8 Round Two: Lyme Disease Research Scavenger Hunt

So I  began a little online scavenger hunt game here at Camp Other, and we completed round one about two weeks ago.

So far, since only one entry has been submitted by Rita - Rita, you are the winner of round one by default. I say even without competition for that round, take a bow for the work you put into researching your answer for round one.

Now I'll present those who wish to play along with our basic game instructions and round two of the scavenger hunt:

This is an online scavenger hunt to determine which Lyme disease research being conducted in which universities and colleges involves or has involved members of the 2006 Lyme disease guidelines group.

I'm going to list Lyme disease related research either completed or currently being done in Column A, and in Column B, list the educational institution where the research was (or is) being conducted.

How to play:

Match the research in Column A with the correct educational institution in Column B.
Determine if members of the department involved are A) currently doing research with a member of the 2006 Lyme disease guideline authors or B) have worked on any research in a past with said guideline author(s).

Write your matches and mentions of any guideline authors in a comment and submit your comment for posting.

You can use google, Wikipedia, and any on and offline tools for your answers.

Roughly one week (perhaps we should make this two?) after I post a round, I'll post the correct answers as well as post the next round of the game. I intend to run the game for several weeks - end date to be announced later.

If anyone wins all rounds, after that win is confirmed, the next post I write will be based on the winner's selected topic of choice and include hand-drawn illustrations by me.

Research Description	Educational Institution
1) Established the rhesus monkey model of Lyme disease. Discovered an immune evasion mechanism that Borrelia burgdorferi, the spirochete that causes the disease, may use to cause persistent infections. Discovered that B cells produce the regulatory cytokine IFN-gamma in animals infected with B. burdoferi. Discovered that spirochetes elicit not only inflammatory but also anti-inflammatory cytokines from monocytes, thus contributing a method to control the inflammation they themselves cause.	A) Medical College of Wisconsin
2) B. burgdorferi binds to members of a family of receptors on the surface of human cells termed "integrins", which are important in many cellular processes, including inflammation and blood vessel growth.  Using a phage display library of B. burgdorferi genomic DNA, we identified a B. burgdorferi protein that mediates bacterial binding to β3-chain integrins, and have defined portions of this protein that participate in integrin recognition. Our current work focuses on determining the role of Borrelia-integrin recognition in the course of infection and the development of Lyme disease in the mouse model.  We have also studied the mammalian cell response to B. burgdorferi strains that do or do not express the β3-chain integrin ligand, and by microarray analyses, have identified several signaling/regulatory pathways that show integrin-ligand specific changes in expression. Some of these may be important to the ability of this organism to disseminate from the site of the tick bite to other tissues. We also discovered that another B. burgdorferi protein, BBB07, signals through integrin α3β1 to promote a proinflammatory response in human chondrocytes, which may contribute to the pathogenesis of Lyme arthritis.  Our phage display library was also used in vivo to identify B. burgdorferi proteins that bind to vessel walls in specific tissues such as the joint and heart, and further characterization of these proteins is underway.	B) Tulane University
3) Critical to this work has been our development of green fluorescent protein (GFP) reporters that enable us to track live spirochetes in ticks and mice. Our live-imaging studies have fundamentally changed our understanding of the transmission process. In order to reach the mouse, spirochetes disseminate through the midgut into the salivary glands in order to access the salivary stream which they “ride” into the vertebrate host. We have found that dissemination of spirochetes in ticks is actually biphasic. In the first phase, which we have termed “adherence-mediated migration, spirochetes replicate in close association with differentiating midgut epithelial cells, “working” their way as aggregates or networks to the base of the epithelium. In the second phase, they transition into typically motile spirochetes, complete the penetration through the midgut, and then move on to the salivary glands en route to the mouse. Most recently, we have found that spirochetes lacking RpoS are deficient in this process and we are developing various strategies to identify the RpoS-dependent genes involved.	C) University of Connecticut

There is much to learn from playing this game in and of itself that you gain something whether you win or lose. (I also have a point to make in playing it, and I'll reveal it at the end of the series... It might not be the point you suspect I'm going to make.)

