A mouse leukemia retrovirus, xenotropic murine leukemia virus-related virus (XMRV retrovirus), has been under consideration as a possible cause of chronic fatigue syndrome (CFS, and also prostate cancer). In a study published in Science in October 2009, Lombardi et al. found XMRV in 67% of CFS patients and 3.7% of controls. Several subsequent studies in the UK, the Netherlands, and the US — by lead authors Erlwein, van Kuppleveld, Groom , Switzer and Henrich — failed to find XMRV at all.
Now a new study published in Retrovirology by Hue et al. shows that the original positive findings were likely erroneous and due to contamination in the lab. The complete article is available online.
We provide several independent lines of evidence that XMRV detected by sensitive PCR methods in patient samples is the likely result of PCR contamination with mouse DNA and that the described clones of XMRV arose from the tumour cell line 22Rv1, which was probably infected with XMRV during xenografting in mice. We propose that XMRV might not be a genuine human pathogen.
During the most recent kerfuffle about whether or not Evidence-Based Medicine can legitimately claim to be science-based medicine, it became clear to me that a whole, new round of discussion and documentation is necessary. This is frustrating because I’ve already done it several times, most recently less than a year ago. Moreover, I’ve provided a table of links to the whole series at the bottom of each post*…Never mind, here goes, and I hope this will be the last time it is necessary because I’ll try to make this the “go to” series of posts for any future such confusions.
The points made in this series, most of which link to posts in which I originally made them, are in response to arguments from statistician Steve Simon, whose essay, Is there something better than Evidence Based Medicine out there?, was the topic of Dr. Gorski’s rebuttal on Monday of this week, and also from several of the comments following that rebuttal. Mr. Simon has since revised his original essay to an extent, which I’ll take into account. I’ll frame this as a series of assertions by those who doubt that EBM is deficient in the ways that we at SBM have argued, followed in each case by my response.
First, a disclaimer: I don’t mean to gang up on Mr. Simon personally; others hold opinions similar to his, but his essay just happens to be a convenient starting point for this discussion. FWIW, prior to this week I perused a bit of his blog, after having read one of his comments here, and found it to be well written and informative.
Humans love to find patterns in the world. Sometimes patterns exist, sometimes they are imaginary. Sometimes you can see a pattern that may be interesting and ignore its significance. As a resident I used to say that anyone who smokes three packs of cigarettes a day has to be schizophrenic, it was meant more as a joke, when, in fact, it was later discovered that tobacco helps ameliorate the symptoms of schizophrenia. I need to pay more attention.
Part of my job is to look for patterns as a key to the patients diagnosis. Diseases and pathogens tend to (more or less) cause reproducible signs and symptoms and looking for that pattern is often the most helpful clue towards finding the diagnosis. Of course things are never as easy as one would like, as you have to consider whether you are seeing common manifestations of a common disease, uncommon manifestations of a common disease, common manifestations of a uncommon disease and, the hardest, uncommon manifestations of an uncommon disease. When I have a complex or uncertain cause, I explicitly run through that, and other, litanies so I do not miss a unusual diagnosis.
Chronic Fatigue Syndrome (CFS) has, at least to my way of thinking, two patterns. I see the occasional CFS patient in clinic and, I hope, pay attention to their disease patterns. I keep in mind I may be seeing a pattern that does not exist, but looking for disease patterns is what doctors are trained to do.
In 1996 the American Physical Society, responding to a request from the National Research Council, was asked to examine the potential health hazards of power lines. One of the concerns was that electromagnetic background fields of 2 milligauss might cause cancer (for comparison the earth’s magnetic field is 500 milligauss and fields generated by human physiological processes are hundreds of thousands of times less than 2 milligauss). Monitors of outdoor exposure for children to wear were marketed to parents. “Some city regulations sought to constrain B fields to less than 2 milligauss”. The report, which was a comprehensive study of the alleged dangers, included both molecular and epidemiologic studies and found that no adverse health effects could be attributed to these low fields.
