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.

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

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.”

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.

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

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.

The apparently concerted effort to deny patients an answer or treatment for our disease continues. Science Magazine published two negative papers today, along with an Editoral Expression of Concern, or EEC. Dr. Mikovits was informed on Friday, before Memorial Day weekend, though the second of the two papers was accepted for publication on May 15. The co-authors of Lombardi et al have unanimously refused to retract.

Here is Dr. Mikovits’ response to the EEC, link, Annette Whittemore’s response, link, and the response of the WPI’s Clinical Advisory Board, link, sent to Science over the weekend.

The timing of the EEC seems “premature”, to put it mildly, with Dr. Lipkin’s and Dr. Maldarelli’s findings still pending. There is nothing new in either paper that should have precipitated this.

I receive many questions about why Dr. Peterson is no longer working with the WPI, which I have generally tried not to answer, because I wasn’t there. But, as of today, I think it safe to say that not only is he not working with us, the people he is collaborating with seem intent on destroying the institute that bears his name. I am in the middle of it, and it is unfathomable to me. I have never met Dr. Peterson, but here is my best guess, as the one following in the wake of this attempt to destroy the institute. It has to be all about intellectual property, and revenge. Nothing else makes sense. Why would he provide already tested specimens to Konstance Knox, who has a vendetta against the WPI? Knox worked as a consultant for VIP Dx and left under “difficult circumstances” related to her business practices. Science should have been aware of this history and made a serious inquiry of it. They were alerted to it, but proceeded to publish this morning anyway.

Taking the sordid details out of it, the Knox paper is yet another entirely negative paper where they proved they couldn’t find it in anyone. Again, there was no real attempt to replicate Lombardi et al, only the innuendo that it was somehow disproved by this paper, by virtue of it being Peterson who provided the specimens. How could Science, a premier journal, publish such shoddy work, sloppier than the Singh paper, though with the same logical fallacy? It can’t be both a contaminant and not there at the same time. Which is it? The totality of the evidence says neither. Why is no one asking the real question? How is it that VIP Dx finds approximately 4 out of 10 patients positive, not zero and not 100%? How do you explain contaminating only some of the specimens in the same run?

And why do all of these scientists feel compelled to practice medicine without licenses? When Konstance Knox gets sick from the infectious contaminants in her lab, shall the doctors remind her that she said to the press that patients shouldn’t have the right to try antiretroviral drugs for the viruses that she is too incompetent to find (or wasn’t really trying to find in the first place)?

Why would scientists who know better reach obviously incorrect conclusions about their own work? Why would anyone want to make XMRV go away, when there’s so much smoke? The money involved is enormous. Did anyone notice that a few of the co-authors on the Knox paper work for Abbott Diagnostics? Do you think Abbott would like to own The Test?

It may be that the sequence diversity from patient to patient is too large to detect by PCR for a particular strain of HGRV (human gamma retrovirus). Replication competence probably involves recombination events. It may be that it isn’t even a few viruses, but many. PCR only finds what it’s looking for. It is going to require rapid deep sequencing. The science is up to that technology, but it is still too expensive to use on the likes of us. They’ve sequenced the entire mitochondrial genome of a Neanderthal. When will they take a look at ours?

So if they make it go away, they can rediscover it later, with enough sequence variation to call it something else. And while the vultures fight over the carrion, new babies are born with it, teenagers are collapsing with an incurable illness and old people are dying prematurely, after decades of relentless suffering without help. Today is 600 days since Lombardi et al was published. It is shameful. Please express your outrage to Science.

The following quote was posted in the comments of the last blog, as Dr. Myhill paraphrasing Dr. Cheney. I am not guaranteeing the accuracy of the quote, or who said what exactly, but the ideas expressed are rampant in the ME/CFS world, and are completely illogical and incorrect in my opinion.

“Oxygen is clearly vital for efficient aerobic metabolism. It allows us as human beings to function at speed and this has massive evolutionary advantages. However, if we cannot handle oxygen this would result in massive pro-oxidant stress and we would quickly collapse and die. So what we actually do when we cannot handle oxygen is that we switch back into safe but slow anaerobic metabolism and hope that our body can repair its antioxidant defences quickly so that we can get back to normal life again. Almost certainly this is the mechanism of fatigue after any exertion whether that be the normal exertion of daily life, an acute illness, acute physical exertion, or whatever. Essentially if we cannot handle oxygen we switch back into safe, but slow anaerobic metabolism and effectively we mimic life as a foetus. As I say we have to do this because if we do not recover our antioxidant defences we die from oxygen toxicity! One example of how toxic oxygen can be – if you give 100% oxygen to a new born baby they will quickly go blind.”

