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Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 1

Background: the distinction between EBM and SBM

An important theme on the Science-Based Medicine blog, and the very reason for its name, has been its emphasis on examining all the evidence—not merely the results of clinical trials—for various claims, particularly for those that are implausible. We’ve discussed the distinction between Science-Based Medicine (SBM) and the more limited Evidence-Based Medicine (EBM) several times, for example here (I began my own discussion here and added a bit of formality here, here, and here). Let me summarize by quoting John Ioannidis:

…the probability that a research finding is indeed true depends on the prior probability of it being true (before doing the study), the statistical power of the study, and the level of statistical significance.

EBM, in a nutshell, ignores prior probability† (unless there is no other available evidence) and falls for the “p-value fallacy”; SBM does not. Please don’t bicker about this if you haven’t read the links above and some of their own references, particularly the EBM Levels of Evidence scheme and two articles by Steven Goodman (here and here). Also, note that it is not necessary to agree with Ioannidis that “most published research findings are false” to agree with his assertion, quoted above, about what determines the probability that a research finding is true.

The distinction between SBM and EBM has important implications for medical practice ethics, research ethics, human subject protections, allocation of scarce resources, epistemology in health care, public perceptions of medical knowledge and of the health professions, and more. EBM, as practiced in the 20 years of its formal existence, is poorly equipped to evaluate implausible claims because it fails to acknowledge that even if scientific plausibility is not sufficient to establish the validity of a new treatment, it is necessary for doing so.

Thus, in their recent foray into applying the tools of EBM to implausible health claims, government and academic investigators have made at least two, serious mistakes: first, they have subjected unwary subjects to dangerous but unnecessary trials in a quest for “evidence,” failing to realize that definitive evidence already exists; second, they have been largely incapable of pronouncing ineffective methods ineffective. At best, even after conducting predictably disconfirming trials of vanishingly unlikely claims, they have declared such methods merely “unproven,” almost always urging “further research.” That may be the proper EBM response, but it is a far cry from the reality. As I opined a couple of years ago, the founders of the EBM movement apparently “never saw ‘CAM’ coming.”

The “Gonzalez” Trial

One such dangerous and unnecessary trial was “Evaluation of Intensive Pancreatic Proteolytic Enzyme Therapy with Ancillary Nutritional Support Versus Gemcitabine Chemotherapy in the Treatment of Inoperable Pancreatic Adenocarcinoma,” begun in 1999. It was funded by the National Cancer Institute (NCI) and the National Center for Complementary and Alternative Medicine (NCCAM), and was conducted by Nicholas Gonzalez and investigators at Columbia University. The ‘enzyme therapy’ part of the trial is more commonly known as the “Gonzalez Detoxification Regimen”:

Patients receive pancreatic enzymes orally every 4 hours and at meals daily on days 1-16, followed by 5 days of rest. Patients receive magnesium citrate and Papaya Plus with the pancreatic enzymes. Additionally, patients receive nutritional supplementation with vitamins, minerals, trace elements, and animal glandular products 4 times per day on days 1-16, followed by 5 days of rest. Courses repeat every 21 days until death despite relapse. Patients consume a moderate vegetarian metabolizer diet during the course of therapy, which excludes red meat, poultry, and white sugar. Coffee enemas are performed twice a day, along with skin brushing daily, skin cleansing once a week with castor oil during the first 6 months of therapy, and a salt and soda bath each week. Patients also undergo a complete liver flush and a clean sweep and purge on a rotating basis each month during the 5 days of rest.

More than two years ago I wrote a series of posts* discussing Gonzalez, the regimen, the history leading to the funding of the trial, and aspects of the trial itself. In summary, Gonzalez appears to be a dangerous quack who should have had his medical license stripped by the state of New York during the 1990s, but was saved at the 11th hour by naïve “alternative medicine” enthusiasm; the regimen was highly implausible; there were no prior animal or clinical studies sufficient to warrant a human trial; its real impetus was the gathering political strength of the anti-intellectual “health freedom” movement in the aftermath of the Laetrile wars, culminating in Congressman Dan Burton’s bullying of NCI Director Richard Klausner; the NCI and Columbia subsequently justified the trial by citing a dubious case series provided by Gonzalez himself; the trial was unethical in numerous ways, amounting to torture-until-death for at least one hapless subject who, desperate for anything that might work, had stumbled into it because of his own scientific naïveté and because his consent was uninformed by existing knowledge—which, of course, the Columbia investigators should have provided him.

Shortly after my first series of posts it became clear that the Columbia investigators had found the Gonzalez regimen sufficiently inferior to the standard chemotherapy regimen to have stopped the trial early, in 2005. Finally, in August of 2009, the report of the trial, by John Chabot and colleagues (Gonzalez’s name was conspicuously missing from the report), was published by the Journal of Clinical Oncology (JCO): subjects in the Gonzalez arm had fared terribly, not only much worse than subjects in the chemotherapy arm, but also worse than 20,000 historical controls gleaned from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute.

In my last post on the topic, I explained numerous problems with the formal report, contrasting it with the Consolidated Standards of Reporting Trials (CONSORT), which the JCO expects authors to honor. I explained that the results were nevertheless sufficient to disqualify the Gonzalez Regimen once and for all, Gonzalez’s own objections notwithstanding. I explained why Gonzalez’s name had not appeared in the article. I reiterated that the trial was unethical in the extreme, and lamented the JCO’s decision to publish the report—in direct violation of this statement in the Declaration of Helsinki, to which the JCO claims allegiance:

30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research… Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

I mentioned ways in which the results of the trial could have been made public without violating that important statement. Since things had not turned out that way, I hoped that the JCO would eventually publish “an editorial acknowledging the ethical problems with the trial and the dilemma involved in choosing to publish the report.” I sent an email to an acquaintance who was a member of the JCO editorial board, asking that he or Editor-in-Chief Daniel Haller would recognize that the issue oughtn’t be ignored. I cited the pertinent SBM posts. I was ignored. When no editorial or other comment appeared in the JCO over the next few months, I stopped looking.

The Editorial

Only recently I noticed that the JCO had solicited an editorial after all; authored by Dr. Mark Levine of McMaster University, it appeared online in March, 2010. The title offered a bit of hope that the journal had finally “got it”:

Conventional and Complementary Therapies: A Tale of Two Research Standards?

Alas, ‘twas not to be. The first clue is found at the beginning of the essay:

In the early 1990s, I began to notice that some patients were choosing alternatives to the mainstream or conventional treatments. These so-called alternative therapies included a range of interventions, such as dietary and behavioral interventions, vitamin supplements and herbs, and traditional systems such as Chinese and homeopathic medicines. Most of these were not supported by sound scientific methods.

Notice the word “methods.” Dr. Levine didn’t write, “most of these were not supported by sound science.” This suggests that he was partially blinded by the EBM understanding of “evidence” and “scientific.” The next clue consists of the entire second paragraph, a series of bland restatements of proponents’ definitions (from the NCCAM, in this case) and ambiguous assertions about “CAM” that have come to be typical for medical academics who ought to know better. But I venture from the main point.

In the third paragraph, Dr. Levine verifies what we had suspected above:

I am fortunate to have spent my entire academic career at McMaster University (Hamilton, Ontario, Canada), the birthplace of evidence-based medicine, and to have had the privilege of learning from colleagues such as David Sackett, MD, and Gord Guyatt, MD.

Before proceeding, let me acknowledge—particularly for the benefit of Dr. Levine or any other EBM aficionados who may read this—that his essay is, in some ways, a good one. He was asked to comment on two reports of “CAM” treatments that had appeared in the JCO: the Gonzalez trial and a trial of acupuncture for hot flashes in women receiving anti-estrogen therapy for breast cancer.  In each case he made valid criticisms of the methods and of the authors’ conclusions. He stressed that the authors hadn’t specified the questions that they were trying to answer. He wrote that “non-inferiority” studies require larger sample sizes than “superiority” studies, but that the authors of these reports hadn’t offered power calculations to justify their (small) sample sizes. He pointed out that the “control” intervention in the acupuncture trial, venlaxafine (Effexor), doesn’t work very well, thus implying that it may mean very little to judge a novel treatment similarly efficacious.

Nevertheless, in regard to the Gonzalez trial Dr. Levine faltered even as he applied what would usually be a solid EBM-style criticism:

The question addressed in the original randomized trial by Chabot et al was not specified. Was the hypothesis that chemotherapy is better than enzyme therapy, or was it that enzyme therapy is no worse than chemotherapy? My answer to this is, “I do not know.”

While this is technically correct, it misses the more important point, which can only be appreciated by looking beyond the trial itself: the interesting question, given the implausible nature of the method, is whether “enzyme therapy” for cancer of the pancreas is anything like what Gonzalez and his patrons had cracked it up to be prior to the trial. The most reasonable cohort to compare this group to, then, is not the chemotherapy arm reported in the JCO article, but Gonzalez’s case series that had ostensibly justified the trial in the first place:

As of 12 January 1999, of 11 patients entered into the study, 9 (81%) survived one year, 5 (45%) survived two years, and at this time, 4 have survived three years. Two patients are alive and doing well: one at three years and the other at four years.

Contrast those results with the 32 “enzyme-group” subjects reported in the JCO: 7 were alive at 10 months, 2 at 20 months, 1 at 30 months, and none at 40 months. Median survival was 4.3 months. We do not need formal statistics or a new, randomized trial with a larger sample size to justify dismissing the Gonzalez regimen.