One of the conclusions emphasized that physical calculations rule out carcinogenic effects because at physiological temperatures thermal noise fields in human cells are larger than the background fields from power lines.1, 2 Thus the political agenda, concerned with fear of carcinogenic mechanisms arising from low level magnetic fields, lost credibility. However, about 10 years later claims for health effects from mattress pads equipped with small magnets were marketed. A study of this was funded by National Institute of Health’s Center for Complementary and Alternative Medicine and claims for their benefits were published in alternative medicine journals.3
Some of the rationale for the claims were ludicrous. I attended one sales pitch which claimed their mattress magnets were better because they incorporated only North Poles. About the same time, small 300 gauss magnets, began to appear on the shelves of drug stores. In 2007 a lawsuit brought by the National Council against Health Fraud against advertisers of these products was successfully settled. I was one of the persons who agreed to appear as an expert witness if needed. The Federal Trade Commission also threatened to prosecute purveyors who claimed healthful benefits for these products.
Back in 2008 I wrote on Near Death Experiences (NDE’s). I have an interest in this topic as I have frequent exposure to near death; my wife has a predilection for watching Judge Judy. Since 2008 there have been a few studies on the topic of NDEs as researchers try and find evidence that consciousness transcends the brain, if that is what a NDE represents. I have also been ill for most of the last week and have not had the usual time to spend generating typos to drive some readers to distraction. Fortunately, I have a miracle cure that is 100% effective in resolving all my self-limited illnesses: time. It passed and with it the illness. As a result I am about 10 days behind in the commitments in my life, so this will be a shorter than usual post.
One of the themes of SBM has been, since the very beginning, how the paradigm of evidence-based medicine discounts plausibility (or, perhaps more appropriately, implausibility) when evaluating whether or not a given therapy works. One of our favorite examples is homeopathy, a therapy that is so implausible on a strictly scientific basis that, for it to work, huge swaths of well-established science supported by equally huge amounts of experimental and observational evidence would have to be found to be all in serious error. While such an occurrence is not per se impossible, it is incredibly unlikely. Moreover, for scientists actually to start to doubt our understanding of chemistry, biochemistry, pharmacology, and physics to the point of thinking that our understanding of them is in such serious error that homeopathy is a valid description of reality, it would take a lot more than a bunch of low-quality or equivocal studies that show no effect due to homeopathy detectably greater than placebo.
On Friday, Kim Atwood undertook an excellent discussion of this very issue. What really caught my attention, though, was how he educated me about a bit of medical history of which I had been completely unaware. Specifically, Kim discussed the strange case of John Lykoudis, a physician in Greece who may have discovered the etiology of peptic ulcer disease (PUD) due to H. pylori more than a quarter century before Barry Marshall and Robin Warren discovered the bacterial etiology of PUD in 1984. One reason that this story intrigued me is the same reason that it intrigued Kimball. Lykoudis’ story very much resembles that of many quacks, in particular Nicholas Gonzalez, in that he claimed results far better than what medicine could produce at the time, fought relentlessly to try to prove his ideas to the medical authorities in Greece at the time, and ultimately failed to do so. Despite his failure, however, he had a very large and loyal following of patients who fervently believed in his methods. The twist on a familiar story, however, is that Lykoudis may very well have been right and have discovered a real, effective treatment long before his time.
Mark Crislip is on vacation, but through an arduous series of shakings and succussions (beating his head against the wall?) we have channeled part of his essence: This post mostly concerns itself with infectious diseases, thanks to several recent posts on SBM that discussed the plausibility of health claims† and that touched on the recent discovery that most peptic ulcer disease (PUD) is caused by a bacterium, Helicobacter pylori. Several comments and statements quoted in those posts reveal recurrent questions regarding both plausibility itself and the history of the H. pylori hypothesis. In this post I’ll attempt to answer some of those questions, but I’ll also insert some new confusion.
Plausibility ≠ Knowing the Mechanism
Let’s first dispense with a simple misunderstanding: We, by which I mean We Supreme Arbiters of Plausibility (We SAPs) here at SBM, do not require knowing the mechanism of some putative effect in order to deem it plausible. This seems so obvious that it ought not be necessary to repeat it over and over again, and yet the topic can’t be broached without some nebbishy South Park do-gooder chanting a litany of “just because you don’t know how it works doesn’t mean it can’t work,” as if that were a compelling or even relevant rebuttal. Let’s get this straight once and for all: IT ISN’T.