The problem is not that we cannot handle oxygen, it’s that there isn’t enough oxygen getting into our cells, in particular, our mitochondria. We switch to anaerobic metabolism because the oxygen that is there gets depleted too quickly. We are unable to produce adequate ATP to sustain aerobic activity, because oxygen is required to produce it. Oxygen must reach the mitochondria of each cell from arterial blood by diffusion along a pressure gradient. With HBOT the partial pressure of oxygen is increased in the plasma. With additional pressure, oxygen, essential for life, is pushed deeper into ischemic tissues, or, more importantly for us, pushed harder into cell compartments, facilitating entry through even damaged membranes.

I did my third mild hyperbaric oxygen treatment yesterday. I breathed twice as much oxygen as normal, ~39%, instead of 21%, with pressure, the equivalent of scuba diving at ~9 feet of sea water, and I didn’t “collapse and die”:). Far from it. I felt wonderful during and after the treatment. Normobaric oxygen helps me too, but this was much more noticeable. The most obvious change was improved sleep after the second and third treatments. I have been sleeping well lately, and even dreaming, but it has gotten even better the last two nights, deeper and more restorative, with long, vivid, complex dreams, after no dreams for many years, then more anemic ones recently. I feel really good, almost well, as I write this. If I look at it in three month increments, my continued improvement is easy to see. My stress tolerance in particular is vastly improved from even a few months ago. I am not the same person I was when I began treatment for XMRV 15 months ago.

There is a tremendous amount known about oxygen toxicity, because of scuba diving. I’m rusty with the calculations, but the treatment I did is safe for many hours without any risk of oxygen toxicity. Assuming that CFS patients are more susceptible to oxygen toxicity than normal people, there is still a very large margin for error, even for the sickest patients.

Retinopathy of prematurity is often used as an example of oxygen being dangerous, not that this is in any way a good analogy of what happens with exposure to hyperoxia in anybody other than premature infants. We are not fetuses. ROP occurs only in the context of undeveloped blood vessels in the retina. Exposure to too much oxygen at that stage of development causes overgrowth of the developing vessels in the retina, a problem not seen in term infants. That doesn’t mean that premies don’t need oxygen, only that it needs to be carefully dosed, maintained at a constant level, and carefully weaned.

All of this reminds me of the mumbo jumbo always rampant in the alternative medicine world. Usually somebody gets stuck on a wrong idea and a whole bunch of people get treated with something harmless. In this case though, the wrong idea has caused a whole bunch of people not to try something that could in fact help. Actually, that’s happened before also, e.g. the Marshall Protocol’s misguided ideas about Vitamin D avoidance. I don’t mean to be hard on the alternative doctors, who have had to function as the doctors of last resort for patients with very difficult problems, practicing in a vacuum, unsupported by the rest of the medical community.

So, how to access oxygen? Oxygen requires a prescription. It can be delivered by tank or concentrator, which pulls it from the air. Here in Santa Fe, most recently I paid $15 for a tank of oxygen, out of pocket. Insurance will sometimes pay for oxygen for migraines.

The recent paper describing MRI changes in the brainstem in CFS patients supports the use of mild hyperbarics as part of an approach to treatment. A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis. Barnden

HBOT also requires a prescription. Hospitals charge usurious rates which are subsidized by insurance companies for a very narrow range of indications. I haven’t checked recently, but the going rate for private chambers in the US when I left practice 7 years ago was about $150 a treatment. The company I rented my chamber from, Genox, has a rent to own program. It is owned by Lance Brubaker, a Lymie scuba diver who discovered the benefits of HBOT for himself in the 90’s, first with hard, then with soft chambers. The smallest chamber, which is pretty small, but should work fine if you’re not claustrophobic, costs $6900 or $690/month for 10 months, plus the cost of a concentrator, $1500 new, or maybe $200/month. A series of 60 treatments in 2 months, and shipping both ways, comes out to about $45/treatment, to find out if it helps you. If a group shares a chamber, and the costs of training, it’s possible to make it quite inexpensive.