Next (this weekend, I promise): Human Studies Ethics: why Science Matters

*The “Gonzalez Regimen” Series:

1. The Ethics of “CAM” Trials: Gonzo (Part I)

2. The Ethics of “CAM” Trials: Gonzo (Part II)

3. The Ethics of “CAM” Trials: Gonzo (Part III)

4. The Ethics of “CAM” Trials: Gonzo (Part IV)

5. The Ethics of “CAM” Trials: Gonzo (Part V)

6. The Ethics of “CAM” Trials: Gonzo (Part VI)

7. The “Gonzalez Trial” for Pancreatic Cancer: Outcome Revealed

8. “Gonzalez Regimen” for Cancer of the Pancreas: Even Worse than We Thought (Part I: Results)

9. “Gonzalez Regimen” for Cancer of the Pancreas: Even Worse than We Thought (Part II: Loose Ends)

10. Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 1

11. Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 2

The Prior Probability, Bayesian vs. Frequentist Inference, and EBM Series:

1. Homeopathy and Evidence-Based Medicine: Back to the Future Part V

2. Prior Probability: The Dirty Little Secret of “Evidence-Based Alternative Medicine”

3. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine”—Continued

4. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine”—Continued Again

5. Yes, Jacqueline: EBM ought to be Synonymous with SBM

6. The 2nd Yale Research Symposium on Complementary and Integrative Medicine. Part II

7. H. Pylori, Plausibility, and Greek Tragedy: the Quirky Case of Dr. John Lykoudis

8. Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 1

9. Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 2

10. Of SBM and EBM Redux. Part I: Does EBM Undervalue Basic Science and Overvalue RCTs?

11. Of SBM and EBM Redux. Part II: Is it a Good Idea to test Highly Implausible Health Claims?

12. Of SBM and EBM Redux. Part III: Parapsychology is the Role Model for “CAM” Research

13. Of SBM and EBM Redux. Part IV: More Cochrane and a little Bayes

14. Of SBM and EBM Redux. Part IV, Continued: More Cochrane and a little Bayes

15. Cochrane is Starting to ‘Get’ SBM!

16. What is Science? 

Posted in: Cancer, Clinical Trials, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

Leave a Comment (59) ↓

59 thoughts on “Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 1

  1. rork says:

    “We do not need formal statistics or a new, randomized trial with a larger sample size to justify dismissing the Gonzalez regimen.”

    I’m offended by the no statistics remark, and failure to make any comparison.
    I rather thought it would be necessary to compare the outcomes with those obtained with other therapies, which I’m sure has been done, but not discussing that comparison here seemed odd, and might be mistaken for the error that just because pancreas cancer has horrible outcomes, any treatment for it can be “dismissed”.

    PS: How should prior probability that Gonsalez regimen beats conventional chemo have been determined? Shouldn’t you admit there’s a bit of trouble there?

  2. cervantes says:

    What Ioannidis is really talking about, and the conceptual underpinning of this entire epistemological discussion, is Bayes Theorem. It’s really astonishing how many people who ought to know better — including most physicians and yep, people doing clinical research and epidemiology who bandy about p values — do not understand Bayes Theorem. This leads to errors in drawing conclusions in research; and in clinical practice, e.g. interpretation of diagnostic and screening tests, and diagnosis in general.

    A post here that just focuses on Bayes would be useful, I think. BTW, even if you don’t have hard numbers to plug in, the qualitative idea is still powerful.

  3. cervantes says:

    rork: Can you read?

    “Shortly after my first series of posts it became clear that the Columbia investigators had found the Gonzalez regimen sufficiently inferior to the standard chemotherapy regimen to have stopped the trial early, in 2005. Finally, in August of 2009, the report of the trial, by John Chabot and colleagues (Gonzalez’s name was conspicuously missing from the report), was published by the Journal of Clinical Oncology (JCO): subjects in the Gonzalez arm had fared terribly, not only much worse than subjects in the chemotherapy arm, but also worse than 20,000 historical controls gleaned from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute.”

  4. qetzal says:

    rork asks:

    PS: How should prior probability that Gonsalez regimen beats conventional chemo have been determined? Shouldn’t you admit there’s a bit of trouble there?

    Dr. Atwood already addressed that in his post:

    [T]he [Gonzalez] regimen was highly implausible; there were no prior animal or clinical studies sufficient to warrant a human trial….

    I agree that it’s difficult to decide on a specific numerical prior probability. Was it less than 0.001? Less than 0.00001? Even lower? Hard to say, but that doesn’t really matter. What matters is whether the prior probability, considering both scientific plausibility and Gonzalez’s ‘case series,’ was sufficient to warrant a formal trial. The answer is unquestionably “No.”

  5. Dr Benway says:

    PS: How should prior probability that Gonsalez regimen beats conventional chemo have been determined? Shouldn’t you admit there’s a bit of trouble there?

    To simplify this discussion, let’s focus upon just one bit of the Gonzalez recipe: the coffee enema.

    What is the prior probability of coffee enemas making teh cancer go away?

    Hmm… Let’s see… I’ve got a dictionary handy and am ready to go fishing.

    What is the prior probability of guano making the cancer go away?

    What is the prior probability of kinetic energy making the cancer go away?

    What is the prior probability of portfolio making the cancer go away?

    What is the prior probability of swordfish making the cancer go away?

    Before addressing the above questions we should ask, is there any reason to prefer one random dictionary fish over another?

    I think that answer is “no.”

    Now, is there anything about the coffee enema to distinguish it from a great many other dictionary fish?

    Again, I think that answer is “no.”

    This brings me to “The Titmouse Rule of Thumb To Save You Time and Money”:

    The prior probability of therapeutic benefit from a given species of dictionary fish is equivalent to that of every other species of dictionary fish.

  6. JMB says:

    Thank you, Dr Atwood and cervantes, for hammering away at the point about a priori information. Bayes approach can be used for more than just the analysis of results of experiments. It can be used as a guide for collecting and organizing information (the a priori information) useful in decisions about direction of research and healthcare (as well as medical practice decisions). The main limitation of the application of the Bayes approach in the selection of treatments for study is the laziness at collecting (and analyzing) information outside of the clinical trial paradigm (EBM increases that limitation). The capabilities of current day information technology can be used to amass our a priori information, and increase our efficiency for advancing medicine.

    That’s pretty much what I advocated 20+ years ago. I am not holding my breath now to see if it will happen. Nowadays, personal computers are powerful enough to crunch a database of 20 million cases of patients with tumors, and yet we still don’t make efficient use of that a priori information. At least SBM is moving in the right direction, advocating use of a priori information.

    If we had more a priori information, then we could formally calculate a priori probabilities (as requested by rork), as opposed to relying on fuzzy logic values. Fuzzy logic values are still better than discarding a priori information.

  7. A post here that just focuses on Bayes would be useful, I think. BTW, even if you don’t have hard numbers to plug in, the qualitative idea is still powerful.

    Good idea. I linked to such posts in the text, but now I’ve added the series links just after the links for the “Gonzalez Regimen” Series.

  8. daedalus2u says:

    Dr Benway, there may be physiology associated with using guano. Guano can be a very powerful source of nitric oxide. An analogous material, crocodile dung (crocodiles and birds both excrete uric acid) was used as a pessary. I have demonstrated that composted chicken manure is a powerful NO source. Depending on how the guano was processed it might be too.

    I am not suggesting that there is any sort of prior plausibility for guano to treat cancer, but for treating other things there is.

  9. cervantes says:

    Thanks Dr. A. Like most of your readers, I suspect, I discovered the site long after that series was posted in 2008.

  10. cervantes says:

    (It’s Bayes’s world, we just live in it.)

  11. Dr Benway says:

    I kid you not, daedalus –I thought of you when I opened my eyes and saw “guano” as the nearest thing-noun to my fingertip as it rested upon the dictionary page that I’d randomly selected.

    One day I might hook the big one –a veritable cure for cancer– from the pages of Webster’s New World Dictionary. But that would just be dumb luck, eh?

    Whether a therapy based upon dictionary fish is helpful or not is really beside the point. We want more than “helpful” or “not helpful.” We want understanding.

    As has been said: “A broken clock is right twice a day, just like Mercola.”

  12. daedalus2u says:

    Dr Benway, yes, but just because a potential treatment sounds crazy does not mean that it is.

    Manure plus soil was used to prevent tetanus infection of umbilical stumps. I read about that in a book, and then later met a midwife who grew up in Africa who mentioned that her mother had told her of a tribe that practiced that umbilical stump treatment.

    It turns out that the Clostridia are exquisitly sensitive to nitric oxide which manure plus soil would produce.

    Dismissing a potential treatment because it “sounds crazy” is no different than accepting a potential treatment because it “sounds great”. Humans are not good at evaluating such things.

  13. Ian says:

    @daedalus2u it would be foolish to do a study on the effect of a treating umbilical stumps with manure soil mix on the rates of tetanus without first understanding the science behind a possible effect. In this case figuring out about the nitric oxide. That’s kind of the whole point of SBM. Get the science straight before doing random studies.

  14. pmoran says:

    The native prior probability of the Gonzales regime was already upset by Gonzales’ published case series.

    In very expert (i.e. “our” :-)) opinion the cases didn’t change the PP by much, but they were confronting in another way. They created a political problem. They were saying, “here we are trying as hard as we can to show you doctors how well our methods can work in the most serious of possible cancers and you STILL sit on your arses”.

    99% of the public and 99.99% of the media might be inclined to regard the resultant claims as likely to be true, or to have a neutral opinion of them, which is nearly as bad in practice.

    So there were two questions, one more political than scientific: “should we study this further?”. The other was “if so, how?”.

