H G Setty, Ragupathy Viswanath, Durga S Gaddam, Owen Wood, Shixing Tang, Jiangqin Zhao, Xue Wang, Veeraswamy Ravichandran, Sherwin Lee, Indira K Hewlett*

"Replication of XMRV could be observed in cervical and lung epithelial cells, T-cell lines Jurkat and H9, B-cell line HL60, U937 cells and in primary PBMC and monocyte-derived macrophages. The levels of XMRV transcripts were lower in primary monocytes compared to T-cell lines suggesting less efficient replication in these cells."

9. Structure of the xenotropic murine leukaemia virus-related virus matrix protein

http://www.retrovirology.com/content/8/S1/A227

Michal Doležal1,2, Iva Pichová1, Tomáš Ruml2, Richard Hrabal3, Michaela Rumlová1*

"Although the protein sequence of the XMRV-MA is very similar to that of the murine leukaemia virus matrix protein (MLV-MA), it varies in several amino acid residues. We compared the structures of the XMRV-MA and MLV-MA and found that those changes are localized in a few domains, mostly on the surface of the protein."

10. Serologic and PCR testing of persons with chronic fatigue syndrome in the United States shows no association with xenotropic or polytropic murine leukemia virus related virus.

http://www.retrovirology.com/content/8/S1/A232

William M Switzer1*, Hongwei Jia1, HaoQiang Zheng1, Shaohua Tang1, Rebecca A Garcia2, Brent C Satterfield2

"Our findings are consistent with previous negative reports and do not support an association of XMRV or MuLV in the majority of CFS cases across the US."

11. Detection of MLV-like gag sequences in blood samples from a New York state CFS cohort

http://www.retrovirology.com/content/8/S1/A234

Maureen R Hanson1 , Li L Lee1, Lin Lin1, David E Bell2, David Ruppert3 and David S Bell4

"gag sequences could be amplified from genomic DNA from LNCaP cells of some subjects after 4 or 6 subcultures following incubation with certain subjects’ plasma, indicating the presence of infectious virus in blood. All gag sequences detected in this cohort were more similar to the MLV-like sequences reported by Lo et al. (2010) than to the XMRV sequences reported by Lombardi et al. (2009). Detection of gag sequences in whole blood genomic DNAs that were negative for mouse IAP and mitochondrial DNA provides strong evidence for infection of humans with MLV-like viruses."

12. Murine leukemia viruses (MuLV) and Xenotropic MuLV-related viruses exhibit inter-tropic complex recombination patterns

http://www.retrovirology.com/content/8/S1/A235

Mattia CF Prosperi , William M Switzer, Walid Heneine and Marco Salemi

"Given the evidence of inter-tropic recombination in MuLV, detection and classification of recombination in XMRV using different MuLV tropism prototypes should be interpreted with caution. Despite using a small dataset, a strong phylogenetic signal in the alignments and highly resolved phylogenies inferred both by full-length and sliding-window approaches, different recombination programs reported conflicting results. These results suggest that identification of parental strains of the potential recombinants is difficult and that recombination in the highly genetically related MuLV have been occurring for some time."

13. In vitro assembly of xenotropic murine leukemia virus-related virus CA-NC protein

http://www.retrovirology.com/content/8/S1/A236

Romana Hadravová, Jitka ¿tokrová, Michal Dole¿al, Iva Pichová, Tomá¿ Ruml and Michaela Rumlová

"We found that purified XMRV full-length CANC, starting with the conserved proline residue at the N-terminus of CA, was not able to assemble into particles. However, a modification of the N-terminus of CANC (modCANC) enabled formation of spherical particles. Moreover, the negative staining of the in vitro assembled particles of XMRV modCANC revealed different organization of protein layers in comparison to CA-NC of M-PMV."

