Dr. Judy’s bankruptcy was final yesterday. She has lost everything financially. Let’s hope the vengeance is now complete. Her homes are being sold and she still doesn’t have her notebooks. She isn’t working as a lab scientist because of the Whittemore’s defamation of her character, despite Dr. Lipkin’s support.
And still the WPI asks for money from the community? For what? They have not published one paper in the year and a half since Dr. Mikovits was fired. Instead they have spent a bunch of money to ensure she is completely stopped. What kind of people would do that? Why wouldn’t they want her to be able to work? To live her life? She gave them five years, trying to help their daughter, but wanted to follow the truth instead of the money, so they did everything they could to destroy her. What’s in those notebooks that they are so concerned about? There is no intellectual property, since XMRV is not a human retrovirus, but a lab contaminant, so there must be something incriminating, something that leaves them vulnerable. But they won. They have the notebooks.
From a big picture perspective, as affects the patient community, the whole misadventure was so wrong, it’s hard to count the ways. We were robbed, on many levels. From a personal perspective, it is still incomprehensible to me that the promise we felt, back when Dr. Judy was being promoted like a rock star, has turned to dust. However, she has told me repeatedly that they have taken her money, but they can never take the most important things from her. From an email last night, after reading my draft for this blog, copied here with permission:
The copies of my notebooks prove my total innocence. I did my job and beyond…their actions prevented the truth and prevented me from getting work, and not only me, my students as well…but as you say it robbed the scientific and patient communities of data paid for by federal dollars and donations to a “non-profit” institution. I could NOT LIE or ALLOW the truth to remain hidden or support those who would not tell the truth in order to take advantage of a vulnerable patient population.
Their intellectual property was unraveling when it was found that XMRV was a Silverman lab contaminant..what they are and were afraid of is that they will be held liable for the fraudulent testing.. Lombardi and the Whittemores lied for 3 years and they all had a financial interest in VIPDx. There simply cannot be intellectual property or diagnostic testing for a virus that does not exist in any natural organism!!!
From my personal perspective it is incomprehensible, that in the United States of America, all of my constitutional rights can be denied in order to cover up the truth …They do not want me to work because they are that vindictive. They know I live for my work in cancer and neuroimmune disease and for patients everywhere. They know my work is my life ..they thought they could take my integrity..but you know what ..THEY FAILED! Because Lipkin applauded my integrity and succeeded at showing the world what Silverman and Lombardi did to this patient population..THEY are the COWARDS and I have my honor and my integrity but most importantly of all, I have the support and confidence of the patient population, not just the CFS patients but the cancer, Chronic Lyme, Autism, MS ALS, Parkinson’s.. that is, ALL the patients to whom I have dedicated my life.
You see, my life was never about money and never will be. I am still working as a volunteer, I enjoyed coffee with two CFS patients yesterday and a cancer patient this morning, before I went with her to an appointment. I have never stopped being a patient advocate and will continue to be one in 2013. As one of my courageous friends with aggressive Parkinson’ s wrote in a Xmas card: “2012 was a year of change and loss, faith..we all needed tremendous faith to survive 2012!! 2013 will be a year of optimism, opportunity and HOPE”.
Today’s song: I Will Not Be Broken by Bonnie Raitt
I have always found this to be a trying time of year, even before I got sick. Our family is one of blended traditions and we often wind up celebrating both Chanukah and Christmas, making the whole ordeal go on and on (bah humbug:-). My husband and I thought we had fulfilled our obligations on that front, but now we have little kids at home again. Our eldest daughter Julie, who is half native American, moved back home last year with her two children who are Pomo Indians, and our son is home from his first semester at Tulane. Talk about a mish mosh!
I am having one of those days where even my arms feel heavy. Hey, who turned up the gravity? I feel tremulous, but it doesn’t show. I would like to go to a Christmas party tonight, but I’m not sure at the moment if I’m up for it or not. I’m replaying my whole tape loop about not wanting to disappoint. It doesn’t mean I won’t feel good to go when the time comes, but it’s up in the air at this moment. I’ll use my oxygen, take an epsom salt bath, and probably get the boost I need. More bothersome than the weakness though, with which I’m accustomed to struggling, is the emotional reactivity that comes with more inflammation. I’m sure many of you can relate…
That particular symptom was one of my first. It started just a few months after the birth of my second baby at 40, and it made me feel like I was becoming a different person. For those of you that don’t know me, I had gradual onset of symptoms, no PEM and no diagnosis for a decade, followed by incorrect diagnoses. I haven’t been bothered by this particular symptom for quite a long time and reexperiencing it is sending me back to the exploration of biofeedback that began when I first became ill in 1995 and was looking for a non-pharmaceutical solution for this and other alarming symptoms. In addition to neurofeedback with Cygnet, which I use in practice, I’m enjoying trying out some of the innovations for biofeedback hometrainers and stim devices on the market now. Advancements in electronics have made for easier to use, more effective and less expensive devices. I am particularly interested in them, because most of my patients can’t access a neurfeedback therapist and I had some devices way back when that might be helpful in this context. I’ll report on this subject at some point in the near future.
The FDA committee’s rejection of Ampligen filled me with mixed emotions. As it has been clear for a long time that only a minority of patients do well on it, and as it has some significant downsides, I’m happy for the would be non-responders who will be spared yet another therapeutic failure. On the other hand, other patient groups with real diseases are allowed to try toxic treatments that have only a small chance of success. I am of course concerned about the people who need the drug being able to get it, but the tragedy for all of us is Hemispherx’s failure to figure out who to treat with their drug; thus they have contributed nothing to our understanding of the pathogensis of our disease. They have also sent a loud and clear message to other would be drug developers to avoid CFS like the plague: SHAREHOLDER ALERT: Pomerantz Law Firm Has Filed a Class Action Against Hemispherx Biopharma, Inc., and Certain Officers
The same problem with patient selection is now happening again with the early experimentation with Rituxan: patient selection is random and there are no markers to follow. If you are sick enough, want it and can pay for it, you can be a guinea pig. I predict the stats won’t be good, for the same reason that the Ampligen results weren’t. There may well be a subset of patients that would have a higher hit rate, but nobody knows which ones. For me, it’s even simpler than that. I don’t want anything to do with it, personally or professionally, if it can kill. ME/CFS is a relapsing remitting illness. MS light. The best place to start is with the safest things, try to encourage remission, which requires synergy of global strategies.
One day soon, coming to a Quest or LabCorp near you, we will have a whole genome sequencing test that insurance will pay for. Then we will finally learn something that might change our options. But until then?
Still trying to understand why oxygen works so well clinically, in the setting of patients with increased oxidative stress, I’ve been reading about “mitohormesis”. Please take a look at these papers. This is a very important concept. Oxygen has been used to good advantage in the autism community and I still believe that the diseases are related, the differences in disease expression being due to the developmental stage at onset of illness. These papers describe the mechanism by which repeated doses of increased reactive oxygen species produce cellular resistance to stress. So repeated doses of hyperoxia in patients unable to exercise might produce better mitochondrial function over time, a theoretical framework for a clinically observed phenomenon.
Since I returned to practice, I’ve been intending to turn my attention to supplement recommendations for my patients. To date, I haven’t had a protocol and my advice has been random and half-baked. The passing of Rich Van Konynenberg left a great hole in our community. I feel a great personal sense of loss, because he and I intended to share with each other and it didn’t happen, completely due to my limitations, all my small supply of energy going to my practice. Now that I am studying the subject in depth and coming across his lectures and posts on the internet, I am very upset with myself. He was a brilliant, giving man. Generous of spirit. I am learning a great deal from him now, since he shared his ideas so freely.