    In my opinion the decision to study the question further was reasonable, but there was an ill-considered response to the second, as Kimball seems to be also implying.

  15. daedalus2u says:

    Ian, yes, I completely agree. But the treating of umbilical stumps with manure and soil is a traditional practice that dates to antiquity. A practice that is likely not practiced much any more. I have seen reference to it being practiced in India as well. Over human history and prehistory, the number of infants that have been treated with manure and soil may be quite large and may even exceed the number that have not. I am not saying we should return to such practices, but we should understand them.

    The problem SBM has is with the concept of prior plausibility. The general public and even most clinicians think prior plausibility means “makes sense to me”, or put forward by someone who “sounds plausible”, and that anecdotes are an acceptable component of prior plausibility. “Prior plausibility” is bandied about as an argument to be won, and who ever wins it will get the funding. Gaming the system to have a high “prior plausibility” is to get the funding.

    Dr Benway was illustrating that non-SBM mindset by bringing up treatments that sound crazy. Maybe they are crazy, but the way to analyze their craziness is not by how they sound.

    The Gonzalez case series is likely a case of the sharpshooter’s fallacy. He had a lot of patients he put through this rigorous, tortuous gauntlet of a treatment, and the ones who couldn’t stay on it (because their cancer progressed) stopped it and died. It was only the ones who were not progressing (for reasons which had nothing to do with his treatments) or were misdiagnosed who could stay on it and survive. They probably would have done even better with no treatment.

    The fetish that proposal reviewers have for “preliminary data” helps people like Gonzalez “game” the system. Unless the data is of a quantity and a quality to shift the Bayesian probability, it doesn’t add any probative value to the proposal. They “triage” out proposals that sound “crazy”, those that don’t have preliminary data, the ones they don’t understand and then what is left?

  16. pmoran says:

    “I am not saying we should return to such practices, but we should understand them. ”

    I agree. For example, those cultures may have used soil and manure on the umbilicial cord stump because they used such remedies for most things.

    It is extremely improbable that that they would have been able to make valid judgements with regard to the prevention of umbilical cord infections, esepcially rarer ones like tetanus or gas gangrene. That requires prospective study.

    In my view, it is equally likely that umbilicial cord infections were being caused by such unhygenic practices, while spurring on their even greater use by those ignorant of the connection. You start off with a sterile field and have to get the bugs in there somehow.

  17. daedalus2u says:

    Yes, and they may have used those remedies for most things because they worked for most things! Nitric oxide is like that!

    Pmoran, such things are only rare now because of sterile procedures. 200 years ago no one even suspected there was such a thing as a sterile procedure. Without doing the experiment, you really don’t know what the incidence of what type of infections would be given what types of umbilical cord treatment.

    Every woman was likely having a pregnancy every year. On average only 2 survived. Maybe a midwife showed up with manure on her hands and noticed that the infant didn’t die of tetanus and the mother didn’t die of puerperal fever.

    Cow manure is probably somewhat better than the mother’s stool which the infant would likely be exposed to during birth. Pathogens of cattle are not so much adapted to humans as human pathogens are. The infant would be inoculated with all the vaginal bacteria which are usually lactic acid bacteria which are also normal skin flora. Putting dirt and manure on the infant and letting the bacteria that best adapt to the skin take hold for a few days before allowing exposure to other humans and the potential pathogens they might be carrying might be the best way to protect an infant. Most “real” pathogens can’t survive being outside the host very well for very long.

    In the “wild”, you can’t keep a surface sterile. It is very likely a lot better to inoculate it with something that isn’t a pathogen and that will suppress pathogens. A great many serious infections happen when the normal bacteria are knocked out. It is probably better even now to inoculate the skin and other exposed surfaces with non-pathogens rather than allowing what ever is in the environment and gets there first and grows the fastest. But people have such a fetish about bacteria that isn’t likely to happen.

    The textbook I first saw it in mentioned it specifically in the context of preventing tetanus, but attributed it to making the wound aerobic. Ammonia oxidizing bacteria really do work as a broad spectrum antimicrobial. The NO/NOx they produce suppresses quorum sensing and makes the infective dose a lot higher. NO has multiple effects on Clostridia, it triggers the sprouting of spores and the vegetative cells are more susceptible to being killed.

  18. nybgrus says:

    I must first admit that I am just finishing my first year of medical school and that my prior experience as a scientist was not very extensive or rigorous so please forgive (and correct) any mis-step I may make in my assertions.

    I believe that the discussion has gone quite off topic here – the notion that a particular “remedy of antiquity” works and there is good science to back it up is not of contention. Using manure or guano or anything else and having good outcomes and then later discovering and discussing the science behind it is a specific example of a larger theme. The reality is that in the past, scientific knowledge was very limited, the structure for rigorous study was undeveloped, and collecting and disseminating information regarding the treatments and outcomes was impossible. Therefore, everything was local or regional and anecdotal. By the very nature of humanity, many completely random things have been tried and by the nature of natural selection, those that are negative selectors tend to be phased out and those that are positive selectors tend to hang around. This is regardless of science, of course. However, it is the middle ground that clings to the throat of medical and scientific progression. Those things that, overall, did not statistically help nor hinder the fitness of the human populations that adopted the practice. Why would this practice be adopted then? Most likely due to temporal correlation being mis-interpreted as causality – a very common trait that humans default to. There are, of course, any number of exceptions that you can point to, but they will inevitably serve to prove the rule.

    So how does this relate to our discussion? Very simply – now we have vastly more scientific knowledge and huge data pools to draw from and make a priori judgements with. No longer do we need to randomly hope a midwife just milked a cow before delivering a baby and then noting a trend of anecdotal positive outcomes to stimulate a study in the matter. And no longer do we need to fish for random things and test them all to determine their efficacy. The idea that just because an idea sounds “crazy” we can dismiss it is a misnomer – I would reckon that those of us here in favour of dismissing “crazy” ideas do not mean crazy in that it offends our sensibilities as a human being or that it is contrary to our past experience and ingrained beliefs. No, “crazy” here means implausible based upon our current understanding of physiology, biology, chemistry, physics, etc. THOSE ideas should be dismissed and any regimen which takes them into account should have their a priori estimates of success concordantly decreased.

    So the fact that indeed, guano and other excrement has been shown to and can have positive health outcomes, does not mean it should be tried for everything – something you have admitted quite plainly. So yes, it is “crazy” to test the efficacy of a bat guano enema for treating pancreatic cancer because there is no rational justification as to why it would work – same as a coffee enema. Additionally, the fact that the mechanism has been elucidated as NO/NOx release inhibiting worse bacteria is not an argument for the use of manure on umbilical stumps – it is an argument for finding a way to replicate the mechanism without the side effects of putting manure on an umbilical stump (i.e. infection from other sources that may or may not be present in your particular sample of manure). This is a specific example in response to that presented above, but the idea is translatable to the very essence of treatment testing and the ethics associated with human trials. By its very nature we will inevitably miss some positive treatment, maybe even a great one, because it (erroneously) sounds “crazy” in the scientific sense. But that is the trade off for having ethically sound testing and ensuring the steady and whole-hearted forward march of science.

    Understanding such practices thus falls under the confines of ethics, which must abide by our current level of scientific understanding. So in cases like the Gonzalez regimen, it can be stated that many aspects of it had a priori “crazy” to them and the trial run itself should have been enough to dismiss it and not conduct a study in the first place. That, I believe, is the point of discussion here. The fact that the regimen (or others like it) MAY have worked and such dismissals may lead us to miss out on potentially life saving treatments does nothing to alter the ethical imperative.

    I apologize for any mistakes I may have made in my understanding and welcome commentary. Now I will try and explore Bayes Theorem since it seems rather important and I never took the time to learn it, even though my poker buddies with PhDs in economics and statistics have long said it is worth knowing.

  19. Dr Benway says:

    Daedelus, “crazy” was not my point.

    Note that you completely ignored the therapeutic value of portfolio and swordfish –that’s good, as dictionary fish are a poor guide to the practice of medicine.

    If only I’d been wise enough to avoid “guano,” when it came up. Then you’d have said, “LOL dictionary fish,” rather than, “ooo shiny!”

    It’s not enough to know that my watch has the correct time. You also need to know that it’s *working,* if you want to rely upon it in the future.

  20. nybgrus says:

    Dr. Benway,

    So much more succinctly said. LOL.

    BTW, I have no read up a bit on Bayes Theorem and find it to be very interesting and powerful! It is quite helpful for putting lab results and diagnostic tests in perspective.

    The problem, of course, is translating that into something your average person can understand and identify with.

  21. red rabbit says:

    I never really grasped the distinction people were trying to make until now, so thank you.

    A recent McMaster grad myself, previously from a more traditional scientific background, I was a little stumped by the McMaster propensity to buy into the woo. This sheds some light upon it.

  22. oderb says:

    As a long time survivor of cancer and patient of Dr Gonzalez (over 20 years) and as a commenter on several occasions on past articles on Gonzalez I once again wearily encounter the same mixture of scorn and bias in this post as I did in earlier posts.

    To focus on plausibility as SBM does seems to me to require that that criteria be examined with great care and rigor. Yet all Dr Atwood does is link to a short non peer reviewed article by Dr Saul Green written over 10 years ago attacking Gonzalez.

    The central component of the Gonzalez therapy is the use of massive quantities of pancreatic enzymes to digest or otherwise neutralize cancer cells. This is based on the extensive theoretical and clinical work of Dr Beard at the turn of the last century. Yet Dr Green dismisses the plausibility of enzymes in no more than a sentence or two by simply saying that cancer is caused by genetic mutations. End of story. Dr Green spends considerably more energy discussing peripheral yet titillating aspects of the Gonzalez program such as hair tests and coffee enemas than he does on enzymes.

