Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Mon 12 Dec 2016 19:45

I too was pointing out the general problem, namely, when evaluating information about Lyme disease, it is important to know something about their past accomplishments and contributions of the investigator (credentials) and what other established investigators think about their views (i.e., publication in prestigious scientific journals after rigorous peer review). That's the reasonable and normal way of making such an evaluation.

Lorima
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Lorima » Tue 13 Dec 2016 17:15

Henry wrote:(i.e., publication in prestigious scientific journals after rigorous peer review). That's the reasonable and normal way of making such an evaluation.
Henry, hv, and necker,

We've discussed the science many times, and you never understand. You can look back at my previous posts to see how I know the IDSA/ALDF model is not well-supported by evidence. So instead of reiterating that argument, I'm going to focus on how one might account for your intransigence or inability to understand it.

The way I think about it, is that LD is a rogue field within the reasonably intelligent and honorable larger field of academic medicine.

Peer review in this rogue field has not been rigorous, from a scientist's perspective.

One doesn't have to posit that the entire medical research endeavor has gone off the rails.

All you have to do is recognize that (1) it is fallible, and that (2)many people's high level of trust in authority and prestige, to the point where they think they don't have to check the assumptions, data and logic of papers after publication, creates a "moral hazard" to which you seem to have fallen victim, if not perpetrated.

I'm speculating that it has something to do with whether one was brought up in an ethical system that prioritized obedience to authority, rather than independent thought. I have early pioneer roots, and a subcultural ethic of routinely watching authorities to help them not screw up. This depends on the skill of the individual operator, so to speak, and can of course lead to various problems, both individual and systemic, just like any other human endeavor. But the basic principle is that there's no infallible guru or pope or strong man in this system, and it is every citizen's responsibility to watch leaders and speak up when they fall into error.

In contrast, there are major ethical systems, even in the US, that are organized hierarchically, in which it is a citizen's duty to support and obey those above him or her in the hierarchy, rather than to question and correct. (I assume you can provide your own examples of these.)

With regard to LD, I f you were reared under the influence of one of those traditions where obedience is a high virtue, then you wouldn't necessarily be embarrassed or ashamed to uphold the leaders of the (rogue) field rather than help unmask them, even if you did have the intellectual ability to understand why the dominant model is a house of cards, scientifically.

Alternatively, you may not have the intellectual ability, and merely built your careers in science by verbal fluency (which I think is a talent independent from reasoning ability) applied to obedience to the field's hierarchy. That way, from my perspective, you're useful tools of this rogue field, and you get the benefit of feeling included in its power structure, despite not having the talent to earn your own place in science by discovery. Maybe it's just unlucky (assuming you originally meant to help sick people) that you got yourselves mixed up in this field, instead of one of the many sound ones.

It's hard to imagine that, after decades devoted to obedience, you'd suddenly fall off your horse and become both braver and smarter. It takes a lifetime of effort to cultivate the skills of independent thought, and some inborn talent to even start. So I suppose the LD field will progress, as Planck had it, one funeral at a time.

Meanwhile, it's good to see these Hopkins scientists bypassing the dogmatic blockade you are manning, and work on the questions that matter.
"I have to understand the world, you see."
Richard Feynman

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Tue 13 Dec 2016 17:33

Lorima: Such sophistry is not worthy of comment.

Lorima
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Lorima » Tue 13 Dec 2016 18:07

Thanks, I don't need a comment. Your previous actions speak louder than any comment you could make, now.
"I have to understand the world, you see."
Richard Feynman

dlf
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by dlf » Sun 18 Dec 2016 1:46

@ hv808ct

I continue to be puzzled by what you were trying to communicate when you wrote:
John Aucott’s position as Hopkins faculty seems as tenuous as my own office space and title at the University of _______. He’s the sole physician at the obscure JHU LD Research Ctr., and both he and Embers seem to spend more of their time maintaining ties to private LD foundations (Bay Area Lyme Foundation, LymeMD, LymeInnovation) than doing fundamental research or collaborating with the two generations of active, productive LD investigators.

AND

No, my job’s secure. Perhaps I shouldn’t have used the word “tenuous.” Perhaps “vague” would have been a better choice.

