6 ILADS 2011 Conference

I was kinda expecting that at some point, this sign would show up on my feed:

No Burrascano. Missed part of Maloney. Horowitz was also MIA. Only got to see part of Jones, as I'd already taken a coffee break.

Maybe tomorrow will be better if I can haul myself out of bed early on a Saturday... If.

More on this event in the future - especially if there is more to see.

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0 An accident leads Yale scientists to tick-borne disease in Russia

The Connecticut Mirror has an article on the backstory behind discovering that Borrelia miyamotoi leads to infection in people:

An accident leads Yale scientists to tick-borne disease in Russia
http://www.ctmirror.org/story/13955/lyme-new-tick-borne-disease-yale

You've got to love this excerpt:

Fish's lab was studying Lyme disease transmission using ticks and mice, exposing ticks to mice that had been infected, and to others that had not. But the ticks exposed to uninfected mice appeared to be infected.

"I gave everybody in the lab hell for wasting a lot of time and resources and stuff, because they screwed up the experiment," said Fish, a professor of epidemiology at the Yale School of Public Health. "And they felt really bad and they couldn't understand how that happened."

In fact, the ticks had a different bacterial organism, not the one that causes Lyme, but a distant relation called Borrelia miyamotoi. It had been identified six years earlier in Japan, but no one knew if it caused illness in humans. Fish spent the better part of a decade trying to get funding to study it, with little success.

I guess I have these questions about this:

1) Has anything similar happened before in other experiments and we don't even know about it - this situation of having uninfected mice be infected by a different organism that is disease-causing?

2) Why wasn't there enough funding to study this? Who decides which projects get funded?

3) I noticed that Borrelia research at the NIH got a lot more funding in the past two years... What were the goals of the bulk of those projects?

I can probably find out the answer to #3 with some digging. The first two questions? Not as easy to answer.

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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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2 Wolfram Alpha On Lyme Disease Diagnosis

So, I'm not sure how familiar my readers are with Wolfram Alpha. If you've ever heard of the Mathematica software package, these are the guys that created it.

Wolfram Alpha is an online tool that uses computational algorithms and data modeling to output objective information on a variety of topics.

In other words: It takes statistics and facts from numerous sources and creates a database on given topics on the fly.

(To learn more about what Wolfram Alpha's online tool does, go here: http://www.wolframalpha.com/tour1.html)

You can go to their homepage and type any term into their search engine and it will build a page based on that term and nothing but that term. Instead of a list of different link results like you see on Google, you get one page with many different kinds of information on that term or topic.

So for fun, I typed "Lyme disease" into their homepage.

The link for that query is this: http://www.wolframalpha.com/input/?i=Lyme+disease

Now, as part of the output for that query, I received the following table of data:

This is one of those moments where my head is breaking, and I can see where they are drawing their data from in the notes below the table - so I need to follow up and see if I can look at the original source for this data.

But just based on what I'm looking at right now, the words "Oh my god, where are they getting these numbers?" escaped my lips.  

According to the footnote, the data is not CDC based, but is based on actual patient visits to US healthcare providers between 2006-2007. I have to wonder why Wolfram Alpha is mining data from this source and not more recent NAMCS/NHAMCS statistics or another source, but it is interesting to see something that is not CDC for a change.

The data in this table does and does not reflect what I've observed online in the Lyme disease patient community.

For one thing, the chart states far more men than women contract Lyme disease and are diagnosed for it than women.  Yet the number of women I see online who discuss Lyme disease outweighs the number of men a great deal.

After reading Polly Murray's book, The Widening Circle, why women are more active online participants and more activist in general has been made more clear to me: the children. If you are sick with Lyme disease, that's bad enough - but if your child is sick, that's worse, and mothers seem to be more likely than fathers to reach out for answers and support online to help not only themselves but their children. (Sorry dads, I don't like the dissing either, and I'm sure a lot of you are active in your child's health - but statistically speaking more women do end up dealing with their kids' health issues for whatever reason.)

This reaching out and forming support groups began with women way before the internet - the internet is just an extension of what happens in real life.