As my second year back in the world comes to a close, my most powerful interventions remain high dose pulsed normobaric oxygen, Deplin, B-12, organic SCD diet, hormone balancing, stopping meds if possible, eliminating environmental toxins and biofeedback. I don’t think such a program will cure anyone, but I believe it can help a lot and is almost risk free. Three and a half years ago, when Ali and I discontinued Lyme treatment, I made deals with the universe that, if Ali got better, I’d be satisfied. Acceptance is my mantra. This recent dip of mine is challenging me to use that mantra, rather than dwell on my losses which only increases suffering.
Ali is spending Christmas eve with her wonderful beau, visiting with his family in Albuquerque, experiencing their traditions, planning to bring him back here in the morning for presents and brunch. She has finished 25 of 120 credits towards her degree at U Mass Lowell with a 4.0 average. I am so grateful that she is able to lead a full life – with disability, it is true, but a happy life nevertheless. Finishing this up, I realize I don’t have it in me to go to a party tonight, then walk in the cold for Santa Fe’s Christmas walk with the kids. I don’t want to hold them up or have them worrying about me. I prefer to save my energy for tomorrow. I’m a little sad that I’m not going, but my husband doesn’t seem disappointed, so it’s all good. It is a glass half empty vs half full moment, sitting by the fire, thinking about friends that are also alone tonight, envisioning a wonderful new year for all of us, filled with peace, love and greater wellerness. Merry Christmas.
Our current predicament reminds me of the Jack Kornfield book, After The Ecstasy, The Laundry. Retroviral causation is still a possibility, but what to do after that flash of illumination? How do we circumvent the despair that comes with getting it and losing it again? I catch myself stuck in negative thinking, feeling like I have gained so much insight into the illness, but it came too late for me to do anything “important” with it. After I wrote the last blog, I felt guilty. I mean, after where we’ve been together as a community, who wants to read about watching your diet?
I returned to work still improving, but I’m not any more. In fact, following a couple of back to back bugs that my grandson brought home from his first grade class, on top of several months of prolonged stress, I’m back to pretty definitely sick. Therefore, I’ve decided to take the next 6 weeks to rehab myself, rather than dive off the cliff again next week, when I was planning to make my first trip to Tucson. Magical thinking pretty clearly isn’t going to get me through this time. I need to take my own advice. Physician heal thyself.
What do I want to do differently with this time, besides lowering my energy output for a while and being more consistent with oxygen, diet, supplements, neurofeedback, all of which I’ve done before? For some time, I’ve wanted to try EWOT or exercise with oxygen therapy. I use oxygen to prevent PEM, but I have never exercised with it on. It requires a high flow concentrator (> 8L/min) and a mask with a reservoir that will stay on, but not restrict air flow. There is literature to support the idea that elite athletes (and rats) can do more work while wearing supplemental oxygen, though results have been equivocal as to whether exercising while hyperoxic improves performance in the long run.
I have wondered if it might not also be true that our exercise capacity could be increased this way, we who are on the low end of the bell curve. There isn’t much to go on in the literature, but there are a few papers about exercising with COPD and an oldie but goodie about using periodic hyperoxia to improve exercise capacity in CHF.
Recent findings have overturned the long-held belief that mitochondrial ROS have only a negative impact on cell function and survival. It is now clear that mitochondrial superoxide and hydrogen peroxide play important roles in a range of cellular functions, and can also activate signaling pathways that promote cell survival and disease resistance…Mitochondrial superoxide production is believed to contribute to damage of neurons in conditions ranging from chronic intermittent cerebral hypoxia to Alzheimer’s disease. However, it has been widely reported that transient exposure of neurons to low levels of superoxide that are converted into hydrogen peroxide can protect the neurons against a subsequent exposure to what would have otherwise been a lethal level of stress. This neuroprotective effect of a subtoxic increase in cellular oxidative stress has been termed “preconditioning” by neuroscientists who study stroke, but clearly falls under the broad umbrella of hormesis… [An] example of trans-cellular hormesis mediated by ROS comes from studies showing that oxidative stress can stimulate angiogenesis in the brain…
Here is another dot to connect:
Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients. In summary, patients with MM show impaired oxidative ATP production in their skeletal muscle, consistent with mitochondrial disease. This study has also shown that increased inspired oxygen concentration improves oxidative function in patients with mitochondrial myopathy, but not sedentary healthy individuals. It is hypothesised that the improvement in oxidative function with increased oxygen inhalation could be the result suboptimal oxygen conductance during exercise.
Oxygen Therapy for Mitochondrial Myopathy. Letter to the editor, so no abstract, but here are excerpts: We report on a physician-patient with a diagnosis of undifferentiated autoimmune disease, pandysautonomia, and mitochondrial dysfunction… Her functional capacity has gradually improved, and her prednisone dose has been substantially decreased for the first time in 8 years. She can now drive around town, walk in a shopping mall, and perform some household chores. In addition, the hair that had previously disappeared from her extremities (thought to be secondary to either the autoimmune disease or medication side effect) has regrown. Prior to oxygen therapy, her soft tissues in the extremities were painful with a boggy firmness, a fibromyalgia-like finding also thought to be part of the autoimmune syndrome. This symptom has gradually, but significantly, improved through a combination of body work (osteopathy and massage) and oxygen therapy. Prior to receiving supplemental oxygen, the same type of body work had been only minimally effective… This case report suggests that supplemental oxygen can enable patients to perform higher levels of cardiopulmonary work with less lactic acid accumulation than room air alone. The use of supplemental oxygen may not only improve functional capacity and certain physiologic abnormalities but may also minimize the mitochondrial stress, which has been postulated to increase the proportion of mutant mitochondria.
I mentioned this paper recently, but it bears a closer look: Normobaric hyperoxia treatment of schizophrenia. It showed that schizophrenics improve sleeping with a nasal cannula at 4-6L/min for 7 hours at night (an uncomfortable treatment). The improvement in symptoms was confirmed by a cross-over design of the treatment and control group. The rat study of periodic vs continuous hyperoxia above suggests that the effects demonstrated in this study might be even more profound with a higher dose for a shorter time. Why would oxygen help this group of patients and what does it have to do with us? Schizophrenia is increasingly recognized as a neuroinflammatory disorder associated with HERV activation. Here is a paper suggesting even more common ground… Antibodies to retroviruses in recent onset psychosis and multi-episode schizophrenia. So, another group of patients who have antibodies that cross react with MuLV sequences, at least in the acute phase.
I wish I could share this whole paper here, because it touches on so many of the questions left in the wake of XMRV. It is well worth a careful read in its entirety: Human retroviral sequences associated with extracellular particles in autoimmune diseases: epiphenomenon or possible role in aetiopathogenesis? Perron. There has been quite a lot of work done on MSRV, a retrovirus, which lies at the interface of endogenous and exogenous retroviruses. Since ME is essentially MS light, MSRV is a good model for us, with a 10 year head start from where we stand right now. Some, but not all MS patients studied express viral particles, which may or may not be infectious. That fits the variable epidemiology seen in our families, where some patients are isolated cases, having never known anyone else with the disease, others have partners and children affected, but otherwise no evidence of being contagious, and there are even a few who believe that they have infected many people through casual contact (food sharing). The idea of recombination and copackaging of viral genomes once again brings to mind the issue of vaccines contaminated with genetic material from animal cells.
As part of the complex ‘biological life’ of such retroviruses, it also appears necessary to study copackaged ERV genomes which may account for their potential pathogenicity by e.g., recombinations or propagation of defective clone expressing pathogenic molecules, and may be at the origin of their rapid loss of infectivity by defective interference and/or ERV takeover. The complexity of retroviral genome studies in these situations, represented in this review by IDDMK in autoimmune diabetes and MSRV in multiple sclerosis, can become a major difficulty for a definite conclusion.