I’m very impressed with how simple and elegant my chamber is. I have no resistance to going in, because it is so easy and comfortable. There is always a tension running a hard shell chamber that isn’t there with this set-up. The low ambient oxygen tensions and low pressures involved minimize the risk. Following a few safety rules is all that is required. The treatment is restful, like being in a safe cocoon. The new plastic smell is gassing off quickly and then Ali will try it. Warning: Proper training is necessary. There is always an increased risk of fire when working with an enriched oxygen environment.

Although the medical care available to our fellow sufferers in the UK is largely barbaric, there is safe, extremely inexpensive HBOT available there, at least for MS, and someone who has availed themselves of the Hyperbaric Trust’s charity chambers posted in the comments that they treat other neurological disorders as well. Phillip James, MD, the founder of the Hyperbaric Trust was one of my heroes when I was in practice (link). He had done a tremendous amount of thinking about the question of oxygen and the premature retina, with respect to outcomes in cerebral palsy. I hope he is well.

It is a very sad state of affairs that something so safe and easy has been denied to patients trapped in relentless suffering, while ineffective, or harmful, pharmaceuticals are passed out like jelly beans by conventional doctors who know nothing about the disease. Eye of newt would be better than what we’ve had. Snake oil, it turns out, is good for you, very high in omega 3’s.

I knew when I posted something positive about the use of oxygen for ME/CFS, I would hear about Dr. Cheney’s views on oxygen toxicity, just as I heard about his views on the use of Klonopin, when I said that I am opposed to any avoidable use of long term benzodiazepines (understanding full well that sometimes it can’t be avoided). I disagree with Dr. Cheney about a lot of things. Gasp! And agree with him about others. I am in the process of launching a Physician Working Group for the WPI and Dr. Cheney will of course be invited. It is wonderful that he and I can disagree and are going to work together to figure it out. There are going to be lots of other people who disagree with me, and each other, about many things. In fact, I’d say, there is absolutely zero chance for consensus in the group I’m putting together, but I am hoping for a melding of minds, nevertheless, for the betterment of patients. One thing I am sure of, we all want the same thing, to help people get well.

My understanding, from email communication with Dr. Cheney some time back, is that he is looking at one parameter, IVRT, of one organ, the heart, by echocardiogram, after administering low-flow oxygen by nasal cannula, as well as exposing patients to other substances in sequence. If I put an oxygen cannula on your face, at a time when you are under stress, and your IVRT, a measure of diastolic function gets worse, what does that mean? Hyperoxia causes vasoconstriction in normal tissues, so a compromised circulatory system might look worse at that moment. So what? I talked about and referenced all the reasons why repeated exposure to higher than normal amounts of inspired oxygen might be a good idea over the long haul, even if the treatment produces a few more free radicals than usual, for which antioxidants can be given. Free radicals are necessary for life, involved in intracellular killing by phagocytes and redox signaling. In hyperbaric wound care, high doses are needed to produce free radicals to kill bugs.

Dr. Cheney described a reaction to oxygen, in which patients become anxious or even obtunded, which I don’t understand. I administered very large doses of oxygen to chronic Lyme patients, who in hindsight had ME/CFS, and lots of patients with other diagnoses, including a couple of post-stroke COPDers with CO2 retention, and never saw anything like what he described, even in a very claustrophobic environment, the inside of a multiplace hyperbaric chamber, that looked kind of like a submarine (link to photos here and here of our chamber at New England Hyperbaric Center 1999). Nor did I ever see anything like that in many years of high volume emergency medicine practice, except in acutely decompensating chronic COPD patients.

The idea that the cells of ME/CFS patients utilize oxygen in such a different way from all other animal cells such that doses safe for other humans would somehow be dangerous for us seems ludicrous to me. I’ve gotten a bunch of confused mail about how ME/CFS patients have “high oxygen” already and more is toxic to them. CFS patients have normal oxygen saturation, O2 Sat, in the blood, meaning the carrying capacity of hemoglobin is normal. Oxygen travels from the arterial blood into cells by diffusion along a pressure gradient. The issue in ME/CFS is cellular hypoxia, meaning the interior of the cells are starved for oxygen and the mitochondria can’t generate ATP properly, due to poor mitochondrial function. So no gas in the tank. The mitochondria are the energy factories of the body and they are mucked up, still producing enough energy for life through the same chemical processes utilized by all eukaryotic cells, but with an inadequate supply of substrates necessary to generate ATP, and inadequate reduced glutathione to prevent damage by free radicals and other reactive oxygen species. Sometimes I wonder if it is more diabolical than gunked up machinery, that the virus doesn’t like oxygen and therefore causes the host not to be able to move. I presented the evidence in the literature for the use of oxygen in autism. Since I believe autism is essentially the same disease as ME/CFS acquired earlier in life, with the same mitochondrial problems, it seems logical to try mild HBOT for ME/CFS, especially in light of the very low risk of harm.