(By 1992 there were over 100 patient support groups for Lyme disease - which kinda chips away at this idea that Lyme disease is a disease spread by reading the internet. What was the internet in 1992? Usenet?*)

But in this table, it's saying far more men get Lyme disease, and I see fewer of them online.

Okay, so another thing about this table,  just so the reader is clear on what they're reading, it doesn't take 22 doctors for one woman to achieve a diagnosis for Lyme disease here, even though I've heard so many stories about this phenomenon - no, what the table means is that for every 22 office visits a doctor sees, one of them will be a woman that gets diagnosed with Lyme disease. 

That one in six visits for men seems really high to me - too high, if you ask me - but in reading the fine print these are estimates and estimates which are weighted for US demographics (how? in what manner?).

I think what's striking about this one year of data is the extrapolation of just how many patients were diagnosed with Lyme disease over the course of 131,748 doctor visits. 

86,700 people in one year... is that closer to reality than the CDC reported 40,000 or so?

I really don't know how much stock to put in this data at all. I feel like writing Wolfram and asking them what gives. How was the estimation made and weighed and why are they drawing their data from NAMCS/NHAMCS - and if so, can they get more recent data or is this it? 

I'm thinking it would be more accurate a head count to get diagnosis numbers from doctors rather than the CDC, because not all cases are reported - but I don't know how reliable these numbers are or how the estimation was computed.

Update:

Just to add to this, check out this other table generated from the same data set:

Interesting.

Now look at the ratio for the number of  men who are diagnosed with Lyme disease to the number of women.  And now look at the total number of estimated cases. 

The only factor changed for initial data output was from "primary diagnosis at visit" to "any diagnosis at visit". What exactly does this mean?

Update #2:

Well, isn't this interesting. I googled "NAMCS" and my first result was this:

http://www.cdc.gov/nchs/ahcd.htm

On this page, we learn:

"The National Ambulatory Medical Care Survey (NAMCS) is a national survey designed to meet the need for objective, reliable information about the provision and use of ambulatory medical care services in the United States. Findings are based on a sample of visits to non-federal employed office-based physicians who are primarily engaged in direct patient care. 

The National Hospital Ambulatory Medical Care Survey (NHAMCS) is designed to collect data on the utilization and provision of ambulatory care services in hospital emergency and outpatient departments. Findings are based on a national sample of visits to the emergency departments and outpatient departments of noninstitutional general and short-stay hospitals."

So wait. This IS data from a survey the CDC knows about?

What percentage of these diagnosed cases are included in the CDC Lyme disease reported cases?

Why aren't these diagnosed cases mentioned on the reporting page for Lyme disease as a separate category of cases -  even if doctors did not fill out an official report?

Or are they mentioned somewhere on the CDC Lyme disease pages and I've missed it? Anyone want to confirm this for me?

Update #3:

Pointed out by an anonymous commenter on the blog just now - from the same page above:

Wow,  let's give the women lots of Ativan and give the guys none?

After reading this, we're all going to need Ativan.

Where they hell are these numbers coming from, though? The footnote here is really not useful.

And I'm sorry, if I am feeling sick with Lyme disease, getting it up is the last thing that would be on my mind... that must refer to a preexisting drug regimen. Even then... ouch.

I really have to wonder about these numbers.

Update #4 (hopefully the last?):

Okay, so I think I've answered some of my own questions here:
http://www.cdc.gov/nchs/ahcd/ahcd_faq.htm

Q. How are the data used? 

A. NAMCS and NHAMCS data are used to statistically describe the patients that utilize physician services and hospital outpatient and emergency department services, the conditions most often treated, and the diagnostic and therapeutic services rendered, including medications prescribed. The data are used by public health policy makers, health services researchers, medical schools, physician associations, epidemiologists, and the print and broadcast media to describe and understand the changes that occur in medical care requirements and practices. The data are disseminated in the form of public health reports, journal articles, and microdata files. 

Q: Can the ambulatory medical care surveys be used to find out how many people have a certain diagnosis?