The HERV-W family is one of the most studied, after the discovery of its MSRV founder member (Perron et al. 1989, 1997b). Our haploid genome contains about 70 gag, 100 pro, and 30 env HERV- W related regions (Voisset et al. 2000), but numbers can vary (Mirsattari et al. 2001; Zawada et al.2003); in silico expression data indicate that 22 complete HERV-W subfamilies from chromosomes 1 to 3, 5 to 8, 10 to 12, 15, 19, and X are randomly expressed in various tissues (Kim et al. 2008). Presently, this family is active and generates new recombinant copies in cancer cells (Yi et al. 2004), retains characteristics of functional retroviral envelopes (An et al. 2001; Kim et al. 2008), and HERV-W transposition and retrosequence integration have been evidenced in the human genome through interactions with active LINE-1 elements (Costas, 2002; Pavlicek et al. 2002). Thus, non-Mendelian genetic rules can apply to HERV-W elements: a key feature to understanding their biology.
None of the known stably inserted HERV-W elements is replication-competent (Blond et al. 1999): a study of HERV-W intragenomic spread (Costas, 2002) confirmed that, in the few individuals used for genomewide analysis, the sequenced HERV-W elements lack intact open reading frames (ORFs) in all genes within a single copy. This finding, and the unusual short period of evolutionary time of HERV-Ws (5 million years, estimated on average integration age of different subfamilies), suggested that MSRV might be either an exogenous HERV-W, as in animal ERVs (Palmarini et al. 1996), or a nonubiquitous replication-competent member, or a partly defective but nonubiquitous copy seldom complemented within the HERV-W family (Perron et al. 1997b, 2000; Komurian-Pradel et al. 1999; Dolei, 2005; Serra et al. 2003). Today, though reasonable arguments in favor of the existence of a replication-competent HERV-W member, which might even be ‘‘exogenous,’’ have been provided (Belshaw et al. 2005; Costas, 2002; Perron et al. 1997b, 1992), the very nature of MSRV remains to be confirmed by future studies (Voisset et al. 2008).
They can follow viral load in patients and there is clinical correlation… From the same paper:
A direct parallelism was found between MSRV positivity and load (in blood, CSF, and brain samples) and MS temporal and clinical stages, as well as active/remission phases (Dolei et al. 2002); at MS onset, 50% of CSFs were MSRV positive, and positivity increased with pro- gression. Importantly, MSRV presence in CSF at MS onset was related to poor prognosis; starting from otherwise comparable conditions, after 3 and 6 years mean EDSS (expanded disability status scale), an- nual relapse rate, therapy requirement, and progres- sion to secondary-progressive MS were significantly higher (Figure 2) in patients with detectable MSRV CSF load at onset (Sotgiu et al. 2002, 2006a).
A recent study (Mameli et al. 2008) found that plasmatic MSRV load of naive patients with active MS was directly related to MS duration; longitudinal evaluation of patients during 1 year of IFNb therapy showed that MS progression index (EDSS/MS years) was reduced for the majority of patients, whose viremia became rapidly undetectable. Notably, one patient had atypically high viremia at enrolment and, after initial virus inhibition and clinical benefit, had MSRV reemergence, accompanied by strong progres- sion with therapy failure. The authors concluded that evaluation of plasmatic MSRV could be considered the first prognostic marker for the individual patient to monitor disease progression and therapy outcome (Mameli et al. 2008).
Just published: HERVs Expression in Autism Spectrum Disorders. Balestriere et al, an addition to the growing literature supporting the idea that activated HERVs are involved in autoimmunity, an appealing idea, providing an explanation of why the immune system might become confused as to what is self and what is not. The authors of this paper found increased expression of HERV-H, one of the HERV families implicated in complex chronic disease, in autistics as compared to controls. They also report expression inversely proportional to age and proportional to disease severity.
Our answers lie at the interface of retrovirology, genetics, molecular medicine and toxicology. The further I go in my attempt to understand the problem on a biochemical level, the less optimistic I am with respect to so called “targeted therapies”. We simply aren’t smart enough and the system we are trying to influence is too complex. This is why therapies that affect the system globally are so attractive. Which brings me back to EWOT. Perhaps the poor, misunderstood Dr. Wessely could let his patients try some oxygen with their GET, now that he says he thinks they do in fact have some sort of a physical problem, in addition to being lazy, crazy and faking.
So, EWOT for ME? I ordered a couple of masks to try. Now I’ve really gone and done it. Set myself up by telling you all about it:). I will report back soon.
I have a lot to say today and too little energy with which to say it, having just lost ten days of life force to red tape and worry about complying with arbitrary and capricious rules. Between states with differing regulations, plus the DEA which has yet a different set of regulations, I feel like I need a law degree to practice medicine. The system is broken and it is incredibly hard to take care of patients appropriately. When I complained about it recently to a doctor friend in an email, he replied, “My tombstone should read: He died of red tape.” It was always bad, but now nobody even pretends it has anything to do with caring for patients.
My recent month long intensive in Hawaii, treating two young women with ME/CFS and many years of disability, has further convinced me that the therapies I am using are able to tip the balance in favor of a slow climb to wellerness. For the most part, the things I’m doing are not enough alone, but together these therapies are synergistic and additive with continued use. Everything I am doing, and why, is documented and referenced on this blog. The search function in the header works well. The patients are fragile and a lot of tinkering is necessary.
In a nutshell, high dose pulsed oxygen (normobaric and mild hyperbaric) to improve inflammation and mitochondrial function, bioavailable folic acid derivatives for improved methylation (Deplin and folinic acid), sublingual or chewable methyl B-12, Vit D3 replacement, infusions of a modified Meyer’s cocktail including taurine, glutathione by IV push and neurofeedback. Most significantly, I see improvement from weaning inessential drugs, replacing synthetics with bioidenticals, and using herbal treatments instead of pharmaceuticals. In particular, medical Cannabis, if tolerated, for patients who live in a legal state, is a more effective and much safer alternative for chronic pain than opiod drugs, which damage the gut and cause central sensitization over time.
I consider diet to be a cornerstone of treatment. Food as medicine. I advocate a modified SCD diet, allowing whole grain rice, for patients with neuroimmune illnesses that almost always include a GI component in the symptom complex. I encourage SCD yogurt as a probiotic, superfemented to be lactose free and have a high live bacteria count. I also advocate eating organic, and no processed or GMO foods. In particular, avoid the excitotoxins, aspartame and MSG. Here is an important YouTube, by Dr. Terry Wahls, in remission from a wheel chair through dietary intervention alone:
I received some flak for saying that I’m a lumper, not a splitter, with respect to segregating subsets of patients, except for research. From the point of view of clinical medicine, breaking it down into separate cohorts doesn’t help me at all. It is all neuro-immune illness. The therapeutic options are extremely limited. The same things are worth trying in other cohorts also. Many, if not most, of the therapies that are being used in the ASD community are applicable to us. ME is on a continuum with MS and ALS. GWI and chronic Lyme Disease wind up clinically indistinguishable from ME. Fibromyalgia is a subset, not a separate illness. Again, the same treatments are applicable for the same reasons, even if the illnesses look a bit different.
The first thing that happens when there is a response to therapy is improved resilience. A push that would have caused a long crash, doesn’t, but brings minor payback only. At first most everything still feels crappy all the time, though some things have improved. Then some moments that aren’t so crappy creep in. Then some actual good moments. Crappy always comes back though, and when it does, it feels like falling back into the black hole. But it passes much more quickly than before. Improvement needs to be judged in fairly large increments of time, at least 6 months to be sure. One of the young women I treated last month posted this on her FaceBook a few days ago, “I had a good day today; I don’t think I’ve said that in 8 years :)”. That, after only a month of nearly risk free treatment. A long way from a cure, but relief is relief.