At the time that I left hyperbaric practice, I was worried about the possibility of an explosive decompression, a potentially lethal event, in a soft chamber, as they are not rated for hundreds of compression cycles. I was opposed to home treatment on that basis, not because of any inadequacy of the treatment. Since then, my understanding is that there have been more than 10,000 FDA approved soft chambers sold, and the thing I was fearing hasn’t happened. If they leak, they give at the zipper and don’t lose pressure suddenly. The only serious accidents have been related to modifications made to allow higher than rated pressures. There are risks, even to mild hyperbarics, and nobody should undertake it without training from a professional, but it’s not that hard, once you get the hang of the concepts.

Whatever is happening with respect to the length of diastole when oxygen is administered, it seems to me that we should be worrying more about the brain than the heart in light of the clinical course of most patients. The brain is very sensitive to ischemia. Whatever the oxygen saturation in the blood, ischemia can be present downstream of vascular spasm. That’s what I was addressing with some of the literature I posted. Not that we are having strokes, but that some of the cognitive issues may come from repeated localized ischemic insults, mini TIAs (transient ischemic attacks), during periods of vascular spasm. It seems rational to me to combat that with oxygen.

This is a blog, evolving opinion, not a statement of fact. I am sharing my thoughts, before even trying things in the present context, before proving anything. I am, however, putting my money where my mouth is, and I will continue to share our unfolding experiment in real time. I do this, not because I am trying to convince anyone that I am right. I could be wrong about anything. I am sharing my thinking as it happens, because we are in uncharted territory and there is so much suffering and desperation. None of us have years to waste. I have experience to tap in to and there is shockingly little information available when considering options. But at no time am I suggesting that anyone else should do what we are doing.

I posted our planned infusions, before knowing the outcome, as I’ve done all along with everything. Some of it for me is an attempt to learn from others, because patients and doctors write to share their experiences and ideas. We have done similar infusions in the past that were not noticeable or effective, concurrent with antibiotics for Lyme Disease. We did our first infusion of the formula I posted yesterday and we are working out the kinks with our doctor. Surprisingly, at least to me, we did feel it, Ali positively, me, not so positively thus far. I’ll let you know. I don’t want to start tweeting, but I put it out there last post thinking that it could only be positive or nothing, and I may want to reconsider that, though I still expect that any adverse effect would be mild and temporary. My sleep was disturbed last night and I was kind of wired today and not as stable as I have been. My guess is that it was from the Leucovorin, a folic acid derivative, the only component I haven’t been exposed to before. Deplin can cause similar adverse reactions which are dose related. I find it encouraging that the infusion was noticeable to both of us, but the formula needs tweaking.

As you might expect, I’ve been doing a lot of thinking about MCS these days, at least in the form that Ali is having it. I was speaking to the father of a patient today who is having severe light and sound sensitivity, much like the very severe patients in the UK and Norway. Ali is being triggered by smells, even natural smells like essential oils. My light bulb for today was that these problems are all very similar, all extremely heightened responses to different sensory stimuli. My first symptom was heightened and altered sense of taste. Many patients, and autistic children, have problems with touch, can’t stand tags in clothing, are hypersensitive to light touch, etc. I suspect it’s a kindling phenomenon, less than seizures, but similar, a little less than a full blown disease, as often happens in ME/CFS. Networks of neurons are being synchronized inappropriately by sensory triggers. Repeated stimulation leads to threshold reduction. I am not saying that biotoxins or petroleum products aren’t the trigger for some, but it doesn’t look to me like that’s what’s happening to Ali. It changes my thinking about how to approach it. If it’s a problem with detox and being unable to handle total toxic burden, one set of possible solutions, but if it’s being set off by smells, it’s the response that needs to be attenuated. I am not saying that we aren’t decontaminating and restructuring things so that she can avoid being triggered, which is a big task for an already over-taxed family, but it isn’t possible to be in the world and avoid smells. It is making me think about neurofeedback again. Another topic for another day…

My improvement seems to be continuing, even at altitude. I had an episode six days ago that was probably a sugar reaction, not common for me anymore. I was sick for a couple of hours followed by a kind of sleep I call “coma”. Other than that, I have been remarkably stable. The travel didn’t cost me much at all. I went out for dinner with my husband last night and realized it was the first night out I’ve had in years where I just had fun without struggling at all, after working most of the day. No faking being all right or overlooking symptoms in order to appreciate the moment.