    Secondly Dr Atwood asserts that there were no prior animal trials sufficient to warrant a human study. I don’t know what sufficiency means in this context but I guess it would have been somewhat inconvenient to Dr Atwood’s argument were he to have quoted from the principal investigators’ conclusion in the trial of Gonzalez’s enzymes in mice published in 2004 in the distinguished journal Pancreas.

    Pancreas, 28(4):401-412, May 2004. PMID: 15097858

    “In summary, PPE (porcine pancreatic enzyme) is the first experimentally and clinically proven agent for the effective treatment of PC (pancreatic cancer). The significant advantages of PPE over any other currently available therapeutic modalities include its effects on physical condition, nutrition and lack of toxicity.”

    Has Dr Atwood or others here uncovered a fatal flaw which would invalidate the Pancreas study? Maybe it’s the well known mice placebo effect? If they have I don’t remember reading about it. And if they haven’t it seems utterly irresponsible to ignore and or dismiss the study.

    Given the central role as I understand it of plausibility in distinguishing EBM from SBM I find it ironic that so little effort is made by Dr Atwood and his colleagues at SBM to objectively and comprehensively ascertain the plausibility of the enzyme theory of cancer.

    A good place to start would be to read Dr Gonzalez’s carefully researched and referenced book on the origins and biological rationale for the use of enzymes to control cancer. I’d bet most anything that no one castigating Gonzalez would have the open mindedness to read the book. Am I wrong? I doubt it.

    I have attempted here to decouple the issues surrounding the Gonzalez/Columbia cancer trial from the plausibility of the theory. I’ve made my comments about the ciinical trial some time ago in this venue and so I have no desire to reopen that issue.

  23. oderb says:

    As a long time survivor of cancer and patient of Dr Gonzalez (over 20 years) and as a commenter on several occasions on the past articles on Gonzalez I once again wearily encounter the same mixture of scorn and bias in this post as I did in earlier posts.

    First to focus on plausibility as SBM does seems to me to require that that criteria be examined with great care and rigor. Yet all Dr Atwood does is link to a short non peer reviewed article by Dr Saul Green written 10 years ago attacking Gonzalez.

    The central component of the Gonzalez therapy is the use of massive quantities of pancreatic enzymes to digest or otherwise neutralize cancer cells. This is based on the extensive theoretical and clinical work of Dr Beard at the turn of the last century. Yet Dr Green dismisses the plausibility of enzymes in no more than a sentence or two by simply saying that cancer is caused by genetic mutations. End of story. Dr Green spends more energy discussing peripheral yet titillating aspects of the Gonzalez program such as hair tests and coffee enemas than he does on enzymes.

    Secondly Dr Atword asserts that there were no prior animal trials sufficient to warrant a human study. I don’t know what sufficiency means but I guess it would have been somewhat inconvenient to Dr Atwood’s argument were he to have quoted from the principal investigators’ conclusion in the trial of Gonzalez’s enzymes in mice published in 2004 in the distinguished journal Pancreas.

    Pancreas, 28(4):401-412, May 2004. PMID: 15097858

    “In summary, PPE (porcine pancreatic enzyme) is the first experimentally and clinically proven agent for the effective treatment of PC (pancreatic cancer). The significant advantages of PPE over any other currently available therapeutic modalities include its effects on physical condition, nutrition and lack of toxicity.”

    Has Dr Atwood or others here uncovered a fatal flaw which would invalidate the Pancreas study? If they have I don’t remember reading about it. And if they haven’t it seems utterly irresponsible to ignore and or dismiss the study.

    Given the central role as I understand it of plausibility in distinguishing EBM from SBM I find it ironic that so little effort is made by Dr Atwood and his colleagues hear at SBM to objectively and comprehensively ascertain the plausibility of the enzyme theory of cancer.

    A good place to start would be to read Dr Gonzalez’s exhaustively researched book on the origins and biological rationale for the use of enzymes to control cancer. I’d bet most anything that no one castigating Gonzalez would have the open mindedness to read the book. Am I wrong?

    I have attempted here to decouple the issues surrounding the Gonzalez/Columbia cancer trial from the plausibility of the theory. I’ve made my comments about the trial some time and I have no desire to reopen that issue in this venue.

  24. phayes says:

    “EBM, in a nutshell, ignores prior probability…”

    in non-Bayesian and simple hypothesis testing terms (perhaps): unless it’s reasonable to suppose that the probability of your alternative hypothesis dominates the probability of the range of possible alternative hypotheses, you are not justified in choosing its negation as your null hypothesis. The crazier your alternative and the more complex and error-prone the experiment, the less justification.

  25. Dr Benway says:

    nybgrus, go forth and spread ye the word of Bayes Theorem, but cautiously during your integrative medicine clerkship lest your dean’s letter be blackened unfairly.

    The other day I wanted to recommend the Ioannidis paper to a psychologist who gave a very good lecture on critical thinking but who also dropped some anti-pharma, pro-acupuncture, pro-alt med comments, followed by “some studies have been positive.” Except I couldn’t remember how to spell “Ioannidis” to save my life.

    I need a mnemonic. The best I can come up with at the moment is an image of a sex crazed woman named Ann standing on one of Jupiter’s moons.

    Ah, mnemonics and med school. Brings back memories. Dr. Novella will likely be familiar with this one for the cranial nerves:

    “Frank Sinatra Takes Four Fifths Seagram’s Seven Each Night To Ease Tension.”

  26. Dr Benway says:

    “EBM, in a nutshell, ignores prior probability…”

    I think the EBM guys assumed a world in which the batsh_t*was off the table automatically (hai daedelus!). And by batsh_t, I mean proposed therapies that violate basic laws of physics or chemistry (homeopathy), or that invoke Nobel prize-winning or Randi million-dollar challenge-winning supernatural mechanisms of action (energy medicine), or that come out of the blue without building upon what is already understood (coffee enema).

    Derp. Look at all the moon-bats flying overhead. We’re never gonna get a table with no batsh_t on it.
    ____
    *did I fool the naughty word filter?

  27. oderb says:

    To focus on plausibility as SBM does seems to me to require that that criteria be examined with great care and rigor. Yet all Dr Atwood does is link to a short non peer reviewed article by Dr Saul Green written 10 years ago attacking Gonzalez.

    The central component of the Gonzalez therapy is the use of massive quantities of pancreatic enzymes to digest or otherwise neutralize cancer cells. This is based on the extensive theoretical and clinical work of Dr Beard at the turn of the last century. Yet Dr Green dismisses the plausibility of enzymes in no more than a sentence or two by simply saying that cancer is caused by genetic mutations. End of story. Dr Green spends more energy discussing peripheral yet titillating aspects of the Gonzalez program such as hair tests and coffee enemas than he does on enzymes.

    Secondly Dr Atword asserts that there were no prior animal trials sufficient to warrant a human study. I don’t know what sufficiency means but I guess it would have been somewhat inconvenient to Dr Atwood’s argument were he to have quoted from the principal investigators’ conclusion in the trial of Gonzalez’s enzymes in mice published in 2004 in the distinguished journal Pancreas.

    Pancreas, 28(4):401-412, May 2004. PMID: 15097858

    “In summary, PPE (porcine pancreatic enzyme) is the first experimentally and clinically proven agent for the effective treatment of PC (pancreatic cancer). The significant advantages of PPE over any other currently available therapeutic modalities include its effects on physical condition, nutrition and lack of toxicity.”

    Has Dr Atwood or others here uncovered a fatal flaw which would invalidate the Pancreas study? If they have I don’t remember reading about it. And if they haven’t it seems utterly irresponsible to ignore and or dismiss the study.

    Given the central role as I understand it of plausibility in distinguishing EBM from SBM I find it ironic that so little effort is made by Dr Atwood and his colleagues hear at SBM to objectively and comprehensively ascertain the plausibility of the enzyme theory of cancer.

    A good place to start would be to read Dr Gonzalez’s exhaustively researched book on the origins and biological rationale for the use of enzymes to control cancer. I’d bet most anything that no one castigating Gonzalez would have the open mindedness to read the book. Am I wrong?

    I have attempted here to decouple the issues surrounding the Gonzalez/Columbia cancer trial from the plausibility of the theory. I’ve made my comments about the trial some time and I have no desire to reopen that issue in this venue.

  28. Wolfy says:

    @ oderb:

    Pancreas, 28(4):401-412, May 2004.

    1. This is the only series of experiments evaluating pancreas enzyme therapy in pancreatic cancer.

    2. These experiments were done by a single group (Gonzalez as an investigator), and do not appear to be confirmed independently by other research groups.

    3. There is little in vitro data to give insight into the pancreas enzyme therapy mechanism of action–other than that proposed in the aforementioned article (I would like to see cytotoxicity data demonstrating that porcine enzymes digest human pancreas adenocarcinoma in vitro, as has been proposed). This is usually necessary in order to obtain precious NIH dollars.

    4. There is only one (heavily biased) human case series.

    As I see it, there was not a great enough body of evidence to ethically bring this proposed “treatment” into human studies. Period.

  29. Dr Benway says:

    The central component of the Gonzalez therapy is the use of massive quantities of pancreatic enzymes to digest or otherwise neutralize cancer cells.

    Yeah that might work… if you eat the cancer after cooking it on the grill first.