A: No. The ambulatory medical care surveys (NAMCS and NHAMCS) are not based on a sample of the population. They are based on a sample of visits rather than a sample of people. The data can be used to find out how many ambulatory care visits were made involving a certain diagnosis. To get an idea of utilization of ambulatory care in the population, the number of visits can be divided by the population of interest to get a rate of visits for a diagnosis of interest.

Okay, partially answered. I still have to wonder how public health policy makers, epidemiologists, etc. use this data, though... and how closely this sample of visits maps to reality.

I really don't think anyone has a true picture of how extensive Lyme disease is and how many people have persisting symptoms of Lyme disease pre- and post-antibiotic treatment, and it would be useful to know how many cases physicians actually diagnose and treat versus report to the CDC as those are different numbers.

Even then, these surveys are only representational of doctor caseloads over a one week period during a given year - they are not solid figures.

* This is not all there was, but there were only 26 web sites in the world at the end of 1992.

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8 Paper: Environmental Stress in Borrelia Burgdorferi

The things you find, just randomly surfing online...

So, this is someone's dissertation for their doctoral degree. In 2004.

RESPONSES TO ENVIRONMENTAL STRESS TRIGGERS DIFFERENTIAL EXPRESSION
AND CELLULAR DAMAGE IN BORRELIA BURGDORFERI

A Dissertation Submitted to the Graduate Faculty of the University of Georgia in Partial
Fulfillment of the Requirements for the Degree
DOCTOR OF PHISOLOPHY
ATHENS, GEORGIA
2004

Should I forgive the typo, on a dissertation?

Well, I will. Just this once, because I am interested in commenting on more of the content inside and think this is a minor oversight. For all I know, there's a minor typo somewhere in my own publications that will come back to haunt me...

First, this section on serological tests for Lyme disease:

"ELISA assays are the most widely available and commonly performed tests, and have replaced IFA which are both labor intensive and subjective in interpretation (54, 77, 176, 192).  However, both ELISA and IFA are prone to both false positives and false negatives.  False positives generally result from the cross reactivity of B. burgdorferi proteins with proteins of other infectious agents (spirochetal, bacterial, rickettsial, rocky mountain spotted fever, EBV) (54, 77, 176, 192)."

 Yes, it's important to know what you're infected with, but in this case, with the exception of EBV - everything there is a bacterial infection requiring antibiotic treatment. So patient history plus serology is more than likely going to nab this one for treatment.

Next, let's look at this section on antibiotic resistance:

"Antibiotic resistance in B. burgdorferi has been investigated in vivo, in vitro, as well as in clinical reports.  B. burgdorferi is resistant to aminoglycosides, ciprofloxacin, rifampin, most first generation cephalosporins and some clinical isolates are erythromycin resistant (40, 134, 136, 138, 154, 192, 199, 220, 293)."

See, that's a lot of different drugs to which it's resistant. Note, please, that aminoglycosides are the first drug mentioned there.

And then we look at which antibiotics affect Borrelia burgdorferi:

"In contrast, it is  sensitive to penicillin and penicillin derivatives along with some macrolides and second generation cephalosporins (9, 40, 134, 136, 138, 154, 199, 220, 273, 277, 310).  To effectively treat B. burgdorferi located in deep tissue, CNS, eye, and within tendons, higher doses are often required (9, 40, 199, 220, 273, 277, 310)."

Okay, I think you could have expected this... this statement is totally within the standard guidelines and on research done to date on these particular antibiotics in vitro.

But then there's this part of the paper:

"Treatment of disseminated and late Lyme disease is much more difficult.  The duration of treatment is longer, the response is often slower and treatment failure is higher due to the presence of B. burgdorferi in the CNS, eye, within tendons and deep tissue (192, 306).  For patients with neurological complications, intravenous treatment regimens can last many months and includes 2 grams daily of ceftriaxone or 20 million units per day of penicillin G in divided doses (192, 306, 309). "

Hm. Okay. This isn't something that's included in the guidelines. Fascinating. This sounds more like the treatment plan that many Lyme disease patients with persisting symptoms have been taking, and getting some flack for from some medical professionals.

So why? If this is good enough for a doctoral dissertation, why isn't it good enough for patients?

Did something happen in 2004 I don't know about? I'm pretty sure the guidelines for treatment at this point did not include this treatment recommendation.