Ali has been struggling with MCS (multiple chemical sensitivity), as a new symptom cluster. She’s had little bits of it before, but nothing like this. It was triggered by an exposure to a new cat litter about a month ago. Since then other chemicals have been triggering her, especially deodorants, perfumes, laundry products. The episodes aren’t medically scary, but involve a dramatic mood shift to blacker than black, ill-defined intolerable, sick feeling. No POTS symptoms particularly, or anything else really. The odd thing to me is that otherwise, she is doing well. Not much OI (orthostatic intolerance). Baseline mood pretty good. With avoidance of the things triggering her, she actually feels fairly well and would be thinking of getting out of the house, but for now, any outings are particularly threatening and would need to be outdoors. We are dealing with eliminating the things she needs us to from the environment.

MCS is a horribly isolating symptom. It makes a hug dangerous. It affects everyone in a household in a more direct way than other symptoms. It comes with tons of psychic overlay. Easy to disbelieve. Looks psychiatric to the uninitiated. Very, very difficult to be a canary in the coal mine.

We recently ran a bunch of labs that were not particularly illuminating, other than our Vitamin D levels are still very low despite replacement. We both still have macrocytosis from AZT, but less than before, expecting it to take 6 months overall to get back to a baseline, because that’s how long it takes to replace all of your red blood cells. Neither of us have serology suggestive of activated EBV, HHV6 or CMV. I have completely negative serology for EBV, strangely given all my years in the ER. We both had high IGF-1’s at baseline, normal now. Ali’s PCOS parameters have improved on treatment (lower LH/FSH ratio), as has my blood sugar on Actos (fasting glucose from 110 to 93, non-fasting from 140 to 110). IgG subunits were normal, my IgG and IgM borderline low. C4a’s and TGF beta-1’s were lost, again; we need to have them redrawn. We’ve been planning to send cytokine and NK cell profiles, but we don’t have baselines, so I doubt that it will tell us much we don’t know.

Our baseline labs consisted of extensive hormone testing and Richie Shoemaker’s panel, which includes all of the very few tests we’ve had that were abnormal in the past, outside of TBD (tick borne disease) testing, and a few fleeting auto-antibodies; I’ve had a mildly elevated nucleolar ANA and we’ve both had mildly elevated anti-cardiolipins. TGF beta-1 was the only test we found that was very high for both of us. When I first learned of the virus, I expected that there would be a viral load measure, but it seems all we have to monitor is downstream effects.

I’ve been receiving questions about my meds. Except for stopping AZT a couple of months ago, nothing has changed significantly since I last reported. I’ve fiddled with my hormones a little. Tried natural menopause for a little while, but it wasn’t pretty, convincing me that bioidentical HRT (hormone replacement therapy) is very important for me. Here’s my current regimen, once daily unless otherwise specified:
Viread 300mg 
Isentress 400mg twice
Cozaar 100mg
Actos 15 mg twice
Deplin 7.5mg
B12 5000 units chewable
Armour thyroid 30mg for years, now 15mg
Estradiol cream 5mg
Testosterone cream 2mg
Prometrium 200mg
Selegilene .5mg cream
Low dose aspirin
Sublingual Zofran 4mg prn nausea
Topical D3 10,000 units, now increasing and adding oral
Meriva SR, undenatured whey protein, L carnitine, glutamine, ALA, Vitamin C, CoQ-10, irregularly
Specific Carbohydrate Diet yogurt, super-fermented to reduce lactose, included here because I think it is a valuable treatment in the setting of inflammatory bowel problems: Making SCD Yogurt

We are both planning to step it up again with supplements, including some we haven’t tried before. It’s a big subject. I will post about this soon.