  30. weing says:

    “The central component of the Gonzalez therapy is the use of massive quantities of pancreatic enzymes to digest or otherwise neutralize cancer cells.”

    So pancreatitis is the answer to pancreatic cancer?

  31. pmoran says:

    daedalus: “In the “wild”, you can’t keep a surface sterile.”

    True, yet the application of soil and excrement is as likely to increase infection rates in any wound as to decrease them, as we surgeons observe whenever we have to open the bowel during surgery. The use of quite potent antiseptics, including oxidising agents, does not eliminate that, or reduce it by much (antibiotics do), so I remain very skeptical that the application of NO-producing excrement would in any context.

    I was also responding to the assumption that the ancient healers were able to make reliable judgments on such matters. About the only ancient medical practices to find a place within recent medicine are herbs possessing unmistakable immediate pharmacological effects.

    It is simply beyond the ability of the typical observer to detect more remote, longer term and variable outcomes and remember them all. At least, the doctors of the last few centuries have proved poor at doing so, and it is unlikely early healers, lacking validated diagnostic systems and heavily into superstitious interpretations of illness ever did better.

    Much is often made of it when herbs used by the ancients are found to have useful medical effects. There is a lot of confirmation bias in that, including assumptions as to whether there was any true concordance in usage. Then there are the thousands of thousands of other highly unlikely ancient medical practices.

  32. @oderb:

    Wolfy has done a good job refuting your suggestion that the mouse study published in Pancreas might constitute a sufficient basis for a human trial.

    Let me add a few other points:

    1. The mouse study was published in 2004; even if it had offered substantial evidence for Gonzalez’s claims, which it did not, how could it have justified a human trial that began in 1999?

    2. You may be surprised to know that I have discussed that mouse study during this long series of posts, but for the reasons given above I would not consider it irresponsible to have ignored it.

    http://www.sciencebasedmedicine.org/?p=97#comment-2978

    3. Saul Green’s critique of Gonzalez’s and similar claims about cancer is comprehensive. Your dismissal of it as “non-peer reviewed” or as “attacking Gonzalez” or as having failed to address the important features of the Gonzalez Regimen is misleading, as any reader can ascertain. Saul Green was a biochemist with an expertise in cancer biology, who was at the Sloan-Kettering Cancer Center for decades; the “biology,” if you can call it that, of the Beard/Gerson/Kelley/Gonzalez cancer claims is primitive and simplistic. Green’s article hardly needed peer review.

    What Green shows is that Gonzalez is utterly wrong about numerous aspects of cancer biology. It also shows that there have been others who based their treatments on Beard’s quaint notions, and that in each case the results have amounted to unsubstantiated claims and unmitigated quackery: Max Gerson, Ernst Krebs Jr. (Laetrile), and William Donald Kelley (Gonzalez’s mentor) are famous examples.

    The various claims other than the “central component” are relevant not only because they are part of the regimen(s), but because they further betray their authors as, well, quacks: hair analysis, coffee enemas, the “Kelley Malignancy Index” (“the most accurate and extensive cancer detection system ever developed”), “the body’s acid/alkaline balance as well as its mineral and enzyme equilibria (being) brought into balance,” “detoxification,” “cancer thriving on anaerobic metabolism,” etc., are all examples of pseudoscientific nonsense.

    I wouldn’t buy a used car from anyone spewing such humbug, and I sure wouldn’t buy a cancer treatment. (Nor, I’d imagine, would any cancer investigators at the NIH or at Columbia University; so why did they feel justified in selling it to innocent experimental subjects?)

    4. To say that “Dr. Green dismisses the plausibility of enzymes in no more than a sentence or two by simply saying that cancer is caused by genetic mutations” is about like saying “Dr. Marshall dismisses the plausibility of stress in no more than a sentence or two by simply saying that peptic ulcers are caused by bacteria.” If it’s already been shown to be true, a sentence or two is adequate to make the point. Nevertheless, Dr. Green does more than that in his conclusions alone.

    5. I’ve discussed other aspects of Gonzalez’s implausible claims elsewhere in this long series, which you are welcome to read (my link to Green above was part of a very brief summary). In the very first post, for example, you’ll find that Gonzalez’s 500 page, unpublished apology for his mentor, Kelley—which Gonzalez squandered his medical training to write—was reviewed in detail by six physicians for the Congressional Office of Technology Assessment and found to be wanting in the most elementary of ways.

    6. Gonzalez’s troubles with the New York medical board in the 1990s reveal a practitioner who knows next to nothing about the very field–cancer–in which he claims expertise.

    Yes, Gonzalez’s claims have been examined “with great care and rigor” by many people, and the result is always the same.

  33. nybgrus says:

    @wolfy: Thanks for writing that up and saving me the trouble.

    @oderb: Wolfy sums it up nicely – one non replicated study and one iffy trial do not evidence for a study make. As I had mentioned in my prior post medical ethics requires studies to meet the demands of scientific rigor. If huge number of animal studies were done, but did not meet the plausibility clause, then there might be wiggle room to say that we simply have not yet elucidated the mechanism of action. That would likely lead to more basic science research and more animal studies in an effort to understand, but MIGHT be (and I stress MIGHT depending on the circumstances) possible to construe it as warranting a human trial. That is not out of the realm of medical ethics and research feasibility

    If the plausibility clause is met, then fewer positive studies would be needed to warrant further investigation via human studies, but still more than one or two would be necessary. And they would have to be GOOD studies.

    Additionally, any treatment which has one potentially good and plausible aspect (in this case, the enzymes as you have stated, though that will be addressed in a second) with a number of other completely inane and non-plausible aspects (the coffee enema) immediately falls into question. Besides the multi-factorial nature of the treatment that then makes a GOOD study harder to do (btw, did the mice get coffee enemas too?)* the very invokation of such bats__t crazy ideas (well said, Dr. Benway) is almost always just a distractor from the central idea – which doesn’t work in the first place. It is an oft used mechanism by hawkers of pseudo-science to promote some sort of synergistic claim “which science can’t explain” and thus sounds appealing to the untrained and non-discriminatory ear. (Yes, I said discriminate and it isn’t inherently a *bad* word).

    Lastly, the idea that a plethora of pancreatic enzymes can treat pancreatic cancer simply does not make sense. First off, ingestion of the enzymes ensures they will enter the gastrointestinal tract – but there is no mechanism for them to then go INTO the pancreas. The pancreatic juice comes out of the pancreas into the lumen of the duodenum, and by design luminal contents are kept from entering retrograde. Second, having an excess of pancreatic enzymes inside the pancreas is proven, without a shadow of doubt, to cause pancreatitis (as weing mentions). Diseases such as CF cause a clogging of the pancreatic duct and a back up of the enzymes, which then proceed to attack the pancreas itself causing inflammation and EXTREME pain. I have seen patients with acute pancreatitis and trust me, I do not wish to be them. Give me a kidney stone any day. This, of course, then brings us into the third point – assuming the oral enzymes have entered the pancreatic duct retrogradely (maybe the coffee enema goes so far up the pancreas wants a sip? :-D) and assuming the other luminal contents are minimally taken up as well (bouncers at the ampulla of Vater keeping the proteins, fats, carbs, fiber, and acid from your stomach out), how does one explain the specificity of the enzymes for cancer cells? Chymotrypsin is a serine protease and will cleave any compatible polypeptide chains it encounters – normal cells and cancer cells alike (that is just one example of a pancreatic enzyme, there are many others, but they would also have zero cancer vs non-cancer specificity). Now that we have established that, could the argument be made that general destruction of the pancreas as a whole would be the “cure” for pancreatic cancer? Well, that would then simply be equivalent to a total pancreatectomy. However, if that were the case, it could be done surgically and spare the poor patient the months of pancreatitis along the way. But even then, there has been shown data that the outcomes are worse, because of the development of brittle diabetes in these patients. So then we are left with the Whipple procedure (pancreaticoduodenectomy). And don’t even get started on metastases which could in no way be touched by a coffee enema or pancreatic enzymes.

    So as we can see, reasonable scientific discourse has quite soundly led us away from Gonzalez without even having to do a study. Based upon our understanding of science, this would make a human trial unethical. However, if there had been overwhelming bench science and animal study trials showing positive outcomes by some yet unknown mechanism we would at least have a foothold to justify spending time and money to find this new link and broaden our scientific knowledge. But those also do not exist here. Therefore, from a medical ethics perspective AND a justifiability of use of resources perspective, the trial is a farce.

    As I have said before and bears repeating once more, this tact MAY in fact lead to missing some amazing breakthroughs in science and medicine. That is the trade off of being ethical and living in a world of limited resources – decisions have to be made and occasionally they WILL be the wrong ones. But if every crackpot and bats__t crazy idea were tested (besides the ethics involved!) there would be no resources left to work out the good ideas! However, based upon all the data so far and coupled with the complete lack of plausibility, I will not be losing sleep over the idea that the Gonzalez regimen may be one of those amazing breakthroughs that has slipped through the cracks of science.

    And don’t forget, as has been said many times here, “The plural of anecdote is not data”

    _____________________________________________
    *I ask partly as a joke, but also because I am currently on a limited web connection and will not have a chance to look up the article till later in the day. If they did, then that point can fall to the wayside, but the rest is quite sufficient, I believe.