So what are papers 192, 306, and 309?

192. Nocton, J. J., and A. C. Steere. 1995. Lyme disease. Adv. Intern. Med. 40:68-115
306. Wilson, M. E. 2002. Prevention of tick-borne diseases. Tick-Borne Diseases 86:219-238.
309. Wormser, G., R. Nadelman, J. Dattwyler, D. Dennis, E. Shapiro, A. C. Steere, T.
Rush, D. W. Rahn, P. K. Coyle, D. H. Persing, D. Fish, and B. J. Luft. 2000. Practice
guidelines for the treatment of Lyme disease. Clin. Infect. Dis. 31:S1-S14.

Wait. I'm really seeing this?

I need to go look at these papers and have a stiff drink.

Okay, paper 192 is http://www.ncbi.nlm.nih.gov/pubmed/7747659 on PubMed, but there is no option to view an abstract of it, or pay for full text access  through PubMed. Advances in Internal Medicine stopped publishing in 2001, so you'll have to get a hard copy elsewhere (Elsevier doesn't have it, either.)

On to the next paper... http://www.ncbi.nlm.nih.gov/pubmed/11982299 which one has to pay for access online, though there is a limited abstract.

And then 309, which is this http://www.ncbi.nlm.nih.gov/pubmed/10982743  Which is the IDSA Lyme disease guidelines for 2000.

And, well, they say about what I expected:

"Late neuroborreliosis affecting the CNS or peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (B-II).

Alternative parenteral therapy may include administration of cefotaxime (2 g iv every 8 h) (B-II) or iv penicillin G (18–24 million units daily, divided into doses given every 4 h for patients with normal renal function) (B-II). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, a 14–28-day course of treatment with ceftriaxone (75–100 mg/kg/d in a single daily iv dose; maximum, 2 g) is recommended (B-II). An alternative is cefotaxime (150–200 mg/kg/d iv, divided into 3 or 4 doses; maximum, 6 g/d) (B-II). Another alternative is iv penicillin G (200,000–400,000 units/kg/d, divided into doses given every 4 h for those with normal renal function; maximum, 18–24 million units/d) (B-II)."

As has been said other places at other times: Why aren't these "reliable objective measures" spelled out in this document?

And how does one determine whether to dose out 2 weeks, 3 weeks, or 4 weeks of ceftriaxone? What's the objective measurement they use to decide between giving a patient 2 weeks versus 4 weeks of IV?

And the next section is...

"Chronic Lyme disease or post–Lyme disease syndrome..."

Yeah, well, let's not even go there right now. Most people reading along already know what that section says...

I suspect that the 2002 Wilson paper is what mentions long term treatment protocols in the dissertation I began writing about - but I'm going to have to look for it elsewhere and see if I can find access available for all my readers. For what it's worth, there is some mention of Sam Donta in the same publication, so perhaps this is where the extended IV protocol in bold came from?

At any rate,  getting back to reading  the 2000 guidelines (and I have yet to reread the 2006 ones), it appears that there weren't many studies back then on large numbers of patients with neuroborreliosis and late stage Lyme disease including encephalopathy. We're talking 7 patients for this one case series, 48 for another... small numbers.

And amid all that, there are studies like this which were conducted:

"From 1986 through 1991, 48 adult and pediatric patients with Lyme arthritis were randomly assigned to receive either doxycycline (100 mg orally twice a day) or amoxicillin and probenecid (500 mg of each 4 times a day), in each instance for 30 days [87]. Eighteen of the 20 evaluable patients treated with doxycycline and 16 of the 18 evaluable patients who completed the amoxicillin regimen had resolution of arthritis within 13 months after enrollment in the study. However, neuroborreliosis later developed in 5 patients, 4 of whom were treated with the amoxicillin/probenecid regimen.

The concomitant use of probenecid with amoxicillin may be inadvisable, because probenecid may impair penetration of b-lactam antibiotics into brain parenchyma [72, 88].

In retrospect, it was noted that all 5 patients reported subtle distal paresthesias or memory impairment at the time of enrollment. It was concluded that patients with Lyme arthritis can usually be treated successfully with oral antibiotics, but practitioners must be aware of subtle neurological symptoms that may require treatment with iv antibiotics."