Replacing the word “tenuous” with “vague” in your sentence, i.e. "John Aucott’s position as Hopkins faculty seems as vague as my own office space and title at the University of _______." does not make your intended message any clearer to me. The word "vague" has several meanings. Perhaps it would help if you would choose one that reflects what you were trying to express.

Definition of Vague by Merriam-Webster

1a : not clearly expressed : stated in indefinite terms
b : not having a precise meaning
2a : not clearly defined, grasped, or understood : indistinct ; also : slight
b : not clearly felt or sensed : somewhat subconscious
3: not thinking or expressing one's thoughts clearly or precisely
4: lacking expression : vacant
5: not sharply outlined : hazy

At any rate, I don't get the sense that John Aucott's position nor the research program at JHU Lyme Center are "vague". He seems to lay out the direction and focus of his research program and what he is doing to advance the science very clearly.

https://www.hopkinsrheumatology.org/spe ... /research/

hv808ct, you also wrote:
Anyway, no, I didn’t miss the $10M news. It just reaffirms the idea that Lyme activists with money tend to support the work that fits their personal narrative.


I think that patients understand that ticks don't discriminate as to who they infect and that the vast majority of those 60,000 additional patients added each year to the numbers of us who continue to have persistent symptoms and unresolved illness after recommended treatment (the ones duncan keeps bringing to the conversation) have few resources to support anything. Most are more concerned with keeping a roof over their heads, food on the table and trying to achieve some level of reasonable functionality.

Sure, supporting research designed to examine hypotheses that could ultimately help patients likely would be (at least in part) motivated by someone's personal narrative, however, philanthropy on this scale is most often driven by altruistic concern for overall human welfare and advancement.

John Aucott has come up with a research program that focuses on elucidating what actually happens in real-world human Lyme patients after infection with Borrelia. It is appealing because although animal models (especially ones that have been altered) can provide considerable additive information to the general pool of scientific knowledge, animals do not by and large have sufficiently similar immune systems, nor do they reflect the human patient experience and all that has come to entail for Lyme patients who continue to have ongoing symptoms and sequelae after IDSA recommended treatment.

I would like to think academic researchers have enough flexibility in research advisory committee meetings that they are able to at least design and choose their own direction. Maybe your office space and title would be a whole lot less "vague" (and possibly more personally gratifying) if you considered the patient experience and perspective as legitimate and valid and worked towards building collaborative efforts with those investigators who are trying to examine and understand the ongoing debilitating health problems that Lyme patients in the real world face, improve public health, and advance the science..........

Just saying.............

dlf
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by dlf » Sun 18 Dec 2016 2:25

by Henry » Mon 12 Dec 2016 19:45
I too was pointing out the general problem, namely, when evaluating information about Lyme disease, it is important to know something about their past accomplishments and contributions of the investigator (credentials) and what other established investigators think about their views (i.e., publication in prestigious scientific journals after rigorous peer review). That's the reasonable and normal way of making such an evaluation.
@ Henry, that way of making such an evaluation might have been useful at one time (and may still be) in some fields of medical and scientific research. I don't think that has been a useful approach for evaluating Lyme research information for a very long time, if it ever was, mainly because of poor and incorrect assumptions made in the early years of investigation that have not been rescinded and still continue to form the underpinnings for current recommendations in spite of newer findings. Additionally, I find it hard to believe that you would be politically naive and therefore not aware of the vested interests which have spawned a legacy of biases among at least some of your colleagues.

As I said, I prefer to discuss each study on its own merits or lack thereof. While it is to be hoped that all scientific research and articles would be additive, for far too many of the publications (particularly ones produced prior to about 2008) that I have read, this has not generally been the case. As such, I think well-qualified professionals with solid track records in other disciplines from outside of the Lyme hierarchy provide fresh eyes and a new perspective to the investigations. Not only have several of these researchers provided new insights into trying to understand and resolve the problems patients are dealing with, they have provided novel directions for primary research and inspired impetus for additional and improved work to be undertaken even among those people you refer to as "established investigators".

There have been some very interesting collaborative efforts in the last number of years and I would hope that these are being driven by an open-mindedness among those of the old guard who are involved and not simply the result of newer investigators needing to bring someone onto a project to get it peer reviewed and published. I also hope the "established investigators" are not there just to keep a watchful eye and put the brakes on new findings.