14. Human infection or lab artifact: will the real XMRV please stand up?

http://www.retrovirology.com/content/8/S1/A241

Robert H Silverman

"Xenotropic murine leukemia virus-related virus (XMRV) was first identified in 2005 in a study of human prostate cancer patients with genetic variants of the antiviral enzyme, RNase L. Subsequent investigations in North America, Europe and Asia have either observed or failed to detect XMRV in patients [prostate cancer, chronic fatigue syndrome-myalgic encephalomyelitis (CFS-ME), immunosuppressed with respiratory tract infections] or normal, healthy control individuals. Among the confounding factors are the potential for lab contamination with similar or identical viruses or viral sequences originating in mice. In some studies, relatively contamination-resistant methods (e.g. IHC, FISH, and antibody detection) suggest that either XMRV or a similar type of virus is present in some patients. Evidence for and against genuine infections of humans with this intriguing virus (and/or related viruses) will be discussed."

15. XMRV infection in human diseases

http://www.retrovirology.com/content/8/S1/A238

Otto Erlwein email, Mark J Robinson, Steve Kaye, Myra O McClure, Marjorie M Walker, Anup Patel, Wun-Jae Kim, Mongkol Uiprasertkul, Ganesh Gopalakrishnan, Takahiro Kimura and Kikkeri Naresh

"The novel gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV) was identified in human prostate cancer tissue in 2006, confirmed in 2009 and later linked to a second human condition chronic fatigue syndrome, CFS. These investigations, all carried out in the US, have not been reproduced in Europe or in China.

We found no evidence for XMRV infection in CFS. Moreover, we failed to find evidence of XMRV infection in UK prostate cancer patients and in prostate cancer tissue taken from patients in India, Korea, Thailand and Japan, or in cancers other than that of the prostate.

Our UK CFS patients were consistently XMRV-free. We did, however, generate false-positive results from prostate cancer patient tissue, despite the fact that the no-template controls in our PCR were consistently negative and the PCR for murine mitochondrial DNA was often also negative.

Sources of this contamination will be discussed in our presentation."

Who Are Our Friends?

2011-06-05T20:28:00.015-06:00

Here are a couple of articles sent by friends this morning... link and link. I read them with my morning coffee and both made me feel sick for different reasons. I hated to dignify the first one with a link, because the site is so appallingly illiterate, but this is what the newly diagnosed will find when they go to the net to learn about their illness, since it looks like they aren't going to get to have a real disease for a little while longer. But not to worry, Kim McCleary says doctors know it when they see it, "like Beethoven's first symphony". Oh you have CFS? Too bad. It's caused by lots of things. Like a "stressful state". XMRV was all a mistake. Take L-carnitine.

The second article blows my mind, because McCleary didn't manage to say one thing I can relate to as a patient, other than yes, my daughter and I both have it. The swift decline and no resolution she describes doesn't even come close to describing the course for many, if not most patients, since recovery to 80 or 90% within a year or two of the first episode is a common history. There are a large number of patients who experienced gradual onset, but wound up in the same place as the ones who remember the moment of onset, and one would expect her to be aware of this. Her description of my disease as "not sexy" is offensive. This woman definitely doesn't speak for me. She's the president and CEO of the CAA, the national organization for the disease we have. How did that come to pass? As I've said before, I'm a newbie. I only figured it out about CFS as an inseparable entity from treatment resistant Lyme when I read the Science paper. Before that I knew the extant drivel in both the conventional and alternative worlds that espoused the "it isn't one thing" theory, but I didn't identify, since the drivel in the Lyme world fit us better.