  34. “I was also responding to the assumption that the ancient healers were able to make reliable judgments on such matters. About the only ancient medical practices to find a place within recent medicine are herbs possessing unmistakable immediate pharmacological effects. ”

    pmoran – I don’t have enough anthropology or history to really dispute you statement, but I wonder about this. Perhaps I’m just misunderstanding. Considering the sophistication of architecture that you see in a historical context, considering the development of agriculture, fermented beverages, food storage, foods that are made palatable or even edible through complex processes, I feel that you may be underestimating the abilities of pre-modern people. Consider the invention of the telescope, navigation, the breeding and popularization of various grains and fruits. In more recent history, consider the development of the foundation of genetics through observation by Gregor Mendel.

    If I know that people observed that meat stored packed in a certain mineral lasted longer and used that knowledge, I don’t have a problem believing that they could also observe that cuts packed with certain poultices tended to heal better (or result in death less often.)

    That said, I’m not going to immediately rush out and get bleed the next time I get a respiratory infection. I don’t believe that just because something’s ancient it must be good, But I don’t think that it should be easily discounted that pre-modern people could make long term observations of a product or process.

    I’m sorry if I am being contrary or misunderstanding. I do admit many of the comments in this thread went well over my head, so perhaps I missed the point.

  35. nybgrus says:

    @micheleinmichigan: Then perhaps I can come to your rescue! One of my undergraduate degrees is in cultural anthropology with a focus in healing practices :-D

    I don’t have much time at this very moment, so this will be brief, but I am happy to write more later in the day if you still have questions.

    Essentially, it ties back with the post I wrote earlier, but I will re-iterate it more simply and to the point(http://www.sciencebasedmedicine.org/?p=6826&cpage=1#comment-56816):

    You are absolutely correct in stating that ancient man had great innovative strength and used observations such as you stated to progress. Mendel’s observations were systematic and stunning – but bear in mind they were so because such level of detailed recording and observation was only at that time coming into fruition (recall he was a 19th century figure). The crux of this lies with the middle ground. As you have said – if you noticed that a poultice healed a wound better or meat lasted longer, etc, then it became adopted more and more widely, because this knowledge conferred a greater fitness (ability to produce more offspring who would then learn this skill). Ones that were negative (the poultice that killed you, for example) would be tossed aside, not so much because it killed you, but because there was no advantage to knowing it – thus the group that had the killer poultice would not flourish like the good poultice group. The middle ground – where it did nothing – is what clings around us to this day. It hangs on because it does nothing, but it became part of tradition.

    Now of course, at the time of these ancient creations, many were truly based in observation and recording (Galileo for example or Jenner and the milkmaid) but the vast majority were literally trial and error – or at best scientific conjecture based on the science AT THE TIME. Science has since progressed and thus the ability to judge such treatments of antiquity is much easier. Something that seems to have worked in the past and has a HUGE amount of anecdote to support this can then be looked at through the framework of modern molecular medicine and objectively determined whether or not it actually has merit. Things like this, cease becoming “alternative” medicine or “traditional” healing and simply become “medicine.” The notion that the antiquity and tradition of something alone can somehow outweigh scientific understanding as we know it is exactly the cornerstone of woo and magic. It is simply impossible for something to have no scientific sense to it, fail in all RCTs and studies, and still have some sort of magical positive effect.

    The other thing to keep in mind is that of progression. Because an ancient treatment was cutting edge at the time and does in fact work for solid scientific reasons does NOT inherently mean it is good enough for us today – it must be BETTER than the current standard of treatment for the particular ailment in question. Otherwise, what is the point of having a number of inferior (or even completely equivalent) options to choose from? That is just a waste of time, money, and resources.

    As a simple analogy, cell phones worked back in the early 1980s – a true testament to our ingenuity – but no one would want to carry that brick around in their pocket when they could have an iPhone and no one would want to research a way to continue using that old and dead 2-bit technology for cell phone development when we have 32 and 64-bit integrated circuits at our disposal. Medicine is no different.

    I will check back here in a bit, so if you have any more questions or something is unclear I am happy to answer. You can also reach me at my email (AndreyAPavlov@gmail.com) I am always happy to try and answer any questions from honestly interested people as best as I can. I will also admit when I simply don’t know and do my best to double check my facts along the way.

  36. daedalus2u says:

    Nybgrus, the most important thing about being a scientist is intellectual honesty. Richard P. Feynman said it well.

    “The first principle is that you must not fool yourself and you are the easiest person to fool.”

    A lot of scientists do what is called “cargo cult science”. That is Feynman’s term. You should read up on it to make sure you don’t fall into that trap.

    Dr Benway has it right, I think the major (and unacknowledged) premise and assumption of EBM is that everyone is being intellectually honest. That is simply not the case with CAM. I think that SBM doesn’t make that assumption and formalizes the data handling every step along the way with Bayesian analysis.

    You can look at things that might be bs crazy with SBM, and come out with the right answer. If you look at things that are bs crazy with EBM, you get equivocal results, especially if the people doing the analysis don’t have the intellectual honesty to acknowledge that the treatment modality they are using doesn’t work. That is why tests of things like acupuncture end up with “toothpicks work too”, “needs more data” and not “acupuncture doesn’t work”.

    If a clinical trial won’t have the power to influence the Bayesian probability of the question under study, it is a waste to do the trial. It is like doing diagnostic tests. If the test is not going to produce a differential diagnosis with a differential treatment, there is no point in doing the test. Since the proponents of CAM never take a negative trial to reduce what they consider to be the Bayesian likelihood of their treatment being useful, there is no point in doing any trials of any CAM treatments.

    Pmoran, when the bowel is opened during surgery, it is an anaerobic bowel spilling into an anaerobic tissue compartment, a sterile anaerobic tissue compartment. Ammonia oxidizing bacteria are not present in the bowel in vivo, and could not live in the anaerobic tissue compartment the bowel spills into. Use of aerobically stored manure on the aerobic stump end of the umbilical cord which is not sterile and which cannot be kept sterile is completely different.

    I have read of a folk remedy for treating a cut, urinating on soil and then using the mud on the minor wound (I read it in Grapes of Wrath as I remember). The urea in urine would be hydrolyzed to ammonia and oxidized to NO/NOx. I have never tried it and don’t plan to. I do use a culture of my bacteria on minor wounds and they seem to heal faster and better. I appreciate that is an anecdote, but using NO to improve healing of wounds is an ongoing topic of research. I think the reason it works is because physiology evolved to utilize the NO/NOx generated in response to NH3 release as a therapeutic healing mechanism.

  37. pmoran says:

    “Pmoran, when the bowel is opened during surgery, it is an anaerobic bowel spilling into an anaerobic tissue compartment, a sterile anaerobic tissue compartment.”

    Did you mean “aerobic tissue compartment”? The only difference between surgical wound infection and umbilical stump infection that the latter quickly becomes avascular, dead, and therefore more prone to infection by anaerobes such as Cl. tetani or Welchii. The surgical wound is aerobic.

  38. nybgrus says:

    daedalus2u: I am aware of both cargo cult science and the cargo cults themselves. I came across the former in my physics studies for my BS and studied the latter in my “Peoples of the Pacific” course for my BA.

    I am unsure of why you feel I may be falling into such a trap of cargo cult science. I certainly do not think I am, but am honestly curious as to what in my writing makes you think so – both so that I may avoid such things and so that I may be more clear in future writings.

    You make some excellent points about the idea of intellectual honesty in EBM, and I am curious as to why you seem to be quite stuck on this notion of using NO/NOx bacteria in the treatment of infection – I don’t think anyone here has said anything at all negative about it and the investigation of such therapy may indeed prove fruitful. But that is not the discussion at hand since the attempted discussion is about the over arching themes of poor science, bad assumptions, and unethical behavior as a general metric by which to judge the Gonzalez trials. Such specificity about guano on stumps and surgical wounds, etc is not elucidating anything relevant to the discussion, as far as I can see.

    I also take minor contention with your assertion that “Since the proponents of CAM never take a negative trial to reduce what they consider to be the Bayesian likelihood of their treatment being useful, there is no point in doing any trials of any CAM treatments.” This is true to an extent, except insofar as that the nomenclature muddles the idea. Dawkins said it the best (and I fully agree) when he said (and I paraphrase, sorry, I don’t have the exact quote handy), “There is no such distinction as CAM vs Western Biomedicine. There is medicine and there is “not-medicine.” If something is labeled as CAM that is because it has either not been tested or because it has failed such tests. If it works, then it ceases to be CAM and is simply medicine.” I believe that the false dichotomy (which arose for reasons we can discuss at another time) creates this antagonism that we see today. But to say that no CAM treatments should ever be trialed ignores the subset that actually meet feasibility criteria. Additionally, whilst the CAM advocates will never be convinced by negative data, having such negative data will provide arsenal for SBM to justifiably not endorse popular but otherwise (potentially) deleterious treatment modalities. Being able to remove such treatments from reimbursement by insurance or using this negative data to keep such treatments out of (now scarcer and scarcer) reputable medical establishments is a distinct upshot to trialing such CAM modalities as become pervasive or have equivocal pre-trial outcomes.

  39. pmoran says:

    Michele: “If I know that people observed that meat stored packed in a certain mineral lasted longer and used that knowledge, I don’t have a problem believing that they could also observe that cuts packed with certain poultices tended to heal better (or result in death less often.)”

    I doubt it. They may derive an impression of healing rates that will be unduly influenced by whatever they remember of the last one of two patients treated and the ability to find excuses whenever a favourite treatment doesn’t work.

    Any sizeable wound packed with anything will take some weeks to heal and there will be a natural variability in healing rate of up to a few weeks depending on various factors including where the wound is situated.

    The human mind is just not capable of holding all the information often needed to accurately compare one treatment over another and it is also rarely aware of all possible confounding influences.