In consultation with our family doctor, Ali and I are about to start weekly intravenous pushes consisting of a modified Meyers’ cocktail and glutathione. Here is the formula we are planning to use:
Vitamin B complex – 100
Dexpanthenol 250mg
Hydroxocobalamin 5000mcg
Pyridoxine HCL 100mg
Leucovorin (folinic acid) 10mg
Vitamin C 500mg
Magnesium Chloride 800mg
Second Push
Glutathione 2000mg

We have also decided to rent a mild hyperbaric chamber (aka soft chamber, altitude sickness or Gamow bag) and supplement with an oxygen concentrator via mask. This safe technology delivers up to 90% FiO2 (fraction inspired oxygen) at 1.3 ATA (atmospheres of pressure), by non-rebreather mask, with a 10 L/min oxygen concentrator. I’ve been meaning to write a post about oxygen for some time. Because of the observation that CFS patients have redox problems (elevated free radicals), some practitioners think that the use of even low dose oxygen, which produces free radicals during administration, is toxic in this setting. I even heard from a patient that they had been afraid to take oxygen when they were in the ER for chest pain. This seems to be completely incorrect thinking to me. Regardless of the downstream difficulties, oxygen is essential and you have to feed the stream, especially in the face of tissue hypoxia and vascular instability, a hallmark of the disease, causing local ischemia. There are too many anecdotal reports of benefit from low flow oxygen, without added pressure, during downswings, to ignore. It is a very simple, safe thing to try. Supplemental oxygen has helped me through some bad moments. I saw too many benefits from HBOT (hyperbaric oxygen therapy) in practice with related chronic conditions, including autism and chronic Lyme Disease, to dismiss it now.

• Normobaric hyperoxia therapy for traumatic brain injury and stroke: a review. Kumaria 
• Normobaric hyperoxia–induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study. Tolias
• A prospective, randomized clinical trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism, intracranial pressure, and oxygen toxicity in severe traumatic brain injury. Rockswold  
• Oxygen therapy in acute ischemic stroke – experimental efficacy and molecular mechanisms. Poli

Administering oxygen is one of the most powerful supportive interventions that we have. Repeated doses of hyperoxia has a salutary effect on the injured brain, whether the injury is ischemic, demyelinating or traumatic. Used therapeutically, repeated exposure to oxygen under pressure is antiinflammatory and antimicrobial. HBOT produces revascularization of ischemic tissues and may encourage mitochondrial biogenesis. Oxygen is regulated like a drug, the argument being that if the dose is high enough, it can kill you, although so can too much water. High dose oxygen can cause CNS hyperexcitability (seizures) in susceptible people. HBOT is “approved” for 13 indications that are treated in hospitals. Approved means reimburseable. Hospital hyperbaricists can be pretty territorial, but using it beyond the approved conditions is legal off-label use of a drug, like using antiretrovirals approved for HIV to treat a different retrovirus, and like the majority of prescriptions written. HBOT probably has broad applicability and nobody wants to pay for it. The technology isn’t patentable, so it hasn’t been studied and optimal dosing for various applications is largely unknown. 

The following papers provide important clues for ME/CFS. The last link will take you to slides of Dr. Rossignol’s lecture for the Autism One conference, this coming week.

• Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Rossignol/Frye
• The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study. Rossignol/Mumper 
• Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial. Rossignol/Mumper 
• Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism. Rossignol 
• Oxygen-induced mitochondrial biogenesis in the rat hippocampus. Gutsaeva/Piantadosi 
• Hyperbaric oxygen therapy may improve symptoms in autistic children.
• Dr. Rossignol’s slides 

Dr. Rossignol’s work seems to me to be hitting on all cylinders. He is beginning to explain why clinically there is an independent pressure effect, since the pO2 (partial pressure of oxygen) for the treatment he is using (FiO2 24% 1.3 ATA) can be reproduced with normobaric oxygen delivered by mask. He is also working on the methylation block question, and his work is suggesting that rather than, or in addition to, a conversion defect, it is yet another (in a long list) of receptor insensitivities, eg insulin, LH, Vitamin D and leptin, overrepresented in ME/CFS patients. This is beginning to get to the heart of the methylation defect. It should be remembered, that methylation is important for retroviral latency.