Hope that test got a do-over, and they found out what was wrong with those 5 patients and they got the help they needed. Would you have included patients with that background in this study? I wouldn't have. Their symptoms match those of neuroborreliosis. Why weren't they excluded from the study earlier on?

I underlined "subtle neurological symptoms" to make a point, by the way: The panelists are always mentioning that they need objective evidence of infection, yet here they are urging practitioners to be aware of subtle neurological symptoms. Which are subjective evidence.

So... what else can you look at as objective measurements other than serology? Because after the first two weeks of infection, CSF tests don't have good yields. And if your patient already had some antibiotics but they were undertreated, will they produce a robust ab response on tests? Can someone tell me?

Okay, here's another study from the 2000 guidelines:

"Patients with late Lyme disease associated with prominent neurological features also respond to antibiotic therapy. In trials conducted from 1987 through 1989, 27 adult patients with Lyme encephalopathy, polyneuropathy, or both were treated with iv ceftriaxone (2 g/d for 2 weeks) [93]. In addition to clinical signs and symptoms, outcome measures included CSF analyses and neuropsychological tests of memory. Response to therapy was usually gradual and did not begin until several months after treatment. When response was measured 6 months after treatment, 17 patients (63%) had uncomplicated improvement, 6 (22%) had improvement but then relapsed, and 4 (15%) had no change in their condition."

So right there, the study outcome was that 6 of 27 patients improved but relapsed, and 4 just didn't get any better.  In this study, 37% of the patients did not have "uncomplicated improvement". (What does that mean, "uncomplicated improvement"? Why not use the words "were cured"? )

No, in this study, 37% did not improve at all as far as we know. Some followup report here would be good.

Moving on to another study from the 2000 guidelines (are you bored yet?):

"In 1987, a case series of 7 patients with Lyme arthritis or chronic neuroborreliosis, who were refractory to oral or iv penicillin therapy were then treated with iv ceftriaxone (2 or 4 g/d for 2 weeks) [83]. All 5 patients who had arthritis responded to ceftriaxone therapy, and for 5 of the 6 patients with limb paresthesias, a reduction in symptoms and improvement of nerve conduction study findings were noted."

So here, again, "reduction in symptoms" and "improvement of nerve conduction study findings were noted"... but I'm not seeing the phrase, "resolution of symptoms". Is this the most patients can hope for with these conditions?

I'm hoping I missed something, and just need to find the original case series paper and read it. But I see this as 5-6 people out of 7 did not have resolution of their symptoms. How else can I read it?

More from the 2000 guidelines:

"In a follow-up study, 23 patients with Lyme arthritis or late neuroborreliosis were randomly assigned to receive penicillin (20 million units per day iv for 10 days) or ceftriaxone (4 g/d iv for 14 days) [84]. Of the 13 patients who received ceftriaxone none had objective evidence of persistent disease after treatment, although 3 had mild arthralgias and 1 complained of fatigue and memory difficulty. In contrast, 5 of the 10 patients who received iv penicillin continued to have fatigue, memory deficit, or recurrent oligoarthritis. For 4 of these 5 patients, symptoms resolved after repeat treatment with ceftriaxone."

Better outcome. Good. I'm glad they figured out ceftriaxone worked better than penicillin.

Still, what happens if ceftriaxone didn't work? Do you try another antibiotic or say, "that's it"? I'm wondering what happened to that fifth person and how they're doing today. And I do wonder what happened to those 3 patients with mild arthalgias and 1 with fatigue and memory problems... were they followed up later on? Did their symptoms resolve or continue? Do they know what caused them? Unanswered questions.

And also:

"In a subsequent study, 31 patients with Lyme arthritis or chronic neuroborreliosis were randomly assigned to receive 2 or 4 g/d of ceftriaxone for 2 weeks [84]. After treatment, 3 of the 31 patients had persistent encephalopathy, 2 had persistent neuropathy, and 3 had no diminishment of their arthritis. The overall frequency of persistent symptoms among patients was 13%, which was similar in both treatment groups."