Now that I'm starting to wonder about the characters and history, which never really interested me before, and trying to consider the most likely motivations of the various players, it's shaping up to have the makings of a rather twisted tale. History driven by the personal needs of a few people, millions of lives at stake. It may rise to the level of allegory. Our knights in shining armour? There's the good old CAA. I've been sick on their watch for 16 years. Suzanne Vernon was spawned by our captors at the CDC, then went to work with the CAA. Take a look at the Banbury Report, about a meeting that took place a few weeks before the Science paper was published, in which Dr. Vernon states that she thinks one of the things she knows for sure is that it isn't a retrovirus. Then there's the HHV-6 Foundation. Dan Peterson is on the board of directors. And let's see, Konstance Knox is an expert in HHV-6. In fact, Knox/Levy is the first paper she's ever published that wasn't about HHV-6. Her lab is heavily invested in an HHV-6 assay. I wonder what HHV-6 Foundation spends it's research dollars on? And as Mindy Kitei asked here, what's Dr. Levy's stake in all this? Ah, what a tangled web... Life is stranger than fiction. Definitely a story fit for an Osler's Web sequel.

Lots of people seem very committed to it not being a retrovirus. Why would that be? I realize that it can't possibly be as black and white as it appears. They can't all be psychopaths. They must at least be lying to themselves, like some of the scientists who said that simple endogenous animal retroviruses couldn't hurt humans, and don't even want to learn the truth now, preferring to be dead before the puzzle is solved.

Here's a letter to Science from patient advocate Chris Douglas, that says it very well. link

Meanwhile, unrepresented patients are starting to organize. This is very important. We need to nurture the sparks of this fire. Don't let it go out. Thank you, from all of us, to the participants. YouTube and Write up

The WPI is a translational medical institute, a discussion in progress, not expecting all the answers to be in before applying the pieces we do have. The mission of the institute is to cure CFS, but it is a small organization and the virus has turned into such an unexpected fight that defending the prior work is a huge task. Each new salvo triggers a wave of self-examination, trying yet again to find the flaw, but despite the multitude of negative studies, nobody has yet explained the most important thing. Only some of the patients are positive. Not none and not all. Far from requesting a retraction, Science, if truly objective, should be demanding answers with respect to the gaping holes in the arguments of the authors of the negative papers. A number of people have written that they hope the work at the WPI will not be limited to XMRV. The most recent Lombardi et al paper, Xenotropic Murine Leukemia Virus-related Virus-associated Chronic Fatigue Syndrome Reveals a Distinct Inflammatory Signature. Lombardi/Mikovits, helps to define the disease, whatever the cause and adding the clinical practice will further broaden the focus of the research.

What if it was all a mistake for some technical reason (though it's hard to see how that could be the case). But say it was all a big accident. Then XMRV may still be a signpost. Paprotka et al found a cell line started in the early 90's that produces it. Although the online supplemental information doesn't tell us how they derived their number for probability of the event, even assuming they are correct, that it's a very unlikely event, it happened once, and think how many chances there have been for similar events. This type of random recombination event may not even be necessary for HGRV infection, as already replication competent viruses may be involved, present in mice not susceptible to infection, but xenotropic, capable of infecting the cells of other animals, including human. Am I just speculating? Well, so are they. But if I'm wrong, some time and money is lost, in the attempt to save millions of people. If they're wrong?

Breaking good news, for a change, from the International Conference on Human Retroviruses, in session now in Belgium, evidence that some labs can find XMRV in human tissue:

A Prototype RT-PCR Assay For The Detection of XMRV In Multiple Human Sample Types. Tang/Abravaya found positives in formalin fixed paraffin embedded prostate cancer specimens and urine pellets, using 22Rv1 for their spiked control, rather than a VP62 clone. Here's a twist- Graham Simmons appears on both this paper and Knox et al. He didn't tell the team he was on that couldn't find it about the team he was on that could? How strange. But the important thing is this group was able to distinguish negatives from positive controls, even though the positive control was not a human isolate, and they found it in human tissue (not blood).