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3 Antiscience letter and conflicts of interest

Since I finally had the opportunity to read the full text of the antiscience and Lyme disease advocacy letter in the Lancet, someone asked me if the letter had any stated conflicts of interest attached to its full text version.

Yes, it does - and here is the stated conflicts of interest portion:

Conflicts of interest

PGA has served as a consultant for Oxford Diagnostics and has participated in expert testimony in two medicolegal suits about possible Lyme disease. He has equity interest in Johnson & Johnson, no products of which are referred to in this article. RJD is part owner of and has stock in Biopeptides Corporation, no product of which is referred to in this article, has received payment for providing expert testimony in malpractice cases and holds patents on vaccine and diagnostic technology with SUNY at Stony Brook Biopeptides. JSD has received support for travel to meetings from DiaSorin and has licence of US patent 5,955,359 to Focus Diagnostics; none of these declarations are directly related to the contents of this article. JJH has served as an expert witness in several medicolegal cases concerning Lyme disease and has equity in Abbott, Bristol-Myers Squibb, Johnson & Johnson, and Merck; no products from these companies are referred to in this article. EMcS was a former programme officer for Lyme disease at the US NIH. RBN has served as an expert witness in malpractice litigation involving Lyme disease. EDS is a board member of the American Lyme Disease Foundation, for which no compensation is received. He has reviewed medical records for the Metropolitan Life Insurance Company and has provided medicolegal testimony. GPW is a board member of the American Lyme Disease Foundation for which no compensation is received, has served as an expert witness in malpractice cases involving Lyme disease, has research grants from the NIH/Immunetics, BioRad, DiaSorin, and BioMerieux to study diagnostic tests for Lyme disease, none of which is mentioned in the manuscript, and has equity in Abbott, a company not known to have any approved product for Lyme disease. JSB, RJD, JSD, JJH, RBN, EDS, ACS, and GPW have served on the panel for the 2006 IDSA Lyme disease guidelines. JSB, SO'C, SKS, ACS, and AW declare that they have no conflicts of interest.


Related to this, here are your questions of the day:

Does having these conflicts of interest affect how the authors of the letter act in the treatment of Lyme disease, if the authors engage in determining the outcome of insurance cases for Lyme disease treatment, develop vaccines and diagnostic tests, and write up guidelines for the treatment of Lyme disease? At what point does one say that one has a conflict of interest versus because one is considered an expert they are called upon to make these decisions by others? How does one separate the two?

In the Lyme disease controversy, Lyme disease patient advocates have pointed out IDSA Lyme disease guideline panelists' conflicts of interest in the past, and in the full text of this letter, the authors pointed out conflicts of interest being held by ILADS members. Is pointing out these conflicts of interest being done in the interest of fairness or in order to engage in a negative campaign against the other party?

Is there anyone out there who is free of conflicts of interest who is involved in the Lyme disease controversy? How do you know they are free of conflicts of interest?

Now that this letter has created a stir in the Lyme disease patient community, what's next? For anyone who has read the full text of the original letter, what is the best next step for resolution of this controversy? Brainstorming is welcome.

Addendum: Regarding Abbott, see this link on their research assays and ask why there isn't a better diagnostic test available for patients.

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2 Admin: Writer's Scatter, Rather Than Writer's Block

A more personal note here from CO:

I think I have the opposite of writer's block at the moment, and I'm calling it writer's scatter. While Lyme disease has left me with shoddy memory at times (Did I leave the water running? Did I leave something in the toaster?) in terms of concentration I am all over the map. I can be intensely focused on something for hours and the rest of the world disappears, or I can be so mentally scattered my mind will not rest on one idea at a time for more than a minute or two.

This is where I am at the moment, and it looks to all the rest of the world like ADHD. Except... for the most part, people don't see me as being hyperactive when my butt is firmly planted to the sofa all the time. But if they could see inside my mind, then what they'd witness is a very different phenomenon. It's one that is making it very hard to write about any one thing now.

I'll give you a peek into my stream of consciousness at the moment, so you can see just how many branches are splitting off the old mental tree:

I'm thinking of the letter that was recently published to the Lancet which I've ranted about, and the reception to that rant. A lot of people visited this site in the past couple days to read that rant, but only few people commented on it here. Why is that?