If a serious goal is to solve the problems of suffering Lyme patients, collaboration and building bridges between the investigators who are genuinely trying to find patient oriented solutions will be an important first step.
by Henry » Wed 7 Dec 2016 14:18

Duncan: And one last point, lest you think I am ignoring the plight of the many sufferers with chronic Lyme disease. What I propose would help more of them than you could possibly imagine. Think about that. Why once the relevant cytokines are identified, drug design technology would enable a skilled pharmacologist to develop a safe and drug to neutralize their effects.
Henry, lately you seem to be focused on the immune dysregulation, dysfunction and resulting cytokines caused by Lyme in patients as being a source of ongoing symptoms and problems. Why not work on your proposal and actually try to encourage a patient oriented way of examining this? There might be far more appropriate ways of investigating the "stuff" you wrote about that you suggested incites cytokine production (for which I suspect you are referring to "immune complexes") in humans rather than relying on studying these things in mice which are quite different immunologically from people.

There may be no need to re-invent the wheel on this:

Schutzer SE, Coyle PK, Reid P, Holland B. Borrelia burgdorferi-specific immune complexes in acute Lyme disease. JAMA. Nov 1999; 282(20): 1942-6.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/10580460/
Abstract

CONTEXT: Diagnosis of infection with Borrelia burgdorferi, the cause of Lyme disease (LD), has been impeded by the lack of effective assays to detect active infection.

OBJECTIVE: To determine whether B. burgdorferi-specific immune complexes are detectable during active infection in LD.

DESIGN, SETTING, AND PATIENTS: Cross-sectional analysis of serum samples from 168 patients fulfilling Centers for Disease Control and Prevention surveillance criteria for LD and 145 healthy and other disease controls conducted over 8 years. Tests were performed blinded.

MAIN OUTCOME MEASURE: Detection of B. burgdorferi immune complexes by enzyme-linked immunosorbent assay and Western blot.

RESULTS: The B. burgdorferi immune complexes were found in 25 of 26 patients with early seronegative erythema migrans (EM) LD; 105 of 107 patients with seropositive EM LD; 6 of 10 samples that were seronegative [corrected] with culture-positive EM; 0 of 12 patients who were treated and recovered from LD; and 13 of 13 patients with neurologic LD without EM. Among 147 controls, B. burgdorferi immune complex was found in 0 of 50 healthy individuals; 0 of 40 patients with persistent fatigue; 0 of 7 individuals with frequent tick exposure; and 2 of 50 patients with other diseases.

CONCLUSION: These data suggest that B. burgdorferi immune complex formation is a common process in active LD. Analysis of the B. burgdorferi immune complexes by a simple technique has the potential to support or exclude a diagnosis of early as well as active LD infection.
Sure, Linda Bockenstedt and colleagues have been working on this to some degree in mice,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052197/

but, some other investigators in North America and in Europe have already done considerable work on cytokine studies and on measuring increased levels of cytokines in Lyme patients.

Henry, if someone were to be genuinely serious about this type of immunological research with a hope of improving the lives of Lyme patients sometime before the first generation of your favored "Lyme experts" all die off, they would be looking to gain this expertise outside the " established investigators" and instead try to create new collaborative relationships with bright immunologists who are recognized as being talented in their own areas of research. Major advances have been made in the field of immunology in the past two decades. From my perspective, likely candidates to consult and acquire insights from regarding manipulating (and ameliorating) immune responses might have research backgrounds and clinical trial experience as drug developers and physicians using some of the new cancer immunotherapy drugs on real live human beings.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783916/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764117/

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Sun 18 Dec 2016 16:42

dlf: I find it troubling and indicative of a deep seated mental problem to be writing and posting on LNE at 1:46am and 2:25 am. Usually, I am soundly asleep at that time. Perhaps you ought to get a bit more rest. It might help to "clarify" your thought process.