And these papers sound promising, but no abstracts:

XMRV replicates preferentially in mucosal sites in vivo: Relevance to XMRV transmission? Villinger/Silverman

Detection of MLV-like gag sequences in blood samples from a New York state CFS cohort. Hansen/Bell

We also heard this from the Invest In ME conference held in London last month:

The final presentation was by Wilfried Bieger (Munich, Germany). He mentioned their earlier studies to detect XMRV, which had been negative. His team had then collaborated with Judy Mikovits and set up a highly sensitive, specific and uncontaminated protocol for virus detection, sequencing of viral DNA and antibody testing with western blot. Viral DNA and RNA were not detected in fresh blood, but after cultivation of PBMCs for 6 weeks under stimulation and using partly co-culture with virus permissive LnCap cells, culture cells turned positive in some patients. Presence of XMRV was confirmed by sequencing XMRV specific DNA. There have been approximately 40% positives so far.

It's more than smoke. It will burst into fire, despite the best efforts of some to smother it. We need to fan the flames. Don't let them forget us again. There are future generations at stake that can't be allowed to go through what we have.

A Comparison of Methods for the Detection and Association of XMRV in Chronic Fatigue Syndrome

2011-06-04T00:20:00.005-06:00

Here is an analysis by the WPI team of the "replication" studies to date. Click on each page to enlarge or download pdf file here.
NP = not performed
NR = not reported

Motivation

2011-06-02T21:07:00.002-06:00

When I started this blog, I was a sick patient, excited about a process of discovery that was unfolding for me. I had a lot of anger and dismay at the information vacuum surrounding the situation. My motivation was to inform and do whatever I could to move the process along. Since then, I've recovered a large degree of function and have returned to private practice in Hawaii. I also work for the WPI, as an independent contractor, in very specific capacities, still intending to help open the clinic in Reno. At this point, of the many perspectives I share in this epic, I identify most with being the mother of a patient, and of a healthy 16 year old son, who has some of the same little things my husband, daughter and I do. I have suspected that he has what we have for eight years. He had the most positive tick borne disease tests of anyone in our family. Dr. Charles Ray Jones, who I believe to be a very fine doctor, decided wisely not to treat him for Lyme. He has done very well, can push the envelope. But under the circumstances, I worry, as we all do for our unaffected children. So my motivation for writing remains essentially unchanged. I only want the truth, so that Ali can have a life and my son not lose his. It's not because of any affiliation, or being invested in anything other than getting to the bottom of it, so that we can all have some meaningful treatment, finally. I want the medicine to move forward, and it shouldn't have to wait until the scientists dot all the i's and cross the last t.

When I learned of the request from Science for retraction of Lombardi et al and the EEC, I cried off and on for a day. The thought that brought on tears was "the work is going to stop." Nobody will put their grad students on it, because it will ruin their careers. No one will spend the money because Knox et al are trying to put the nail in the coffin. This can't be allowed to happen. I'm not the best person to pick the paper apart technically, though it has some obvious flaws that the scientists will address, I'm sure. But the logical flaw is more basic than any of the details. Unless someone has a test that can identify a sick person, a negative study, using different methods from the original study, doesn't contribute anything new. Absence of proof is not proof of absence.

The only thing new in the Knox study was Dr. Peterson's participation, the authors trying to suggest some sort of uniformity of patient selection with the original study, as if patients are hard to come by. Since they weren't the patients from the original study, the fact that they came from his practice contributes nothing. That only means that they came from a doctor with a conflict of interest. All the paper shows, along with some inane speculation, is that Knox's lab couldn't reproduce VIP Dx's results. I am guessing that Abbott developed the serology test which didn't work that was used in the study, but the discussion of their negative serology data is too superficial to consider seriously. Serology, in the end will be the clinical key. Patients don't make antibodies to contaminated specimens and PCR is clearly too finicky. Serology has been left out of most of the discussion to date. We know so far that tests derived from monkeys infected with a VP62 clone don't work on humans. We don't think the currently available test from VIP Dx is sensitive enough. We believe that positives are true positives, but there are false negatives, including people with positive cultures. The right test should be a goldmine for someone. It's not that it's a problem for us if someone makes money on our disease, it's that sometimes the quest to own the patent supercedes the good of the patients. If greed is the motivator, so be it, as long as it leads to progress. In this case, people went to a lot of trouble to slow progress.