    For example, much of the reputation of honey in healing varicose ulcers is from hospital staff observing how rapidly ulcers often heal with this treatment. But varicose ulcers heal remarkably rapidly with best rest and elevation in hospital, even if previously static under common forms of outpatient care.

    The same applies to death rates. One of the earliest ever controlled trials was performed because doctors could not agree whether a serum treatment reduced death rates fro diphtheria –surely an easy matter to judge!

  40. daedalus2u says:

    nygrus, I wrote that shortly after your first comment when you spoke in (what I perceived to be) quite unsure terms about your science cred. There was nothing that you said that led me to believe you were a cargo cult scientist.

  41. daedalus2u says:

    Pmoran, yes the surgical field is aerobic while it is open, but once it is closed it becomes anaerobic. Sorry I was inarticulate in how I expressed it. The external umbilical cord remains aerobic. NO from aerobic manure can diffuse from the exterior to the interior whether the interior is aerobic or anaerobic. That is especially true in dead tissue because the blood doesn’t carry the NO away.

    Nygrus, the reason I am so enamored with NO/NOx is that is the focus of my research, and especially NO/NOx produced by ammonia oxidizing bacteria. I have found that they are normal human commensals that live on the external skin and set the basal NO/NOx level by oxidizing the ammonia released during sweating to NO/NOx which is then absorbed. I tend to bring up NO/NOx from the bacteria I am working with at every opportunity as my attempt to move the Overton window to allow their rational consideration. That you seem to think it is not an unreasonable idea means my plan is working ;)

    I completely agree with the sentiment that there is medicine and not medicine and that what is thought of CAM is not medicine.

    I apologize for bringing up cargo cult science as if that might be something you would need to be personally concerned with. It is great that you have particular expertise in that area. I look forward to more comments from you about it. It is very common in science, and to a large extent that is the kind of “science” that EBM does. Doing a clinical trial on acupuncture is cargo cult science. It is going through the motions of a scientific trial but without the intellectual honesty to change your world view when the trial shows that acupuncture is a placebo.

    The clinical trial that this thread was about was cargo cult science. It was going through the motions of a trial, dictated by an authority (political pressure) that doesn’t understand the science (and doesn’t care that they don’t understand) and had no scientific rationale for expecting therapeutic results. Not acknowledging that that there was no scientific basis and that therefore the trial was unethical and violated the Declaration of Helsinki is also intellectual dishonesty.

    I agree with Kimball that this was misconduct. The problem with how the idea of scientific misconduct is used these days is that it is used as a weapon for political purposes. Mann was investigated for scientific misconduct because he presented data and analysis that showed global warming was happening, not because there was evidence of misconduct. People are pretending performing this trial was not misconduct because to acknowledge misconduct would be to destroy the careers of the clinicians involved and have no effect on the politicians who pressured them into doing the trial.

  42. daedalus2u says:

    Nybgrus, just so you know, I have talked with multiple researchers working on the Human Microbiome project and none of them have been the slightest bit interested in considering autotrophic ammonia oxidizing bacteria or in deviating from their “scientific” protocols to look at someone who has a stable and self sustaining biofilm of them.

  43. JMB says:

    @phayes

    Perhaps I am misunderstanding your post. Are you arguing EBM does consider a priori probability in the selection of hypothesis?

  44. phayes says:

    @JMB

    No, clearly it doesn’t, and I’m just pointing out that the fact that e.g. a homeopathy CT is futile cargo cult science can be seen without invoking Bayes. I know EBM doesn’t consider the consequences of a very low prior probability but – to my astonishment and dismay – I’ve found that nor do many sceptics and scientists. I don’t know why that is but in case it’s because they’re not convinced by the argument in its usual Bayesian form…

  45. JMB says:

    @phayes
    Thanks for the clarification.

    I also like your point about the complexity of the experiment interfering with the reliability of the result. Some integrative medicine advocates are pushing the use of more complex experimental designs, ignoring the difficulties the complexities present with the assumptions of the statistical techniques used for analysis.

  46. pmoran says:

    “Pmoran, yes the surgical field is aerobic while it is open, but once it is closed it becomes anaerobic. ”

    I’m sorry, that is definitely not true either.

    Look, neither of us has direct evidence one way or the other on the question of whether it is good to smear manure and/or soil on a newborn baby’s umbilical area.

    However you should be warned that most doctors and every surgeon would react to the idea with “are you insane?”.

    It is also a potentially dangerous speculation. These days there could well be someone somewhere willing to try it out.

    Someone has to say firmly that any weak antiseptic effects of NO within manure are highly unlikely to cancel out other likely adverse effects of the practice.

  47. daedalus2u says:

    I completely agree that no one should put manure on an infant’s umbilical cord. I don’t think I came across as advocating it and hope no one thinks I did. I was just pointing out that it was done in the past and there may have been some legitimate data behind. I agree there is no justification for doing it now when there are alternatives with essentially zero adverse risk available. Manure is not a zero risk material. I might put the risk of infection and death at only 10%, you might put it at 50%. That is quibbling. Neither is acceptable. But in the “wild”, if the risk of infection and death with no manure was 20%, something that gave a 10% risk of death would be a wonder drug.

    If you were the village midwife and delivered 50 babies a year for 20 years you might be able to see the difference between 10% risk of death and 20%.

    Again, I am not advocating doing it, I am advocating talking about it and understanding it. Getting reactions like “are you insane” is not conducive to a dialog and understanding.

  48. JMB says:

    There is a wide separation between the laboratory scientist and the physician practicing SBM. The scientist thinks in terms of information to support plausibility for grant application. The practicing physician thinks in term of seeing patients who have suffered the consequence of trying some remedy. The practicing SBM physician wants active ingredients identified, purified, and assayed in preparation. That lengthy process of science gives the practicing physician a reliable risk versus benefit calculation to present to the patient.

  49. Wolfy says:

    @Dr Atwood

    “1. The mouse study was published in 2004; even if it had offered substantial evidence for Gonzalez’s claims, which it did not, how could it have justified a human trial that began in 1999?”

    Thanks for raising this important point; something I missed when I initially surveyed the article.

  50. nybgrus says:

    @daedalus2u: Thank you for the clarification. I strive with every step to have the utmost intellectual honesty I can, knowing that I will inevitably fail somehow, some way along the path. I only hope that my failure will be minor and/or recognized and caught. I stressed my lack of scientific experience simply because I recognize that while I find myself to be, shall we say, MUCH more informed than your average human (especially in the States) I do not consider myself an expert – and probably never will. I find the internet conducive to people touting that they are right and definitively know an answer and that immediately makes me question their intellectual honesty. That reasonable people may round off the error in overwhelming circumstances is sadly proving to be a slippery slope where pseudo-science takes a foot hold. If I, as an educated person, can round something with 95% certainty to the level of truth and fact then the uninformed masses say “Why, not my 90%? or my 80%?” and then start making up numbers and finally settle to say “you aren’t certain, and I am not certain, so why not just agree that BOTH our points have merit?” And henceforth comes pseudo-science, magic, woo, creationism, and what have you. The preamble was my attempt at intellectual honesty to state clearly that I would make assertions through my statement, but that I am not infallible, and the close was to actually invoke commentary since critique is an excellent way to learn. So, thank you for your commentary, and I am glad that my statements are not inane.

    As for your NO/NOx – I do find the arena of microbiomes to be quite interesting. The previously “sterile” alveoli have been found to contain numerous species of bacteria found only through DNA testing. Intractable C. difficile has been cured with fecal transplant. And now, here in Australia, they are looking at using Necator spp. as a treatment for Crohn’s disease (the idea being that the autoimmunity is caused be “boredom” of the immune system and giving it Necator to fight will divert the response away from the colon). And of course, on paper, a lot of these ideas seem “crazy.” I try and keep an open mind about things in general, and am certainly open to showing me a mechanism of something like the manure/stump idea. I hope that the rest of the scientific community has such open mindedness, though of course I’m sure it is lacking.

    However, as a closing note – things that do have scientific plausibility and can help humanity will hopefully be championed by passionate people who see this and bring it forth to the light. However, those who have no champion must fall to the wayside, and as I have said before, such is the price we pay for rigor and ethics. Of course, I’m sure you understand that this champion of the cause/underdog bit is huge in the human psyche and also fuels the huge pseudo-science and woo fiasco – and for this very reason, many a good thing (such as potentially your NO/NOx ideas) simply get swallowed up by the massive maw of stupidity.

  51. daedalus2u says:

    Thanks for the clarification, and encouragement.

    “With people of limited ability modesty is merely honesty. But with those who possess great talent it is hypocrisy.” Arthur Schopenhauer

    To my understanding the most important thing any expert needs to know is the limits of their expertise. If someone knows that, then they are an expert in my book, an expert that can be relied upon to not make mistakes through ignorance.

    I don’t think it is the maw of stupidity that swallows up good ideas, it is the maw of competition, vested interests and the barriers to entry they erect. Most competition is necessarily a zero-sum game, for every winner there must be losers. That need not be the case in science, but virtually everyone doesn’t know how to “compete” or to set up competitions in other than a zero-sum manner. This is incredibly wasteful in science, with lots of people chasing the same things with kudos only going to the one that gets there first. There isn’t a shortage of things to investigate and there won’t be for centuries.

    I have a lot of stuff on NO/NOx from my bacteria on my blog, and eventually this will be recognized as being important (because it is). There is no aspect of health that it does not have major effects on.

  52. evilrobotxoxo says:

    “There is no aspect of health that it does not have major effects on.”