And... and... oh, here's one with more people, and it's randomized:

"In an open-label, randomized, multicenter study, 143 evaluable patients with manifestations of late Lyme disease, primarily Lyme arthritis, were treated with iv ceftriaxone (2 g/d for either 2 or 4 weeks) [85]. In 76% of those treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved after treatment (the P value was not significant). The most common persistent symptoms were arthralgia, pain, weakness, malaise, and fatigue."

Okay, so 76% of patients treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved. Now what about the other 24% and 30% respectively? Their symptoms must not have resolved?

Now I can't keep going on with posting all of these, it's getting tedious - there are more examples of the work they were doing in the guidelines and you can check them out for yourself.

Let's review the treatment recommendation for Late stage Lyme neuroborreliosis, shall we?

"Late neuroborreliosis affecting the CNS or the peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (tables 3 and 4) (B-II). Alternative parenteral therapy may include administration of cefotaxime (B-II) or penicillin G (BII). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, treatment with ceftriaxone is recommended (tables 3 and 4) (BII). Cefotaxime or penicillin G administered iv are alternatives (B-II)."

So this is the recommendation for 2000.

I really need to take a look at the guidelines for 2006 and compare them.

But just looking at the 2000 guidelines as their own sort of universe, what is puzzling me is why they are recommending treatment guidelines which don't lead to resolution of symptoms for everyone. At least a greater number of people?

If the reason these other cases failed - and with the bigger studies, we're looking at 24-37% of patients did not have resolution of their symptoms - was because they had this particular human leukocyte antigen–DR4 specificity and antibody reactivity with OspA of the spirochete... that isn't stated for ANY of these studies.

It is stated for one study they mentioned later on with 16 patients though - but it's the only one mentioned where they tested for this marker. One study. Sixteen people.

I'm hoping when I look at the next set of guidelines, it will be data rich. Right now, I'm just reeling a bit from this, and wondering if the author of the dissertation saw these results and wondered about them, too.

How do you tell the difference between late stage Lyme disease that relapsed or continued versus what they are calling PLDS?

Getting back to the dissertation (remember the dissertation I first began writing about? It's okay if you don't - I almost forgot it myself):

I found this bit of microbiology trivia for those interested:

"Finally, in contrast to most bacteria, B. burgdorferi phospholipids, lipoproteins and glycolipids contain unsaturated fatty acids, such as linoleic, linolenic, and arachidonic acids, which are derived from the host (35, 38, 121, 171)."

The damned things are just parasites, really.

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4 Video: What The Internet Is Hiding From You

I just watched this video with Eli Pariser, where he talks about what the internet doesn't let you see because it is tailored with you in mind.

This is almost ten minutes of video you don't want to miss, because it talks about how completely different results are shown for two people who are looking up the same keyword.

This means that one person who is interested in Lyme disease and conspiracy theories will get more results that include those two concepts - whereas a person who is interested in Lyme disease and scientific research will get more results that include those two concepts when they type the keywords, "Lyme disease" into their browsers.

It's important to be aware that what you don't see can be as important as - if not more important than - what you are actually seeing online. Anything that makes you uncomfortable, challenges your point of view, or is different may be hidden from you by design.

Watch this video. I think everyone should see it, the message is important whether you are looking up information on Lyme disease, US politics, health care plans, and anything you can think of entering into that little search box at the top of your browser...



How do you fix this?

Google needs to set it up so we have the option to turn filters on and off that involve personalization.

Until then, the wider a variety of different terms you use frequently in searches - including ones that you disagree with - the wider the number of results you are bound to get in return. They'll just get included in your filter by default if you use them often enough - even if you don't read all the results.

If you're liberal and searching for something on politics, put "GOP", "Republican", and "conservative values" into your searches every once in a while. Use "liberal Democrats" "social Democrats", "progressive values" into searches if you're conservative every once in a while. And for good measure, throw in "libertarians", "green politics", and "economy" in with any of those randomly and see what crops up.

You can do the same thing with just about anything to throw off Google's existing filter system, and use different search engines with different data sets just to see how their own internal algorithms work. Consider it your own science experiment in data manipulation - it's better you manipulate your own data than to let someone else do it.