Here are some new noteworthy references with respect to oxygen therapy:
I had the pleasure of hearing Dr. Mikovits on Sue Vogan’s radio show, In Short Order, finally able to speak openly in public. The interview is archived here. I thought she was very clear and brave as she answered all the hard questions. XMRV is not a human pathogen. There could be other retroviruses as yet undetected. The mistakes made will inform future research. I personally felt abandoned after the Lipkin paper, subsequent interview by Dr. Lipkin and the press conference, but I am encouraged to hear that he and Dr. Ruscetti are still working on our behalf. They don’t know what the positive serologies mean. It is tragic that she can’t go back and find out what went wrong so that everyone can learn from it, but much has been learned nevertheless. The only thing she said that I took exception with was that there is no evidence that XMRV has ever infected an animal. Persistent infection has been demonstrated in Macaques after parenteral introduction of virus, exposures similar to what has been happening regularly throughout the history of injected biologicals, dating back to vaccinations with the exudate of cow pox lesions, which certainly contained bovine leukemia viruses, similar to HTLV, and are artificially transferrable to other non-bovine species:
So it isn’t XMRV. Other cell lines express other infectious animal retroviruses. Live attenuated vaccines are grown in animal cells that express exogenous retroviruses. Other vaccines contain DNA fragments. Here is the government’s list of vaccine excipients: Vaccine Excipient & Media Summary by vaccine and by excipient. That’s now. The early vaccines were attenuated in live animals. Mouse brains injected into people.
The hypothesis that human endogenous retroviruses (HERVs) play a role in autoimmune diseases is subject to increasing attention. HERVs represent both putative susceptibility genes and putative pathogenic viruses in the immune-mediated neurological disease multiple sclerosis (MS). Gammaretroviral HERV sequences are found in reverse transcriptase-positive virions produced by cultured mononuclear cells from MS patients, and they have been isolated from MS samples of plasma, serum and CSF, and characterised to some extent at the nucleotide, protein/enzyme, virion and immunogenic level. Two types of sequences, HERV-H and HERV-W, have been reported. No known HERV-H or HERV-W copy contains complete ORFs in all prerequisite genes, although several copies have coding potential, and several such sequences are specifically activated in MS, apparently resulting in the production of complete, competent virions. Increased antibody reactivity to specific Gammaretroviral HERV epitopes is found in MS serum and CSF, and cell-mediated immune responses have also been reported. Further, HERV-encoded proteins can have neuropathogenic effects. The activating factor(s) in the process resulting in protein or virion production may be members of the Herpesviridae. Several herpes viruses, such as HSV-1, VZV, EBV and HHV-6, have been associated with MS pathogenesis, and retroviruses and herpes viruses have complex interactions. The current understanding of HERVs, and specifically the investigations of HERV activation and expression in MS are the major subjects of this review, which also proposes to synergise the herpes and HERV findings, and presents several possible pathogenic mechanisms for HERVs in MS.
Or antiretrovirals, reverse transcriptase and integrase inhibitors, might be inhibiting retroposons:
Reverse transcriptase inhibitors presumably inhibit other viruses besides retroviruses if reverses transcription is required in the replicative process. Viread is used to treat chronic hepatitis B, for example. Hepatitis B is a DNA virus that replicates through an RNA intermediate and uses reverse transcription.
Telomerase is a reverse transcriptase. Therefore, arguably RTI’s might cause faster aging, but might tip the balance away from developing cancer. The more you think about it all, the more you realize that, like all drugs, antiretrovirals are blunt swords with many possible mechanisms of effect, all of which says that clinical trials are in order. One would think that the manufacturers would be interested in new indications for their drugs.
Protein from helper viruses and recombination events can rescue defective virus. Innumerable chances have occurred: Science Fiction or Fact? 35 years ago, when I was in medical school, autism and MS were rare. Autoimmunity has skyrocketed beyond belief, as has cancer.
It’s been a very strange and unusual three years. The Lipkin study was the closing of the door opened by the Science paper in October 2009. For me, the shift from thinking about neuroborreliosis to retroviral causation for ME/CFS led to clinical decisions that have resulted in great improvement for both Ali and me. We are not well, but we are both leading full and meaningful lives, within the confines of illness. Existing within the confines of illness means the same thing for us that it does for other people with disabilities who need accommodations. It does not mean trapped in endless suffering with no help in sight. Prior to the fall of 2009, Ali and I spent a few really grim years couch bound together, wondering if a quick merciful end wouldn’t be a good thing. Now we are working and going to school. We are even playing some. We need to do it “our way”, but it is happening.
My personal journey through the world of XMRV was littered with betrayal and abandonment, so in a sense, I’m glad that part of it is over. I’m left to practice medicine much as I did before, but with new insight. Three years of reading retrovirology has changed my view of many things, medical, scientific and political. I’m in Hawaii right now treating two young ME women. Much of what I’m doing is a refinement of what I did in my last practice a decade ago. My own emotional adjustment to the collapse of the science involves accepting that the tools I have now are all there is likely to be for a long time. There isn’t going to be a cure and it is a long way off before conventional medicine has anything better to offer than what’s listed on the Mayo Clinic site: sleep meds and antidepressants, which many of us don’t tolerate. Not even pain meds or anxiolytics. Exercise and therapy, because we are so overly focused on our symptoms. Back on the trash heap.
So where’s the redemption in this story that makes it worth writing about? ME, or ME/CFS, or CFIDS (since I’m a lumper, not a splitter) is a relapsing, remitting illness. It can be coaxed into remission. Remission doesn’t mean normal or healthy. It means not suffering so much. It is a process of encouraging healing and discouraging inflammation, requiring a gentle, multi-pronged approach that relies on synergy, tinkering and luck. Find some maneuvering room, a key for the lock. It is possible to stop the downward spiral, tip the balance and start the slow climb out. Unfortunately, there is never a uniform response to a given therapy with this illness, so treatment can’t be formulaic. When recovery does start, it is slow and fragile. It must be nurtured and it takes years, that from personal experience, since I have only been back in practice for a little over a year. Although, I have heard of spontaneous recoveries many years in, most involve hard work and careful choices. One thing I know for sure. There was never a patient population less suited to medical heroics.
Meanwhile, I sit here in the weird position of being better and still apparently improving on Viread for 2 1/2 years. I was so bad 4 years ago, nobody expected me to do anything productive ever again. Ask my ex-Lyme doc. I had a sleep disorder to rival any of my readers and I know some of you have pretty spectacular sleep problems. I now sleep normally. Even normal dreaming has returned in the last 6 months or so. My gut is also functioning normally on a modified SCD diet, 6 years after emergency surgery for a small bowel obstruction and a Crohn’s diagnosis. My intractable peripheral neuropathy pain, which once required opiates, is now little more than background noise except at the worst moments. PEM is reduced, but still problematic. I can exercise a little, being careful not to overdo, because it feels good in the moment. I won’t list Ali’s symptoms, but she is similarly improved on Viread and Isentress. Her horizons are ever expanding, her illness less and less restrictive. Have we done other things at the same time? Yes. Will antiretrovirals for ME/CFS be studied at all? Not a chance. Our government just spent a couple of million dollars to ensure that ideas like mine stay marginalized.
Dr. Lipkin was quoted on the IMEA FaceBook page in response to questions about whether any “positives” were found, “The investigators reported results as positive or negative according to their own criteria. The only requirement was that once criteria were established results could not be changed through modifications in criteria. I know this is not the intention of those who continue to pose these questions; nonetheless, the impact of this continued challenge to work of the team is that some people in the scientific community who might contribute are becoming reluctant to work on CFS/ME.” Yet, at the press conference, he encouraged us to advocate for ourselves more effectively. So we need to ACT UP, but be nice about it. Any ideas? We are a group in desperate need of effective advocacy. It’s not only the middle aged going down. There is a tidal wave of young people. They are not as visible as their autistic cousins, but just as profoundly disabled. Who is going to care for them when their parents are gone? We need to start advocating for them effectively now.