I'm thinking about how being a doctor is different from being a researcher and what that means when someone is discussing treatment versus discussing evidence-based medicine. Are these two things always the same things? Are they different things? When is and isn't that okay?

I'm thinking about the use of ketamine in mice to sedate them during experiments and wondering how that might influence the outcome of testing the effect of Borrelia burgdorferi on the immune system. I even wrote a post about it months ago but have never posted it, thinking few people would want to read about it.

I'm thinking about this stack of paperwork I have to sort through and find irritating to do so. I have to make some phone calls in the morning. I need to sign and put some forms in the mail. I am bound to not do half of what I need to do even if I write it down.

I'm thinking about my posts from months ago where at the bottom of each, I've written "to be continued in part 2" or "more in a future post on this topic", and part 2 hasn't been written nor has a future post addressed that topic. Where do I begin, when so many other topics and news have grabbed my attention and inspired me to write - and these old threads which have been postponed have not?

I'm thinking about how readers have suggested topics for me to write on and I haven't gotten to those, either.

I'm thinking about how it is that on some Lyme disease support groups - if you don't share the same opinion as the majority does and your difference of opinion makes others bristle rather than ask questions out of curiosity - how difficult that is for you to find support when you are already marginalized by illness.

I'm thinking about how the hell the kitchen is going to get clean given the state it's currently in. It looks like someone put a detonator in the crockpot and it went off. Five alarm chili just might mean anyone who looks in that kitchen is going to be alarmed... It is going to take a long time for me to do anything about it and I can only chip away at it for a few minutes at a time before my arms get too worn out.

I'm thinking about coming up with my own lazy bachelor with a chronic illness cookbook. It must include mixed drinks and easy snacks. Some of the recipes need to burn the roof of your mouth and clean out the sinuses, too. I don't want these recipes to be bland by any stretch of the imagination.

I'm thinking about all my friends who were in the path of the hurricane and lost their power. (Mine is fine, thankfully.) I've heard from most of them - their basements are soggy but they are alive and mostly well.

I'm thinking about how a year ago I told someone I don't want to be defined by this disease and I want my life back. And here I am, writing this damned blog. How did that happen? I swore I would get better and never do something like this. Yet here I am.

My ears are ringing. I need more sleep. So I'll end things here for the night.

Besides, I will just continue to have more random thoughts racing through my head like this until I pass out.

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0 News: In Wisconsin, Illnesses spread by ticks on rise

The Wisconsin Rapids Tribune has this article on tap today:

Illnesses spread by ticks on rise

Excerpts:

Consistent testing and an increase in deer ticks are driving up the number of tick-borne illnesses reported annually in Wisconsin, health officials said.

Statewide, cases of the bacteria infections anaplasmosis and ehrlichiosis -- both spread by deer ticks -- increased 70 percent from 2009 to 2010, when 546 cases were reported, according to state data.

"It's nice to be able to pick (anaplasmosis and ehrlichiosis) up, so a patient can be properly treated," said Diep Hoang Johnson, an epidemiologist for Wisconsin's Division of Public Health. "If lyme disease (tests) come back negative, they may not get treated and they may have one of these diseases."

and

"Marx said the increase in tick diseases other than lyme likely is because of more efficient testing and health care providers' improved efforts to report the illnesses."

Comments:

It's important to keep in mind that not every tick bite leads to a case of Lyme disease, and a negative Lyme disease test result does not necessarily mean the patient does not have Lyme disease (antibodies may not have been present at the time the test was taken) - nor does it indicate what other tickborne infections a person may have such as Ehrlichiosis or Babesiosis (as well as a few viruses which are spread by tick bites).

It's important for doctors and patients to familiarize themselves with the range of tickborne infections which are out there and be aware of the symptom spectrum for all them, as well as for doctors to take a detailed history from patients to see where they have traveled and resided to determine which tickborne diseases they are at greater risk of contracting. This provides a starting point for which coinfections to test for - but is by no means definitive as these diseases spread and even change in geographic location and density.