There are two related neuroimmune diseases with which we already have significant HBOT experience:
   Autism. I personally had wonderful experiences treating autism with low pressure HBOT. Autistic children have many of the same metabolic problems that ME/CFS patients do, including the mitochondrial defect. They have similar brain vulnerabilities as well. I treated children who demonstrated remarkable cognitive gains and improved sensory processing over a very short period of time.
   MS. In the UK there is a network of charity chambers, salvaged military chambers that aren’t rated to go to the depth required to treat wounds or acute carbon monoxide poisoning. At the time I closed my chamber, they had done more than a million treatments over a couple of decades. Their experience is completely uncontrolled. But it’s not that much fun, and people don’t keep doing it for years and years if they aren’t pretty sure it’s helping. There were a couple of studies that indicated benefit, but a negative Cochrane report shut down serious study. Also there’s a medical society, called the UHMS, controlled by the insurers, that exists to be sure nobody gets HBOT for anything but a short list of reimburseable conditions. They also want to make sure that nobody gets treated in anything but a hard chamber, declaring on their website that HBOT requires 1.4 ATA when soft chambers are only rated to go to 1.3 ATA. Rather transparent I would say.

Here is a potpourri of literature that in my opinion collectively support the use of HBOT as part of a coherent treatment strategy for ME/CFS:

• Hyperbaric oxygen therapy in Thai autistic children.
• Hyperbaric oxygen therapy improves spatial learning and memory in a rat model of chronic traumatic brain injury. Harch
• Evaluation of hyperbaric oxygen treatment of neuropsychiatric disorders following traumatic brain injury. Shi
• Chronic hyperbaric oxygen treatment elicits an anti-oxidant response and attenuates atherosclerosis in apoE knockout mice. Kudchodkar
• Hyperbaric oxygen treatment attenuates the pro-inflammatory and immune responses in apolipoprotein E knockout mice. Kudchodkar
• HIV: reactive oxygen species, enveloped viruses and hyperbaric oxygen. Baugh
• Hyperbaric oxygen treatment induces antioxidant gene expression. Godman
• Involvement of the mitochondrial ATP-sensitive potassium channel in the neuroprotective effect of hyperbaric oxygenation after cerebral ischemia. Lou
• Oxygen therapy in stroke: past, present, and future. Singhal
• Effect of large dose hyperbaric oxygenation therapy on prognosis and oxidative stress of acute permanent cerebral ischemic stroke in rats. Xue
• Hyperbaric oxygen preconditioning induces neuroprotection against ischemia in transient not permanent middle cerebral artery occlusion rat model. Xiong
• Optimal dosing as a necessary condition for the efficacy of hyperbaric oxygen therapy in acute ischemic stroke: a critical review. Rogatsky
• Effect of hyperbaric oxygen on the expression of proteins Bcl-2 and Bax in the gerbil hippocampus CA1 following forebrain ischemia reperfusion. Zhou
• Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI. Schäbitz
• Integrated brain restoration after ischemic stroke–medical management, risk factors, nutrients, and other interventions for managing inflammation and enhancing brain plasticity. Kidd
• Effects of hyperbaric oxygen exposure on experimental hepatic ischemia reperfusion injury: relationship between its timing and neutrophil sequestration. Kihara
• Hyperbaric oxygen therapy for reduction of secondary brain damage in head injury: an animal model of brain contusion. Palzur
• Low pressure hyperbaric oxygen therapy and SPECT brain imaging in the treatment of blast-induced chronic traumatic brain injury (post-concussion syndrome) and post traumatic stress disorder: a case report. Harch
• Hyperbaric oxygen in the treatment of patients with cerebral stroke, brain trauma, and neurologic disease. Al-Waili
• Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients. Rockswold
• Effects of hyperbaric oxygen therapy on facial nerve regeneration. Vilela
• Hyperbaric oxygen limits infarct size in ischemic rabbit myocardium in vivo. Sterlin

We know that changing the environment, internally, externally, in this way or that, has made the difference for some people. We also know that there are many people who stay relatively well, at least well enough to function, doing nothing at all, except living their lives within the limits of their disease. I speak to many patients who have had essentially no medical care for years who describe what for ME/CFS is a pretty good course, stable with periods of very mild symptoms only. That makes it unwise to choose a therapy that might do significant harm. Or at least, save the heroics for the sickest patients. It is ironic that using extra oxygen is more questionable than prescribing dangerous drugs for symptom relief. There was a time when prescribing B12 shots was tantamount to quackery, but how many ME/CFS patients have been helped by B12 shots? Lots. When I was in practice, I was struck by how controversial it was to prescribe oxygen for an autistic child, but SSRI’s, tricyclics, benzodiazepines, speed, whatever pharmaceutical was acceptable. I was also struck by how much some patients improved just by stopping medications. When things are going south, always consider what you can stop. I can’t know of course if this next leg of the journey will help us or not, but I’m pretty sure that it won’t hurt, except in the pocketbook. I’ll keep you posted.