The Lipkin study buries XMRV once and for all, completely leaving aside the question of an infectious chimera out and about that contaminates a clean lab in a matter of days and is capable of infecting monkeys. But it wasn’t in the blood of the patients or controls in this study. That much is clear, forgetting the unscientific claim that this study, or any study, is definitive of anything. Science is self-correcting, as Dr. Lipkin reminded us, but only if the game isn’t rigged. This is a repeat performance of the definitive study that showed that the MMR doesn’t cause autism, which also side-stepped the bigger question. The use of the word definitive tells us we are dealing with politics, not science. Sleight of hand.
The paper didn’t even try to speculate as to the one positive finding, that 6% of the study group, patients and controls, cross reacted with a test designed to detect SFFV, a nasty murine retrovirus. Whatever it is they are picking up with this serology test, “modified slightly” from the one once used at the WPI, the various PCR’s used in this study, optimized to detect XMRV and a piece of a “generic” pMLV, couldn’t detect it. But that doesn’t mean it isn’t there.
A young friend emailed after watching the press conference asking that I blog because my blogs are hopeful. I’m not sure how to spin this as hopeful other than XMRV got us into national news as having a real disease. It’s good that there are people studying us, even if they are abandoning the hypothesis of best fit. So, as my friend asked, do we still have retroviruses? The answer is everybody has retroviruses. 8% of the human genome consists of retroviral sequences. It is becoming accepted that these sequences are capable of causing trouble in some people, whether they produce fully replicative virus or not. SFFV is a replication-defective virus that causes disease in mice: The spleen focus-forming virus (SFFV) envelope gene, when introduced into mice in the absence of other SFFV genes, induces acute erythroleukemia. S Ruscetti
The Lipkin study in no way disproves the hypothesis that simple animal retroviruses, alpha, beta and gamma, parenterally introduced, in the form of vaccines and from other sources, e.g. hybridomas, xenografts, etc., have recombined and rescued defective endogenous retroviruses, and/or created new and as yet unrecognized exogenous retroviruses. The existence of XMRV, is supportive of this theory. There have been so many chances for it to happen, in addition to the possibility that it happened naturally. This means that we each may have something a little different. Which is why they can’t find “it”.
Personally, as a defender of Dr. Mikovits during this entire mess, I appreciated Dr. Lipkin for openly defending her struggle against the Whittemores. The scientist who put the nail in XMRV’s coffin. Dr.’s Mikovits, Ruscetti and Alter completed the difficult task of acknowledging they’d been mistaken. Our disease has finally been deemed “serious and life threatening” to enable fast tracking of drugs, should there be any drugs worth fast tracking, which seems unlikely if nobody is studying the root cause of the disease, only looking at downstream effects.
I’m not even going to question the study design, patient selection, specimen handling, that the patients chose their own controls, etc. I accept at face value that Dr. Lipkin put together a convincing study in order to put the final nail in the coffin about XMRV. No surprise there. I assumed the study would be negative. But I expected the authors to have the intellectual integrity to state that ruling out XMRV does not rule out retroviruses. Instead they allowed the press to distort in predictable ways. I therefore must conclude that Dr. Lipkin plays for the home team. His task was to kill it and reassimilate the renegade scientists into the group. To make sure that nobody does any clinical trials of arv’s, the paper suggests that the patient community has been saved from that terrible fate by this definitive paper. Mikovits’ name right there with Coffin’s. Task accomplished. But even Coffin said that it might be another retrovirus. Smart people allowing distortion and partial truths. It looks to me like we’ve been thrown back on the trash heap. From the Wall Street Journal. Viruses not to blame for chronic fatigue syndrome after all. Thank you Mr. WSJ editor for that headline, suitable for a tabloid.
Why do I still believe retroviruses are involved in causation in the face of so much evidence against XMRV? Even though we don’t have XMRV or active replicating virus with some certain degree of sequence homology to a piece of a “generic” pMLV, retroviral causation has not been ruled out. It is still the best explanation for all of the observed phenomena. It works as a clinical model to explain the symptoms and put treatments in context. It even explains the obvious but still unstudied epidemiology. Dr. Mikovits was trying to sequence what she believed were positive cultures that were negative for XMRV. She sent out letters to that effect to patients.
Then there is the response to antiretrovirals. Dr. Snyderman has presented amazing data, that most of the scientists involved in this story have seen and ignored. He has not been cured, but his leukemic cells and his cells capable of making cytokines have decreased with treatment. Cancer treated like a chronic disease, like diabetes or AIDS. I don’t think they are stupid, so they don’t want to know. Why not?
If the response of longstanding ME/CFS patients to limited arv’s (RTI’s and II’s alone) had been more robust, we wouldn’t even be having this discussion. It wasn’t. There were early responses that were encouraging, but with no way to follow, after a while, you’re left not knowing what is happening. Meaning we don’t know how to use the drugs, not that they have no value. Maybe they should be pulsed or given low dose for N chain termination. Maybe a protease inhibitor is necessary for full effect. Dr. Snyderman is documenting an ongoing response to Kaletra. The best case we heard about anecdotally was a teenager, hadn’t been sick long, responded fully and the drugs were stopped at 6 months, remaining well as far as I know. It is beyond sad that this case was not published. While new teenagers get sick with an “untreatable” disease, they are denied a trial of very safe existing drugs. It could have been studied for a lot less than the 2 million dollars spent to prove it isn’t XMRV.
I have tried to discontinue Viread on three occasions, since our drug co-pays are a problem, and I haven’t been able to do it. I get sicker within days and feel better quickly after restarting. Can I prove it? No of course not. The disease is a relapsing remitting illness all on it’s own. However, I didn’t have trouble stopping AZT or Isentress. I have been under enormous stress since June, with one thing after another, one of those times in life when the waves just keep coming, too close together for recovery. I am a little worse than I was, but only a little. I’ve even been able to ride the tandem a couple of times recently, only 5 miles on the flat, but no PEM after. Ali continues to do extremely well on Viread and Isentress. She has considered stopping arv’s, but has decided not to rock the boat at this time, since improvement seems to be continuing very, very slowly. The possible downside besides financial? I don’t know of any for Ali. I’ve aged a lot in the last couple of years, though it is on time, coming after a late menopause, so I can’t really blame Viread for that. I heard from a patient yesterday who did well on AZT, Viread and Isentress for a year, but then went back to baseline for another year with some new symptoms that could have been drug related, though hard to know. As I said, we don’t know how to use these drugs. We have no way to monitor. That doesn’t mean they have no value.
But Dr. Lipkin told Dr. Racaniello:
I know some in the community –the scientific community—feel that this was not money well spent, but the fact is, I think that we have obviated a lot of, you know, missteps that might have followed with clinical trials and such for antiretrovirals. And in addition, we have been able to establish a sample bank that will be helpful for years to come. And we’ve been able to hold, I think, the attention of the community.
So Dr. Snyderman, Ali and I are missteps…
From the 3rd paragraph of the paper:
Since the index publications, clinics have been established for the treatment of ME/CFS with antiretroviral drugs…
This is a complete fabrication. Where are these clinics?
It is completely incorrect, and unscientific, to conclude anything from the Lipkin study other than they didn’t find XMRV or a particular pMLV sequence. That’s a long way from no viruses or even no retroviruses in CFS. How is it that 2 million dollars was spent to tell us what we already knew a year ago? No reproducible assay. 2 million dollars and all that effort to prove what isn’t. For three years, we’ve been waiting for the scientific community to run with the ball. Now it is pretty clear, the ball has been dropped, while they huddle to congratulate each other on a job well done. The status quo is restored.
Today’s song: Who’ll Stop The Rain by Creedence Clearwater Revival
The quest for identifying and treating retroviruses that are involved in the pathogenesis or CFS/ME, neuroimmune, autoimmune and neoplastic disorders will not end today despite the negative results of the XMRV, pMLV study. I have CFS/ME and cancer. My data supports the presence and importance of retroviruses in the pathogenesis of both disorders and the potential for anti-retroviral drugs to help us.
