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

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

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

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

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

Michael Snyderman, MD

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

Introduction 

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

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

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

Results

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

Discussion

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

The greatly increased risk for B-cell malignancy in a potentially HGRV/MLRV infected population may be due to infection of the B-cell line by the HGRV/MLRVs. Retroviruses have been thought to cause cancer by insertional mutagenesis. This mechanism requires that the retrovirus proviral DNA be integrated into host cell DNA next to a proto-oncogene thereby inducing activation of the proto-oncogene. A more important mechanism with MLRVs may be the ability of viral proteins to change host cell gene expression. Twenty-four to forty-eight hours after a permissive cell line is infected with XMRV, multiple cellular genes are expressed: “10 genes are implicated in cell morphology, 11 genes in cellular development, 12 genes in cell-to-cell signaling and interaction, 11 genes in cellular movement and 13 genes in cellular growth and proliferation” [17]. Spadafaro has shown that reverse transcriptase can cause gene activation and lead to the malignant phenotype [18]. In some retrovirus related cancers, Env [19] and Gag [20] may also be important in malignant transformation.

The finding that XMRV did not cause malignant transformation de novo in tissue culture [21] would be irrelevant to the clinical reality of human cancer. It is accepted that multiple events are necessary to convert a cell line into a pre-neoplasm or a clinically important neoplasm. Human cancers have mutated genes and changes in gene expression that could make them permissive to infection by retroviruses. The retroviruses could induce further changes in gene expression that would make the infected cell line behave in a more malignant fashion. The corollary to this is that treatment that would block viral protein influence in a neoplastic cell line could make the neoplastic cell behave in a less malignant way.

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

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

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

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

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

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

References

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

Click figures to enlarge:

Figure 1

Figure 2

Figure 3

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

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

click to enlarge

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

And now we have the Rituxan study from Norway:

• Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series 
• Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

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

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

• Changes in B and T lymphocytes and chemokines with rituximab treatment in multiple sclerosis. Piccio
• The anti-CD20 antibody rituximab reduces the Th17 cell response. van de Veerdonk 
• A dose-escalation study of rituximab for treatment of systemic lupus erythematosus and Evans’ syndrome: immunological analysis of B cells, T cells and cytokines. Tamimoto
• Rituximab infusion induces NK activation in lymphoma patients with the high-affinity CD16 polymorphism. Veeramani
• Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Bar-Or

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

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

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

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

Dr. Michael Snyderman’s comments of this morning:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dear Jason, 

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

“In the beginner’s mind there are many possibilities, but in the expert’s mind there are few.”
~ Shunryu Suzuki

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

I don’t think that you can fully consider the hypothesis without understanding the pathophysiology of CFS, autism, Gulf War Illness, Lyme Disease. Also human and animal retroviral disease. The veterinary literature is very telling. What you will find when you start to look into viral etiology of CFS is literature proving it isn’t EBV or HHV-6. There is nothing but the recent furor to connect CFS to retroviruses. Other than Michael Snyderman’s data, published as a poster presentation. So the only choice is to start with a hypothesis and work backwards. Please bear in mind, I am a doctor, not a scientist. I sit in a room with people who want to die because they have lost everything, are suffering unbelievably and are laughed at by doctors and scientists. Imagine having the worst day of flu of your life and having it never go away (not the way I got sick btw). Then maybe a hundred other horrible symptoms, pain, nausea, intractable headache, chronic cramps and diarrhea, sleep deprivation. Then your doctor sends you to a psychiatrist who says you are too focused on your symptoms. Cowboy up. Only you can’t even sit up. Then your kids and husband start getting sick too, and nobody cares. 
 
I have never claimed to be ‘objective’. It was an ah-ha for me. A 15 year mystery, that almost cost me my life (transfusion, emergency surgery, small bowel resection at midnight, TPN), beginning to give up its secrets. A mystery that ended any chance for a normal life for my beloved daughter at 13. I am tearing up as I write this, thinking of what she was like when she was the size of your precious baby. Not that she isn’t wonderful now, but her life is so diminished compared to the one she could have had. I was 41 and a successful doctor, so I had something to fall back on each time I’ve recovered enough to do something, but the kids who get sick in adolescence never get to live at all. The second generation is sicker. The youngest person I’ve heard of with CFS is 4, not autism, CFS, 3rd generation. Grandma is very sick. Mother, a doctor, a little sick. Doctors and nurses are over represented in the patient group. Also vets. You should be able to share in my outrage at the lack of epidemiological studies, since it doesn’t impact your field, once you start to hear what the patients are saying about their families (some on my blog). I am looking forward to your figuring out how little money has been spent on a disease that affects so many and causes so much disability. You wouldn’t believe the untapped talent in my mail. 

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

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

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

The ‘souless freak’,
Jamie 

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

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

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

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

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