Read more of this news article at: http://www.wisconsinrapidstribune.com/article/20110828/CWS0101/108280518/Illnesses-spread-by-ticks-rise

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21 Letter: Antiscience and ethical concerns associated with advocacy of Lyme disease

Well, it's time for a little commentary on a recent publication which has been making the rounds in the Lyme disease patient community - this time on a letter which has been published to the Lancet recently. The letter is basically about those who believe Lyme disease can be a chronic, difficult to diagnose disease are part of an antiscience movement, and how the media, politics, and advocacy groups have supported unorthodox views concerning Lyme disease and other tickborne infections.

I'll post the excerpts in full first, and then a second time with my commentary interspersed.

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Excerpts from: Antiscience and ethical concerns associated with advocacy of Lyme disease.

Auwaerter PG, et al. Lancet Inf. Dis. Aug 22 2011.

Aspects of Lyme disease advocacy are an important example of this antiscience movement. For the purposes of this Personal View, we will define this antiscience outlook to also include the promotion of pseudoscience and science that has weak credibility or validity because of fundamental flaws in its design or poor reproducibility.

For two decades, many Lyme disease activists have portrayed Lyme disease, a tick-borne infection, as an insidious, ubiquitous, difficult to diagnose, and often incurable disease, which causes mainly non-specific symptoms such as chronic fatigue, musculoskeletal pain, and neurocognitive dysfunction that can be treated only through the use of antibiotics for months or years.

As with other antiscience groups, some Lyme disease activists have created a parallel universe of pseudoscientific practitioners, research, publications, and meetings, arranged public protests and made accusations of corruption and conspiracy, used harassment and occasional death threats, and advocated legislative efforts to subvert evidence-based medicine and peer-reviewed science.
Politicians, the media, and the public have been left trying to discern the scientific facts from the pseudoscientific ones, with many regarding both as equally valid as they try to be fair and balanced.

When such inappropriate and uncritical weighting occurs, public and government officials unknowingly come to accept or even endorse highly unconventional and sometimes dangerous theories and therapies.

Many individuals who represent themselves as Lyme disease activists and LLMDs hold and promote views of a tick-borne infectious disease that is inconsistent with credible scientific evidence. Although relatively small in number, their effect should not be underestimated.

Their unorthodox perspectives and resulting practices have contributed to injury and even deaths of patients. Millions of dollars have been spent refuting their claims, and thousands of hours have been spent responding to false allegations, legal threats, congressional queries, and other harassments.

At a time when unnecessary healthcare expenditures are being scrutinised and widespread bacterial resistance has been linked to overuse of antibiotics, it is particularly important that unsubstantiated treatments be avoided.

This situation is not likely to end anytime soon. As with other antiscience groups, many Lyme disease activists are well funded and often connected to influential political and media sources.

Treatment of Lyme disease with long-term antibiotics is profitable for LLMDs and can be falsely reassuring to patients, who believe that they have a debilitating chronic infection and thus do not seek diagnosis and treatment for other disorders.

There is no deficiency of either new patients or activists. The medical anthropologist Sharon Kaufman wrote that “Information technology has transformed the way trust and knowledge are produced”. Most people now find medical information on the internet, and the websites of LLMDs and activists are often viewed as legitimate and reliable sources of information, which they may not be.

Such misplaced trust has also contributed to a similar situation in Europe, with increasing pressure being brought on authorities there to sanction the use of prolonged antibiotic treatment for patients without credible evidence of Lyme disease by groups such as the German Borreliosis Society and Dutch Lyme Association. This ill-founded advocacy is being extended to other, less common, tick-borne infections (and to non-Ixodes tick-transmitted pathogens such as Bartonella).

In conclusion, activists, through public appeal and political lobbying, have managed to divert attention away from existing evidence-based medicine in their quest to redefine Lyme disease. There is a serious concern that they will further endanger the public’s health unless responsible physicians, scientists, government leaders, and the media firmly stand up for an evidence-based approach to this infection that is based on high-quality scientific studies.

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1 Immune + Infection = HLA-DR alleles determine responsiveness to Borrelia burgdoferi

Recently I've been reviewing the relationship between specific genetic haplotypes and alleles and the development of chronic Lyme arthritis. One speculation that I had made early on was that I suspected chronic and persisting symptoms were the result of both immune dysregulation and persisting infection - and here is one paper which points out this may be the case...

HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens
Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.

Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828865

The authors of this particular paper wrote up their own informative article, Sometimes It's All In Your Genes with descriptions of their project for the layperson. I highly recommend reading it, as it is an educational and easily readable description of their research in greater detail from the perspective of the researchers themselves.

In the above study, researchers experimented with mice who have the genetic profiles of HLA-DR4 (which is related to developing arthritis) and HLA-DR11 (which is predicted to clear spirochetes quickly).They infected both groups of mice with Borrelia burgdorferi and monitored their ability to clear spirochetes and develop signs of arthritis.

According to the researchers, mice with HLA-DR4 alleles produced lots of interferon gamma and very few antibodies to the spirochete - whereas those with HLA-DR11 alleles produced lots of antibodies but no interferon gamma.

To translate:

Interferon gamma = Produces LOTS of inflammation, which hurts and sucks.
Very few antibodies = Nothing much to fight off the infection.
Lots of antibodies + No Interferon gamma = Fight off infection while having little or no inflammation.

When you look at the paper itself, this is of particular note:

"We found that DR11 tg mice mount a vigorous Ab response, but are defective in IFN-γ production. In addition, Bb-infected DR11 tg mice had decreased spirochete burden compared to DR4 tg mice, measured by qPCR of Bb DNA. This is in contrast to DR4 tg mice, which produce an inflammatory response characterized by high level of IFN-γ production, in accordance with our published results (10). Furthermore, the Ab response to Bb-antigens was significantly lower than that of DR11 tg mice, which is consistent with the higher spirochete burden observed in DR4 tg mice after Bb-infection. Thus, our data provide a possible explanation for the differential regulation of the immune response in DR4+ and DR11+ patients upon Bb-infection; namely, HLA-DR4 would predispose individuals to chronic Lyme arthritis by generating an inflammatory milieu to Bb-infection, while HLA-DR11 would exert a protective role through the production of anti-spirochetal Abs."

So, to review, in this study:

HLA-DR4 mice have a significantly lower antibody response to Bb antigens compared to HLA-DR11 mice.

HLA-DR4 mice have a significantly higher inflammatory response (measured as Interferon gamma or IFN-γ ). (It sounds as if HLA-DR11 has no real inflammatory response.)

HLA-DR4 mice have a significantly higher spirochetal load compared to HLA-DR11 mice.

If you look at figure 5b & c (if I'm to read the caption properly based on the full text) the amount  of spirochetal DNA present in an ear punch sample was twice as high in the HLA-DR4 mice compared to the HLA-DR11 mice, and the amount of spirochetal DNA present in the joints appears to be about 6 times higher in HLA-DR4 mice compared to the HLA-DR11 mice.

That's a huge difference.

To add to this, the study also immunized two groups of mice with these alleles with rOspA and found out that:

HLA-DR4 mice mount a poor response to rOspA.

HLA-DR11 mice mount a strong antibody response to rOspA. They have a good humoral response.

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So upon learning this, of course there are more questions:

1. How does this study apply to humans with Lyme arthritis?
   
2. How does this study apply to humans with post-treatment chronic Lyme disease?
   
3. How does this data relate to findings in the recent Alaedini paper about those with post-treatment chronic Lyme disease having had infections for a long time (and Alaedini's speculations about different antibody responses and a possible need for more aggressive treatment)?
   
4. How does this data relate to Steere's study suggesting an additional month of antibiotic treatment is needed for some patients with Lyme arthritis?
   
   (Re:"Patients with Lyme arthritis were treated with oral antibiotics for one or two months, and in those for whom the arthritis did not resolve, IV antibiotics were administered for an additional month. If they had persistent arthritis despite three months of antibiotics, patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).")
   
5. How does the existence of more virulent and quickly disseminating RST of Bb affect hosts which are HLA-DR4 versus HLA-DR11?
   
6. What kind of mice were studied in this recent study by Barthold et al?
7. Is there a reason found here as to why some people experience relief with longer courses of antibiotics? Is it because they just don't have an immune response needed to clear the infection but antibiotics both help keep infection under control plus act as an anti-inflammatory in the presence of interferon gamma?

So much to think about here, tying these studies together.

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