    Daedalus, based on reading your posts here, I respect you, but such hyperbolic statements really don’t help your case. Arguing that all of human disease shares ANY common mechanism, regardless of what it is, only serves to display one’s ignorance of pathophysiology.

  53. nybgrus says:

    Kind words, thank you daedalus2u. I agree with the notion that a lot of science is a zero sum game, but I don’t think it is because that is the way scientists want it. That is the way society has set things up and since the money and funds come from somewhere….

    I say the maw of stupidity, because if, in our magical dreamworld of unicorns and lollipops, all stupidity was removed and intellectual honesty was rampant, then even with the way our system is set up, the zero sum would fade away from science since those massive negatives would have evaporated and there would be much more money and resources for honest science.

    And lastly, I’ll say that while I understand your passion I must agree with evilrobotxoxo – hyperbole (even when warranted) is rarely the best tact to take. I find myself oft to make hyperbole myself, and over the years have simply found better and better ways to restrain myself. This often leads to my girlfriend and my best friend (and fellow skeptic, med student, and a scientist beyond me) hearing all my pent up hyperbole. I do not mean this as a dig at you – truly, I understand your passion and excitement. It is just to say that intentional modulation and attenuation of said passion and excitement is usually a better way to get your point across and win people over. That, of course, is purely anecdotal from my experiences, but seems to hold very true in nearly every circumstance I have encountered. Just my two cents.

    Best to you.

  54. daedalus2u says:

    But it isn’t hyperbole.

    The only things I don’t think it will help with is already existing cancer (it might make it worse by acting as a growth factor), but it will work as a preventative.

    It won’t replace insulin for diabetes type 1. It will reverse diabetes type 2, but it will take at least several months, maybe longer. Off the top of my head I can’t think of anything chronic it won’t help. There are some acute things it might not, but even most acute things it will help.

    But you are right, making statements that people don’t understand and are unwilling to listen to their derivation and try to understand the very solid chain of facts and logic behind them doesn’t help me. I don’t know how to explain it other than with facts and logic and people just don’t have the time or desire to acquire the background to understand it.

  55. JMB says:

    The only things I don’t think it will help with is already existing cancer (it might make it worse by acting as a growth factor), but it will work as a preventative.

    Proper tissue oxygenation will also help most disease processes. However, in most disease processes the body responds and provides proper tissue oxygenation. There are some disease processes in which the body is incapable of supplying proper tissue oxygenation. Although healing of most disease processes benefits from proper tissue oxygenation, the treatment of only some diseases is focused on measures to improve tissue oxygenation. Demonstrating that a physiologic process is essential for healing the disease process is different than showing that a body will benefit through supplementing that physiologic response. The bodies healing response is one reason for differences in results observed between in vitro and in vivo experiments.

  56. nybgrus says:

    @daedalus2u: I can see you are extremely passionate about your NO/NOx bacteria. I can also see that you are indeed an educated fellow. The main reason I have become active in this blog, on YouTube, and in many other media forums is because I am also educated and passionate and want to find the best ways to get my ideas across to people and effect the most change. In other words, the internet is my testing ground for everything from outright insult to sickeningly sweet pandering and everything in between, simply to gauge response, learn rebuttal and ferret out the commonest arguments against me and my science. And, in places like this, to test my mettle and get constructive critiques.

    You are quite apt in saying, “..making statements that people don’t understand and are unwilling to listen to their derivation and try to understand the very solid chain of facts and logic behind them doesn’t help me. I don’t know how to explain it other than with facts and logic and people just don’t have the time or desire to acquire the background to understand it.” That is THE issue. Science has become so complex as to escape not just the imbecile, but intelligent people who simply are not trained in it. And this is causing the anti-science backlash we are seeing. However, we cannot expect everyone to become experts in our fields to then see our view, so I strive to find ways to work around this and other barriers. My girlfriend scoffs, calls them stupid, and deals not with them. But she is a hypersonics engineer and can sit in her lofty lab dreaming up rockets and what not (really, I barely understand what she does). I, however, will be dealing with people on the ground daily once I am a practicing physician. This is a skill I need to develop and one that I am passionate about because I cannot bear the idea of my 7 year old nephew being taught by a pseudo-science teacher.

    I apologize for the lengthy preamble, but my point is this – it doesn’t matter if it is or isn’t hyperbole. It matters if it SOUNDS like hyperbole. I can fully appreciate you feeling it isn’t but all I can offer is my personal opinion that you do seem hyperbolic about the topic. Based on the commentary from others, I would reckon they agree. So my humbly offered and unsolicited advice is to take that as a metric and retain your passion whilst finding new ways to spread your message. I know it is certainly much more complex than that and I am being very simplistic in my analysis, but remember that the end goal is what is vital. Whether you screamed (false OR true) hyperbole from the mountaintops or quietly underrated yourself along the way, if your research and ideas prove meritorious and become widely accepted no one will care, least of all you.

    Having said that, I need to learn to be much less verbose!

  57. daedalus2u says:

    JMB, yes, proper vascularization is regulated by NO. The body doesn’t sense a need for O2 and configure the vasculature to supply it, rather it senses the NO level and configures the vasculature to keep the NO level in the right range, not too high and not too low.

    Sensing O2 doesn’t work to determine when there is too much vascularization and when some needs to be ablated (as when a tissue compartment shrinks). The O2 level in blood is close to atmospheric saturation and a tissue compartment at near atmospheric O2 levels has enough vascularization and can’t tell when it has too much.

    What the vasculature needs to do is configure itself such that each cell is diffusively close to oxyhemoglobin. That is a better control mechanism than whether there is enough O2 because O2 levels change over time (the heart O2 need can change by an order of magnitude). Configuring the vasculature to bring O2Hb diffusively close to cells allows for O2 delivery to be regulated separately from vascular morphology. If a cell is diffusively too close to too much O2Hb, then some of the vasculature in the vicinity should be ablated. Capillaries should be remodeled until they are farther apart.

    It turns out the O2Hb is not only the source of O2, it is also the sink for NO. NO and O2 have very similar diffusional properties, so the local NO level can be used to measure if a tissue compartment is diffusively close to O2Hb. That measurement can be done independent of the O2 demand of the tissue. Because the affinity of O2Hb for NO is ~10^6+ times higher than for O2, the measurement can be done with NO levels that are 10^6+ times lower, nM/L instead of mM/L.

    So what happens if the NO level is too low? The cells “think” they are diffusively close to O2Hb (the sink for NO), even when they are not, so they ablate what they think is excess vasculature and move capillaries farther apart. I am pretty sure this is the source of the capillary rarefaction observed in systemic sclerosis, Raynaud’s, hypertension and diabetes type 2, congestive heart failure and disorders characterized by white matter hyperintensities (and not a few others).

    The only way to fix it is to get the basal NO level back up to where it should be. I discuss this in greater detail and with links on my blog

    http://daedalus2u.blogspot.com/2008/10/role-of-low-basal-no-in-capillary-and.html

    Every health problem that has issues with insufficient vascularization will be helped by more NO, provided that NO is delivered at the right place, at the right time, in the right amounts and as the right NO/NOx species. It is the control issues of NO delivery that are the most difficult. It is involved in too many systems for non-physiological delivery mechanisms to be effective.

    The vasculopathy of diabetes is not caused by too much glucose, it is caused by not enough NO caused by too much glucose producing superoxide. The cells too far from a capillary can’t get “enough” of what it is that capillaries supply, O2, glucose, insulin. When cells are not getting enough glucose they send out starvation signals and physiology does the only thing it can do, raise blood sugar. Blood sugar in diabetes (type 1 and type 2) remains fully under control. The control setpoint isn’t glucose concentration in the blood, it is energy substrates in the peripheral cells. If cells are not getting enough glucose, the body will raise blood sugar until they do. Insulin works to relieve diabetes not because it lowers blood sugar, but because it raises glucose levels inside cells. The replete cells then signal their lack of need for more glucose and the body turns down the glucose level of blood.

  58. JMB says:

    Insufficient vascularization is only one mechanism of diminished tissue oxygenation. There are different disease processes that lead to insufficient vascular supply. There is also a time dependency in which some tissues may infarct before the body can produce revascularization. Vascular insufficiency may occur at different levels in the vascular tree. Revascularization is a treatment goal in disease processes in which decreased oxygen tension in the tissues is the result of insufficient vascular flow, but the sequela of the disease process may be time dependent on the rate of revascularization. In the study of pathologic processes that lead to disease, there are many different steps (or state transitions if you prefer mathematical models) that lead to disease. Manipulation of any of the steps may produce some amelioration of the disease. (Addressing psychology/sociology of illness will ameliorate illness.) The ultimate goal is to cure the disease by finding one or more steps in the disease process that the body is unlikely to reverse quick enough by the healing process, manipulate those steps to break the cascading chain of events, and make it possible for the body to heal itself without lasting diminished function.

    It is entirely appropriate for a researcher to focus on one aspect of physiologic processes in the study of diseases. They become an expert in that field of study. Focusing on certain aspects of physiology may produce beneficial treatments for many diverse diseases. Doctors in practice tend to be skeptical of the power of universal treatments because of past promises of breakthroughs that have never materialized. The history of medicine is replete with treatments with sound scientific basis that have never proved successful in randomized clinical trials. Failure of a treatment in a randomized clinical trial does not mean that the basic science is incorrect. The power of manipulating the physiologic process may have been overestimated.

    I am sure somebody here will jump on my back because I repeatedly advocate better understanding of mathematics in both models of disease processes, statistics, and decisions. At least your repeated advocacy of effects of NOx has resulted in my further study of physiology of NOx.

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