My data shows the presence of a clonal T-lymphocyte expansion which is probably CD8 cells. Having a clonal T-lymphocyte expansion is abnormal. In addition, I have increased monocytes (monocytosis). I have looked at 56 of my patients with various types of cancer and half of them also have a detectable T-lymphocyte expansion and monocytosis. My point is that what I see in myself may be a common phenomenon and actually may be happening in millions of people. I haven’t looked in CFS/ME, because I limit my practice to Hematology-Oncology.
T-lymphocytes and monocytes are important because they are permissive of retroviral invasion and because they are pre-programmed to make cytokines. Presumably the increased numbers of these cells after infection has occurred would lead to increased amounts of cytokines that would dysregulate the immune system. In addition, monocytes give rise to the microglial cells which migrate to the brain and spinal cord and potentially could deposit abnormal amounts of cytokines in direct proximity to the neural elements.
Dr. Lipkin mentioned a polyclonal expansion of B-lymphocytes as important in our type of disorder and this could be a result of the increased amount of cytokines. In fact, in my patients who had a clonal T-lymphocyte expansion and/or monocytosis, 50% had autoimmune markers. What is reasonable to postulate is that we now have explained the known connection between inflammation and cancer and neurodegenerative disorders and it all goes back to the retroviruses.
I have previously shown response of my leukemia, monocytosis and clonal T-cells to AZT, raltegravir and after relapse a second response to the addition of tenofovir. I had hoped to demonstrate that a PI would be valuable treatment and waited to add this category of drug until relapse. My leukemia responded and relapsed in parallel with the monocytosis and clonal T-cell expansion but at a somewhat different rate.
The last graph shows that the clonal T-lymphocytes, CD8 lymphocytes and monocytes were increasing after relapse on AZT, raltegravir and tenofovir. Quest discontinued doing the quantitative TCRγ in 2011. As a favor to me, Quest put it up but with different reagents so that the results from the new assay are not superimposable over 2011’s. Please note that the clonal TCRγ values are a ratio rather than an absolute number of cells.
I didn’t have the new clonal T-cell assay available until later in the graph and didn’t think of looking for CD8 cells initially. After the relapse was clearly documented, I added the PI, lopinavir. The T-cell parameters and monocytes continued to trend up for the next 4-8 weeks before clearly trending down.
The only reasonable explanation for what has happened to me and what I have found in half of my cancer patients is that retroviruses participate in the pathogenesis of our illnesses. Please note that I do not claim that the retroviruses cause the illnesses but emphasize that the retroviruses participate in the pathogenesis. The likelihood is that genetic susceptibility and toxic exposure determines whether an infected person would develop disease and how it would be manifested.
It is clear to me from the data I have, that many people have susceptibility to develop disease after infection with retroviruses. It is now up to the scientists to identify the infection and the basis of genetic susceptibility. Once there are easy methods to identify who is infected and with what, treatment trials could be started. We must go forward.
“This is a court of law, young man, not a court of justice.”
~ Oliver Wendell Holmes, Jr.
The WPI’s lawsuit against it’s former chief scientist continues to cut its swath of destruction through the heart of the ME/CFS community. Dr. Judy was forced to declare bankruptcy yesterday. She has already spent her retirement on lawyers and now she will lose one, if not both, of her two small condominiums, which one still to be determined by a bankruptcy trustee. And most importantly, she isn’t working on our behalf…
Here’s a letter posted this morning on the Messages of Support for Dr. Judy Mikovits FaceBook page (there are several such pages with hundreds of members):
It is beyond me that in this day and age this injustice is allowed. I am not a naive person but I had hoped that the 21st Century would bring a greater justice and compassion to the world.
How can these corrupt people be able to ruin, mentally, physically and personally an innocent and truly good individual?
I am deeply sad.
Me too. It is beyond crazy. A travesty of justice. A misuse of the system. The WPI, a non-profit, spent large amounts of money on lawyers to write hundreds of pages of legal documents, to destroy what was in fact their only resource. To what end? They knew there was nothing to get monetarily. An apology? What a joke. Even if they were right, which they aren’t, what would someone interested in the greater good have done when confronted with the problems that Annette Whittemore was confronted with?
In a nutshell, this is where the case stands. The first judge ruled against Dr. Mikovits in a default judgement because she wouldn’t give up her personal email which contained confidential information on many study participants. Then he recused himself to make sure there was no appearance of impropriety, since he had received significant campaign contributions from Harvey Whittemore, who is under indictment for making illegal political contributions and lying to the FBI, not to mention his other business problems: Ex-business partners: Whittemores owe more than $24M. Of course, Harvey claims to have nothing to do with the WPI. So a new judge was appointed. One would have thought that the opportunity would have been seized to right the wrong and run the case as it should have been run in the first place, but no, the judge decided to continue where the old judge left off, leaving the judgement in place, with a “prove up” hearing scheduled for today, to determine an amount, thus forcing the bankruptcy.
The WPI wants Dr. Mikovits to pay for their loss of donations compared to before she was fired. As if they didn’t cause it all with their own actions!! They didn’t have a fund raiser this year because who would be there? They want back her entire 5 years of salary, during which she was desperately trying to, and in fact did, help their daughter. Plus, they want the entire cost of the research program from inception. Oh, and the punitive multiplier for her “bad behavior” since she was fired! And they want their legal fees, so they don’t have to defraud the community and the NIH to pay their lawyers. Of course Dr. Mikovits has no money…
In July 2011 she told Harvey Whittemore of the potential contamination, she says, and expected that the VIP Dx lab would cease testing patients for the XMRV virus. “I just kept saying, stop it, stop it, stop it. We have to sort this out,” Mikovits says. According to Mikovits, the testing did not stop. And after a tense summer, she was fired in September.
Let’s not forget what this is really about, not some imaginary IP in some old notebooks, but the thousands of bogus tests that were sold, some after they knew they were bogus, some paid for by Medicare?
The fall out from it all? The WPI’s legacy, from an advocate of 20 years, posted to FaceBook last night and republished with permission.
My Opinion: We’ve been ized
~by John Herd
The Whittemores overly self-mesmerized
Their grandiosity so fantasized
Just because of money legitimized?
They expected to be idealized
Constructive input demonized
As sound advocates often minimalized
While many amongst us patronized
And those with differing views were ostracized
Stupid actions authorized
Moral integrity compromised
“For the sake of patients” bastardized
Sound PR strategies brutalized
With so much about WPI fictionalized
In fake news coverage televised
Fabrications on the Internet digitalized
Research assets cannibalized
Clinically unvalidated test commercialized
Protecting scientific data criminalized
While Judy Mikovits sat in jail demoralized
Judicial corruption legalized
Their lavish travel and living publicized
Questionable scientific integrity sanitized
As their research director was victimized
The whole view of CFS jeopardized
By the WPI saga being so scandalized
An insult to patients already traumatized
From misinformed views of the illness so hypothesized
All WPI’s books should be scrutinized
With all their records analyzed
If they’ve not yet been sterilized
And financial assets vaporized
From the CFS world they should be exorcised
Because they added to our being even more stigmatized
Let’s face it, we’ve been sodomized
But oh how nicely Annette is accessorized
Today’s song: Which Side Are You On? Performed by Natalie Merchant
And a modern version of this classic protest song by Ani Difranco
The arrogance continues with the latest “contribution” from our government at work:
Curr Opin Virol. 2012 Jul 17. [Epub ahead of print]
Recombinant origin, contamination, and de-discovery of XMRV.
Delviks-Frankenberry K, Cingöz O, Coffin JM, Pathak VK.