I accept that there will be some people who don't like me for speaking out. Now that I'm not powerless anymore, I'm supposed to be more circumspect. Use my inside voice. It's worth it for me to take the flak, for the many patients who say that sharing my thoughts helps them to think about their illness and options. So let's see what I've said that's so inflammatory. Konstance Knox once had a relationship with the WPI, that didn't end well. Easily verifiable. Dr. Peterson also had a relationship with the WPI that didn't end well. I am not discounting all of the work that he did for ME/CFS in the past, but that was then, this is now. If he was concerned that there was a problem with the testing, why didn't he use the resources at his disposal to work on it with the scientists at his own institute? Instead he gave specimens to a scientist with a conflict of interest. All of this must have been a confusing nightmare for the patients involved. What did he accomplish? Res ipsa loquitor.

As I've said, I don't know Dr. Peterson personally, but I am working with the same people he did and I know what motivates them. The Whittemores have put it all on the line. They are dedicated to getting to the bottom of the illness, whatever the answer, for the most personal of reasons. Dr. Mikovits is an honest person who cares deeply for the patients. I am proud to call her my friend and it breaks my heart that she has to live through this. She in no way deserves to have her integrity questioned. She has no financial stake. She is staying to weather the storm for us, the patients. It started out for her as science, but getting to know the patients has really affected her on a personal level. Nobody wants to get to the bottom of it more than she does. She should be getting assistance, not a bunch of people trying to discredit her.

I don't believe that my writing should alienate anyone who truly wants to help. I hope that at the very least, it makes the protagonists consider their own motivation. I haven't criticized anyone whose heart is with us. I am being cast by some as an angry conspiracy theorist. In my opinion, human frailty is almost always a better explanation than nefarious schemes. Greed, ego, shame, desire for revenge are generally enough to explain what moved a particular situation. In this case, there was a joint effort involving disgruntled former contributors, people working for a company that makes it's money on lab tests, and a doctor in an academic setting (about whose motivation I know nothing). It doesn't really qualify as a conspiracy, but it smells. And Science's cooperation with it smells. Harmful to patients everywhere if it stops research. As for anger, I'm mostly not angry anymore. When I'm not agitated about the lack of scientific progress, I'm a pretty happy person. However, the events of the weekend, really shook me up, made me very mad, and sad. And scared, that the work could stop.

The idea that 22Rv1 was created in a lab after CFS already existed, therefore proving that XMRV is a lab contaminant and nothing more, is another logical fallacy. It's pretty clear at this point, that XMRV isn't the whole story. Similar events to the one described in Paprotka et al, with other proviruses could have happened before that, including naturally, even before modern tissue culture or xenografting techniques. Neuromyasthenia is hardly a new phenomenon, first described a few hundred years ago. What is new, is how common it has become. I can't imagine why there isn't more concern that the cell line produces a fully replicative exogenous retrovirus capable of infecting human cells. But we can all relax now because Konstance Knox says that human serum restricts it in vitro, in some unspecified way and any antibodies that might be found are only some kind of "autoantibodies". Well, that's a relief for the human race.

The over the top concern about the use of antiretrovirals seems the height of paternalism, especially when you consider that HIV drugs are used to prevent transmission to healthy high risk people and unborn babies. Here's an exciting article, suggesting another possible long-term benefit of antiretrovirals for us: Mouse viruses and human disease. Stewart/Cameron

I've been asked now and again why I don't wait until I know the outcome of the therapies we try before reporting. Whether a particular therapy does or doesn't help us is almost irrelevant, as many things help a few people and not lots of others. The important thing is to share the ideas in order to further the discussion. We are beginning to have enough information to think ahead. Physicians are supposed to connect the dots to help their patients. In this case the dots turn into a pretty frightening picture. It is unfortunate that writing about the implications of human gamma retroviral infection makes one sound like Chicken Little. But the sky really is falling.