Additional note: The spinning disk in the middle of the screen is a TED issue, if you see it - nothing to do with Camp Other. Keep watching despite it - it's worth the effort and you can see what you need to even with it there.

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8 The Friday Four

In this edition of the Friday Four, we'll look at using bacteria itself to deliver antibiotics and treat cancer, a huge touchscreen microscope, the value of Vitamin A in B1 cell immunity, and the mystery of lateral gene transfer between Chagas disease pathogens and its host.

1) 'Bacterial dirigibles' emerge as next-generation disease fighters

Link: http://www.sciencedaily.com/releases/2011/03/110329134120.htm

Summary: ScienceDaily (2011-03-30) -- Scientists have developed bacteria that serve as mobile pharmaceutical factories, both producing disease-fighting substances and delivering the potentially life-saving cargo to diseased areas of the body. They reported on this new candidate for treating diseases ranging from food poisoning to cancer -- termed "bacterial dirigibles."

Comments:


I don't know how many people are aware how much genetic engineering already goes on. Once the industry took off... well, it took off like wildfire. It's pretty common to do exactly what is stated in this article: "...Traditional genetic engineering reprograms bacteria so that they produce antibiotics, insulin, and other medicines and materials. The bacteria grow in nutrient solutions in enormous stainless steel vats in factories. They release antibiotics or insulin into vats, and technicians harvest the medicine for processing and eventual use in people."


In this experiment, they programmed E. coli not to pump out antibiotics into a vat in some factory somewhere... No, they created a version of E. coli that could target a portion of the intestine and adhere to it, and begin sending out chemical signals that influenced the production of proteins in different cells around it.


So I'm trying to understand this. They took E. coli, the bacteria that often makes people sick, and made a version that delivers itself to a specific part of the body and is programmed to affect other cells near it. Crazy.


What if this sort of "bacterial dirigible" could seek out and find remote Borrelia burgdorferi in collagen-rich tissues, in the adventitia of the heart, and in the brain? Does this have potential for killing the remaining spirochetes that may survive the initial onslaught of antibiotics?


2) Researchers in Finland Build Giant Multitouch Microscope

This is just too cool.  I want one. I want to see my spirochetes on this sucker.  [Time 1:43]

I think Leeuwenhoek would have just about shit himself if he saw one of those...

3) In the absence of Vitamin A, the body loses immune cells that put the brakes on the earliest stages of infection

Link: http://www.physorg.com/news/2011-04-absence-vitamin-body-immune-cells.html

Summary: Scientists have recognized the immune-boosting capabilities of vitamin A for the better part of a century, even without fully understanding how it helps the body fight off bacteria and viruses. "Soon after its discovery, vitamin A was termed ‘the anti-infective vitamin’ and was widely used to enhance recovery; but with the introduction of antibiotics, the therapeutic use of vitamin A diminished," says Sidonia Fagarasan of the RIKEN Center for Allergy and Immunology in Yokohama, Japan.

Comments:


So these researchers fed these mice a Vitamin A-free diet, and when they did, the mice had lower levels of IgA and IgM. They were given pneumonia vaccines and produced zero response. And then, the researchers tried to transplant B1 cells from healthy mice to these deficient mice - only to find that the B1 cells deteriorated, didn't last that long, and died off over several days.


However, the good news is, they found out the stem cells in the deficient mice's bone marrow could give rise to B1 cells - but they wouldn't do it unless they had some Vitamin A.


The researchers found out that a transcription factor protein found in activated T cells (NFATc1), regulates expression of numerous important genes in B1 cells. The researchers observed reduced NFATc1 levels in the mice's deficient B1 cells, but found that expression could be largely restored if these mice were injected with ATRA, a product of cellular vitamin A metabolism. After this injection, B cells increased more than four fold in number in ten days.


Having a balanced diet is definitely important for the immune system, and being deficient in Vitamin A would be problematic. Something so simple.


Even though it sounds like a good idea to take lots of Vitamin A given the immune system benefit, it doesn't work that way: if you're deficient, you need more; if you're taking too much, you need less because it can damage your liver and by extension kidneys because of too much calcium there. (It's also bad to consume high quantities during pregnancy - it can lead to failure to thrive in newborns.)


