- 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.