When I first heard that a retrovirus had been identified as a possible cause of chronic fatigue syndrome, I withheld judgment and awaited further developments. When I heard that two subsequent studies had failed to replicate the findings of the first, I assumed that the first had been a false alarm and would be disregarded. Not so.
It’s a classic case of wishful thinking outweighing good judgment. One unconfirmed report of an association between the XMRV virus and chronic fatigue syndrome (CFS) resulted in a rush to test for the virus, speculation about possible implications, and even suggestions for treatment. And the subsequent negative studies did little or nothing to reverse the trend.
XMRV is Xenotropic murine leukemia virus-related virus. In the past, there were reports that this retrovirus was associated with prostate cancer, but then other reports found no link. In 2009 a study was published in Science, “Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome” by Lombardi et al., reporting an association with CFS:
we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%) healthy controls. (more…)
First some background. I was first directed to the Marshall protocol by a reader who wondered about the information the found on the web. So I went to the web and looked at the available information, much as any patient would, and discussed what I found there.
I have subsequently been lead to believe that none of the information on the website http://www.marshallprotocol.com can be considered up to date or accurate. As as result of, I have told that my post is chockablock with errors, although, outside of writing doxycycline where I should have put minocycline, I am left in the dark as to exactly what my errors are. I am told that it is my responsibility to locate the errors in the last post, yet I can find none when compared to the website.
However, to remedy the deficiency of having reviewed inaccurate and out of date material, I have been sent 6 articles that I am informed represent the state of the art in understanding the science behind the Marshall protocol. Ah, the peer reviewed medical literature. An opportunity to carefully read and critique new ideas. It is one of the reasons people publish: to see if their ideas can withstand the scrutiny of others.
Several of these papers concern Vitamin D, the Vitamin D receptor, and olmesartan which I will review, perhaps, another time. I don’t find them a compelling read, but it not an area about which I have more than a standard medical knowledge. The other papers concern the role of infection in autoimmune diseases, which I will discuss here. It is easier as an infectious disease doctor to read this literature as I am, as least as far as the American Board on Internal Medicine is concerned, a specialist in the field. Alternatively, I am a closed minded tool of the medical industrial complex who only seeks to push his own twisted, narrow agenda at the expense of suffering patients (1). We can’t all be perfect.
In searching for just what FM is, one has to in a way read between lines. Claiming to treat the “underlying cause” of a condition raises the usual straw man argument that modern medicine does not, which of course is untrue. It also implies that there are underlying causes known to them and not to straights. FM claims to treat chronic disease which FM claims is inadequately treated by medicine. FM claims to be a more advanced approach both in conceptual thinking and in practical management. Such claims are on the face doubtful, but hard to disprove. The way to find out would be to analyze cases they manage and critique them.
I tried to see specific examples of treatments but the web page text book links were not working at the time. I understand others have seen the contents and perhaps can add some information. I sense a difference between “CAM” and FM – at least among the MDs and DOs - is that FMers tend to use methods and substances with some degree of scientific or biochemical rationale, even if not proved, moreso than many of the CAMers. Many seem to practice both systems or do not distinguish between the two systems. In order to get a sense of the degree to which FM is known, I requested from the web page the names of practitioners in a 50 mile radius of my home (near Palo Alto, Calif.). The names ranged from Santa Cruz (40 miles) to Berkeley (50) and San Francosco (40) and Marin County (Sausalito – 50 miles) The population of that area is about 5 million. They sent 46 names: MD/DO 31 – (including a nephrologist formerly on the staff of my teaching hospital) PhD 1 DC 8 Lac 3 ND 2 RN 1 Because I had become aware of FM only 1-2 years ago, I thought 46 was a relatively large number. The Web page lists four text books published in the past few years. A manuscript of the first one is available on line for downloading (not functioning when I tried.) . 21st Century Medicine: A New Model for Medical Education and PracticeMonograph Set – Functional Medicine Clinical Monograph Set – CME Available Textbook of Functional Medicine Clinical Nutrition: A Functional ApproachAs mentioned, I could not activate the links to those books, and did not have time to get to them individually. No authors were listed.