Incidentally, several investigators have tried to reproduce the findings of Schutzer et al. and have been unable to do so. That is the real reason why such a concept has little or no credibility. You can do a PubMed search and find several reports that Borelia possess lipoproteins that can generate the release of inflammatory cytokines in both humans and animals during infection. This phenomenon has nothing to do with and is independent of immune complex formation. It has been shown that isolated Borrelia lipoproteins as well as dead intact Borrelia cells -- or their debris-- also are able to elicit such pharmacological effects. Bockenstedt and others are now pursuing the clinical relevance of such findings. That is work in progress.

dlf
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by dlf » Mon 19 Dec 2016 1:57

Ummm, Henry, you seem to be confused again. You do understand that this is an international discussion forum, don't you? Given your personal focus on Lyme in the U.S., I doubt you really live in the same European time zone as the lymeneteurope clock. Sometimes I wonder why I hope it would even be possible to able to carry on a sensible discussion with you since you seem to have difficulties even understanding world time. Your concern over my sleep (and mental) hygiene is quite unnecessary. In my part of the world, there is a time difference between my local time and when messages are time stamped in the forum.

Not that it matters with regard to this conversation, but according to Brunner, the investigators who tried to reproduce the findings of Schutzer et al. apparently didn't try to reproduce those findings very accurately.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1391946/

Report Refuting Value of Immune Complexes To Diagnose Lyme Disease Is Invalid
Michael Brunner
Attempts to disprove the concept of IC by merely claiming to repeat a procedure with poor materials, techniques, and multiple simultaneous methodological changes should be discounted. Their conclusions are invalid, counterproductive, and a disservice to patients with or suspected of LD.
Be that as it may, this is a red herring, immune complexes are real things. They do exist and are acknowledged to be a factor in a wide range of diseases including arthritic, other autoimmune and microbial types.

https://www.ncbi.nlm.nih.gov/pmc/articl ... 8-0216.pdf

I am aware that Borrelia lipoproteins could stimulate this cytokine production on their own. Would it really make any difference at all whether the inflammatory cytokines produced in a host as a result of a Lyme infection are generated by ICs, or Borrelia lipoproteins, or detritus? The issue is that cytokines are not isolated proteins with no purpose and no downstream effects. Inflammation is responsible for activating both innate and adaptive immune responses. These things are all intimately tied together.

Bockenstedt and her research group are looking towards creating a new cytokine-based immunoassay for the diagnosis of Lyme disease and thankfully (at long last) are looking to characterize these cytokines in actual human patients instead of mice.

http://agingportfolio.org/projects/proj ... I100191-04

I do hope they figure it out because the world certainly needs a better method of testing than we are now saddled with. This work, however, would seem to fall waaay short of helping to elucidate the broader clinical relevance of cytokine signalling triggered by Lyme, not to mention incapable of beginning to determine how to ameliorate the effects in patients with chronic symptoms. Because cytokine signalling is common and non-specific in most if not all diseases and disorders, so far this project looks like yet another one destined to produce a decent income for the investigators, but no validatable test, nor much else.

If you are proposing that the wave of the future for Lyme research that would most help patients will be in regard to cytokine over-expression and the resulting effects, then it should be time to drop the protectionist attitude and get people with some expertise in the appropriate field to weigh in.

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Mon 19 Dec 2016 3:47

dlf: As I noted in a previous posting on this topic, the work you describe re: cytokines in humans is now in progress. Bockenstedt is but one of the investigators examining this issue.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Mon 19 Dec 2016 14:49

Henry, maybe you can forward this Johns Hopkins article to Bockenstedt.

So, let me see if I understand this disrupted immune system hypothesis in the context of this study. Studies like this, and from the likes of Lewis and Embers, suggest front-line abx may not eradicate Bb. So, IDSA-recommended therapy comes up short, potentially.

The way you counter that is by saying Lyme patients' immune systems will mop of the remnants, yes? But if I understand correctly, Bockenstedt and her friends are positing that Bb corrupts the immune system in some Lyme patients. Right? On a basic level, it alters the immune system's norm? And isn't it Steere that has been searching for some sort of autoimmune disorder - specific to knees - triggered by Borrelia? Have I got that right?

If Bb causes the immune system to act in an aberrant manner, why in the world would anyone presume that those compromised/affected immune systems would be capable of doing what front-line abx were incapable of doing in the first place?

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