Viral Mutation Section, NCI, HIV DRP, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
The discovery and de-discovery of the xenotropic murine leukemia virus-related virus (XMRV) has been a tumultuous roller-coaster ride for scientists and patients. The initial associations of XMRV with chronic fatigue syndrome and prostate cancer, while providing much hope and optimism, have now been discredited and/or retracted following overwhelming evidence that (1) numerous patient cohorts from around the world areXMRV-negative, (2) the initial reports of XMRV-positive patients were due to contamination with mouse DNA, XMRV plasmid DNA, or virus from the 22Rv1 cell line and (3) XMRV is a laboratory-derived virus generated in the mid 1990s through recombination during passage of a prostate tumor xenograft in immuno-compromised mice. While these developments are disappointing to scientists and patients, they provide a valuable road map of potential pitfalls to the would-be microbe hunters.
Game. Set. Match. Everyone can take a sigh of relief. The human race is safe, as they’ve said all along. Scientists in a power postition at the NIH have closed their minds to retroviruses other than HIV and HTLV contributing to human disease. Is this really a scientific assessment of all the available data? Or a ploy to keep the blinders on a while longer? Baffle ‘em with bullshit.
There’s a giant elephant in the room. Several elephants actually. What if there’s more than this one virus that they acknowledge they created in the early 90′s? It seems likely that it’s happened more than once, given how many chances there have been to recombine and infect human cells? But they only infect human cells in tissue culture they say, not in vivo because we have restriction factors.
Here’s an experiment with human lymphoid tissue concluding we are safe:
Susceptibility of Human Lymphoid Tissue Cultured ex vivo to Xenotropic Murine Leukemia Virus-Related Virus (XMRV) Infection. Curriu et al.
Background: Xenotropic murine leukemia virus-related virus (XMRV) was generated after a recombination event between two endogenous murine leukemia viruses during the production of a prostate cancer cell line. Although the associations of the XMRV infection with human diseases appear unlikely, the XMRV is a retrovirus of undefined pathogenic potential, able to replicate in human cells in vitro. Since recent studies using animal models for infection have yielded conflicting results, we set out an ex vivo model for XMRV infection of human tonsillar tissue to determine whether XMRV produced by 22Rv1 cells is able to replicate in human lymphoid organs. Tonsil blocks were infected and infection kinetics and its pathogenic effects were monitored
Results: XMRV, though restricted by APOBEC, enters and integrates into the tissue cells. The infection did not result in changes of T or B-cells, immune activation, nor inflammatory chemokines. Infectious viruses could be recovered from supernatants of infected tonsils by reinfecting DERSE XMRV indicator cell line, although these supernatants could not establish a new infection in fresh tonsil culture, indicating that in our model, the viral replication is controlled by innate antiviral restriction factors.
Conclusions: Overall, the replication-competent retrovirus XMRV, present in a high number of laboratories, is able to infect human lymphoid tissue and produce infectious viruses, even though they were unable to establish a new infection in fresh tonsillar tissue. Hereby, laboratories working with cell lines producing XMRV should have knowledge and understanding of the potential biological biohazardous risks of this virus.
So maybe they’ll take a few extra biohazard precautions for themselves, since they are working directly with these lab anomalies, but nothing to worry about for the general public. Never mind the millions of human canaries illuminating the destructive path we are on. Never mind that this could explain the observed increase in neuroimmune diseases, autoimmunity and cancer. Never mind that we’ve been mainlining attenuated viruses cultured in animal cells which express exogenous retroviruses for eighty years now. Never mind that these viruses cause similar diseases in other mammals to that which we are observing in humans. Never mind all the clinical evidence that several large patient cohorts, ME/CFS, ASD, GWI, chronic Lyme Disease, PANDAS, RRMS are related and contagious diseases. Leave it in the realm of genetic weaknesses for now. Better to be an ostrich for a while longer since the cat is so out of the bag. Let’s remain in denial for as long as we possibly can, which I guess will be until Quest has a DNA sequencing test that insurance will pay for. They are allowed to be literal and have limited vision in the name of science.
Comparing PreXMRV-2 gag sequence diversity in laboratory and wild mice using deep sequencing. Mayer et al.
It has recently been reported that the xenotropic murine leukemia virus-related virus (XMRV) derives from a laboratory recombinant. However, sequences with characteristics of the 5′ half of XMRV (termed PreXMRV-2) have been identified in several laboratory mouse genomes and cell lines suggesting parts of the XMRV genome exist as naturally occurring retroviruses in mice. We compare here PreXMRV-2 gag sequence diversity in mice to that of reported XMRV-like sequences by testing a panel of wild mouse and common inbred laboratory mouse strain genomic DNAs and by using high throughput amplicon sequencing. Sequences with features typical of previously reported PreXMRV-2 sequences, among them a 24 nt deletion, were repeatedly identified in different wild mice and inbred mouse strains within a high background of non-XMRV-like sequences. However, Sanger sequencing of clones from amplicons failed to retrieve such sequences effectively. Phylogenetic analysis suggests that PreXMRV-2 gag sequences from mice, cell lines and patient samples belong to the same evolutionarily young clade and that such sequences are diverse and widespread within Mus musculus domesticus and laboratory mice derived from this species. No evidence of PreXMRV-2 like gag sequences could be obtained outside of the M. musculus lineage. The results suggest that accurate determination of presence, absence and relationships of specific murine retroviral strains benefit greatly from deep sequencing analysis.
Meaning that most of the work that has been done so far has been a meaningless waste of time, energy and money… More from this paper:
… in both the Sanger sequencing and high- throughput datasets, PreXMRV-2 like gag sequences were not majority sequences in any mouse DNA sample, even when account- ing for possible clonal artifacts due to PCR or emulsion PCR before GS FLX deep sequencing preferentially amplifying one sequence over another in a complex mixture. Thus, and also in the light of an often unknown sequence heterogeneity provided by mouse ERVs, we feel that high-throughput sequencing should generally be applied when attempting to detect relatively rare sequences such as PreXMRV-2 from complex retroviral mixtures. High-throughput sequencing is a common strategy used for identifying rare human immunodeficiency virus 1 variants and may need to be employed more broadly.
Here’s a paper that shows that mixing XMRV with Maloney MuLV produces a more dangerous virus. Simple animal retroviruses recombine and one can “rescue” another by providing missing pieces that evolution has silenced with mutations to protect us.
Moloney murine leukemia virus glyco-gag facilitates xenotropic murine leukemia virus-related virus replication through human APOBEC3-independent mechanism. Nitta et al.
One of the unique features of gammaretroviruses is that they contain an additional extended form of Gag, glyco-gag, which initiates in the leader sequence. MuLV glyco-gag, gPr80Gag, promotes retrovirus replication and disease progression. Although virtually all infectious MuLVs encode glyco-gag, XMRV (xenotropic murine leukemia virus-related virus) lacks the classical gPr80Gag sequence. We examined XMRV to determine if its leader sequence contains glyco-gag activity, whether the presence of conventional gPr80Gag affects replication of XMRV, and we describe the evolution of glyco-gag-deficient MuLVs in Mus.
We introduced several mutations disrupting two putative but noncanonical glyco-gag proteins in the leader sequence region in XMRV and found that those mutations did not affect virus
release nor susceptibility to the antiviral activity of hA3G (human APOBEC3G). A chimeric XMRV encoding the Moloney MuLV (M-MuLV) leader sequence (MXMRV) demonstrated that M-MuLV glyco-gag facilitated MXMRV release and increased infectivity. Infectivity assays with several cell lines showed that glyco-gag increases XMRV infectivity in all cell lines tested, but the level of this increase varies in different cell lines. Because MuLV glyco- gag counteracts mouse APOBEC3, we investigated whether M-MuLV glyco-gag enhances XMRV infection by counteracting human APOBEC3. Comparison of hAPOBEC3 isoforms expressed in different cell lines indicated that hA3B was the most likely candidate for a restrictive hA3. However over-expression of hA3B showed no enhanced restriction of infection by XMRV compared to MXMRV. Endogenous MuLVs in the sequenced mouse genome were screened for canonical glyco-gag, which was identified in two clades of xenotropic MuLVs (X-MuLVs) and ecotropic MuLVs, but not in other X-MuLVs or in any polytropic MuLVs.
M-MuLV glyco-gag facilitates XMRV replication, and the leader sequence region in XMRV does not encode proteins equivalent to M-MuLV glyco-gag. The fact that the ability of glyco- gag to enhance XMRV infection varies in different cell lines suggests a glyco-gag sensitive restrictive factor that further reduces XMRV infectivity. The M-MuLV glyco-gag enhancement for XMRV replication is through a hAPOBEC3 independent mechanism. The absence of glyco-gag in MuLVs carried by western European mice suggests that loss of this sequence is a relatively recent event with limited subspecies distribution.
While the decades long coffee break continues at the CDC, I’m trying to be well enough to work, in order to care for members of the most medically underserved population I’ve ever taken care of, including medical school in the Bronx and 10 years in the ED at Santa Clara Valley Medical Center, the county hospital in San Jose, CA, where the patients are a composite of third world misery. Those patients had nothing on this group in terms of lack of informed care; almost every patient I have has received abysmal care, due to ignorance and a lack of compassion because they have an invisible disease. Benign neglect is as good as it gets.
The last blog was the least controversial I’ve ever written judging from the comments. I have received many expressions of concern for Andrew that the ball was dropped. I would like to reassure everyone that I forwarded my findings and recommendations to Andrew’s doctor in Northern Ireland. Andrew has been seen twice since he returned home and is reportedly much better than before his trip. So the most important thing happened. Taking it all at face value, Andrew improved with oxygen and Deplin. He received about 30 hours of oxygen. In hyperbaric practice, I used to do a series of 40 hours and expect it to last for at least several months if the response was robust. I only hope that if it fades, he will be able to access more oxygen and L-methylfolate, available over the counter, as explained in my last blog.
I tremendously appreciate all of the expressions of support from friends around the world. I did hear back channel from a few people who were upset that I said that some ME/CFS patients are difficult from a physician’s perspective. I almost didn’t leave it in after I wrote it, but decided to, because it is important grist for the mill. There are several perversions that have befallen us, by virtue of being seen as lazy, crazy and faking. One is the need to refute that therapy could be useful for us in some way, since it is being forced down throats by the same people who say there is no physical basis. Therapy with people trying to talk you out of what is real isn’t very useful, but in the context of being believed, it might do a lot of good. Same goes for exercise. It is the context that is the problem. Another perversion is the need to be good if we ever want to be seen as sick or worthy of help. Well, Alzheimer’s Disease doesn’t make most patients particularly nice, but the disease still gets studied, and not only by psychiatrists. Neuroinflammation has behaviorial consequences, just as cardiac inflammation produces palpitations and GI inflammation causes diarrhea. It is a lack of compassion on the part of the medical profession to blame this on the patients. It could never have happened except that the disease doesn’t cause true dementia even when very long standing. It happened because doctors blame patients for what they fear and don’t understand, pure and simple.
The need to reaffirm one’s illness all the time leads to a further distortion, oft repeated in the patient group, the view that ME/CFS is the worst disease in the world. This is far from the truth, but the degree of injustice makes for a need to catastrophize, that word used all the time to accuse us of making too much of our little nuisance complaints.
All chronic illness is superimposed on preexisting personality. When it comes to inflammation of the brain, dysfunction impacts thought content. My experiences treating brain injury and developmental disorders with EEG biofeedback and oxygen taught me that strong emotions are not unlike other types of paroxysmal brain activity and similar therapeutic interventions are effective across the board for patients living with unstable brain states. People with a lot of fear who get this disease are prone to recurrent or persistent panic states. PTSD is another manifestation of cortisol exacerbated neuroinflammation which shows up often in the patient group. It is organic. Difficult brain states make for tricky management from a doctor’s point of view. The word encephalomyelitis means inflammation of the brain and spinal cord. Of course there are behavioral consequences.
The truth is that it is not the worst disease in the world by any stretch of the imagination. It has the potential to become a living hell due to ignorance of what it is or what to do about it. The safest things we have at our disposal are oxygen, improved methylation, stress reduction and various antiinflammatory strategies, including addressing insulin problems and doing whatever possible to heal the leaky gut, a key factor. My early practice experience with a small number of patients is that these strategies are effective for reducing the degree of suffering.
Speaking of gut inflammation, our family is working on our diet. Patients who have tried everything for many years are often resistant to changing diet. It is so much more work than just about any other therapeutic intervention you can come up with. Physical work is a problem for the patient group and eating well is more work. Also the results of dietary interventions are usually slow. Food is gratification when everything else goes to hell. But you are what you eat. I advocate a whole foods, unprocessed, organic, if possible, diet that restricts sugar. Wash any sprayed produce carefully. Avoid chemicals, especially the excitotoxins MSG and aspartame. I tell my patients to read ingredient lists and don’t buy it if there are things in it that you don’t know what a handful of it looks like. The average American consumes pounds of chemicals a year. Whether there is a retrovirus or not, the disease doesn’t kill directly, life can go on for a very long time and the quality of life of human beings is dependent upon what they put in their mouths.
A member of my husband’s family brought my attention to a film called Forks Over Knives, available on instant Netflix. It proposes a vegan diet as the way to health. I was a vegan for a few years when I was young, and whether it is or isn’t a healthy lifestyle, the premise put forth in Diet For A Small Planet in 1971, which seemed true to me way back when, is still a good argument for not eating animals, but ethical considerations and attempts to save the planet aside, the movie doesn’t draw the correct conclusions from it’s own observations in my opinion, or at least it doesn’t prove it’s premise. It is just as likely that the avoidance of the sugar, chemicals, hormones and antibiotics involved in the eating of meat and processed foods in our culture is at the bottom of the adverse health consequences of our modern diet, not meat in and of itself. Still the movie is worth watching if you are thinking about food, and the review found here: “Forks Over Knives”: Is the Science Legit? is also worth a look.
I had a Crohn’s diagnosis at one point and spent a summer on TPN (total parenteral nutrition) before being saved by a surgeon. Afterwards, the diet that facilitated healing most was the SCD or Specific Carbohydrate Diet. It is based on the premise that the inflamed gut is harmed by exposure to disaccharides and polysaccharides, contributing to dysbiosis. It allows some simple sugars. It eliminates grains and dairy products, except for hard cheese and SCD yogurt, superfermented for 24 hours to break down the lactose. SCD yogurt is an excellent probiotic, unless you are cassein sensitive. The list of SCD legal/illegal foods is here. My family is cheating with brown and wild rice. It’s tough for me to keep weight on and I am grateful to my daughters for supporting this now, since I have a hard time doing the right things for myself. It has much to do with the many years of ritual abuse involved in becoming and being a doctor. I was trained to overlook the needs of my own body and carry on no matter what, relying on magical thinking to keep going:). It isn’t working too well for me now. A bit late in the game for repatterning, but I guess it’s never too late to learn, or at least I hope not.
It has been a long time since anything went right with respect to the fiasco at the WPI, but this evening, the tide appears to be turning. The terrible injustice that was done to Dr. Mikovits has been righted at long last with the dismissal of the charges against her. I guess somebody’s enthusiasm for jailing scientists is waning with the growing fishy smell coming from the direction of the accusers.
Writing this, I see people celebrating on FaceBook, friends of Judy’s from all over the world. As we held our collective breath, we can exhale again. Our most dedicated scientist and loyal friend is free once more; may her brave and genuine heart find its way back to the work so cruelly taken from her. And from us. The justice system is meting out a little justice for a change, even while the people who did this continue to suck up a significant percentage of all the dollars the US government spends on our disease, apparently so they can pay for all their lawyers.