So get a test to see if you're deficient in Vitamin A first - and if so, then it's pretty easy to find foods full of  Vitamin A.


One thing that comes to mind after reading this is that recently I've read a paper, 'The Important And Diverse Roles of Antibodies in Host Response to Borrelia' by Laroca and Benach. In it, it mentions that B1 cell or x-linked immunodeficiency leads to more severe spirochetemia with B. hermsii... B1 b cells are needed for IgM antibody response.

Source publication:

Maruya, M., Suzuki, et al. Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells. Proceedings of the National Academy of Sciences USA 108, 722–727 (2011). http://www.pnas.org/content/108/2/722.short

4) Two new studies seek to validate the results of a retracted 2004 paper on parasite-to-host gene transfer, but skepticism lingers

Link: http://www.the-scientist.com/news/display/58093/

Do not let this bug kiss you - it can
carry Chagas disease parasites...

Summary: The microparasite that causes Chagas disease really can integrate bits of its genetic material into its host's genome, where it can then be inherited by the host's offspring, according to two studies published in PLoS ONE and PLoS Neglected Tropical Diseases (PLoS NTD).

Comments:


So this is kind of insane. Interesting and insane. The claim is being made for what might be the first documented instance of lateral gene transfer from the parasite that causes Chagas disease to not only its host but also a following vertical transfer to the host's offspring.


WTF. This is almost as far out as Lynn Margulis' claims about Borrelia burgdorferi.


These two recent studies are supposed to confirm the research found in a 2004 paper published in Cell which was later retracted. That paper showed - or supposedly showed - that University of Brasilia researchers found that T. cruzi could transfer genetic material to its rabbit, chicken, and human hosts. This sort of gene transfer - specifically of mitochondrial kinetoplast DNA (kDNA) - may contribute to the disease by disrupting host gene function and causing an autoimmune response.


Those looking at the newer research are eyeing it cautiously because of the earlier publication's retraction, which was done because Cell's staff made the determination that certain important information was missing from the paper. Speculation was that it was because identification and analysis of the specific sites of DNA integration were omitted.


I think this study and the two subsequent studies recently done will need to be repeated by another party not related to them, since this would be pretty big news if it's true. Also, someone needs to make sure their PCR methods don't create weird chimeras in passing.

Source publications:

M.M. Hecht et al., "Inheritance of DNA transferred from American trypanosomes to human hosts," PLoS ONE, 5: e918, 2010. 

A.R.L. Teixeira et al., "Trypanosoma cruzi in the chicken model: Chagas-like heart disease in the absence of parasitism," PLoS Negl Trop Dism, 5: e1000, 2011. 

---

And here's a bonus link set for my readers who are interested in aberrant and unusual contrails in the sky:

http://www.nature.com/nclimate/journal/v1/n1/full/nclimate1078.html

Here is the study to which the above article refers:

http://www.nature.com/nclimate/journal/v1/n1/full/nclimate1068.html

It was posted at the source on March 29, so I reassure you that it was not an April Fool news item.

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7 Patent Watch: VMP-Like Sequences of Pathogenic Borrelia

To the dude that keeps writing in his blog that chronic Lyme patients are hypochondriacs, and to A.C. Steere, who in his March 2010 Powerpoint presentation insisted that there is no such thing as Chronic Lyme Disease and it is a misnomer, I have one question to ask:

If Lyme disease is easy to diagnose and treat and not chronic - as you and the IDSA have stated - why do people in the field put this stuff in a patent application posted December 2010?

Application number: 12/853,019
Publication number: US 2010/0317026 A1
Filing date: Aug 9, 2010

Check it out on Google Patents. You can download it as a PDF file on the upper right corner of your window.

Select snippets for your viewing enjoyment:

First, we'll start with the abstract so you know what they plan to do with these VMP-Like Sequences of DNA, anyway. Oh, vaccines? Why yes. But also possibility of therapeutic applications and in immunoblots as reagents.

If you download and read the entire thing, though, you either need to a) have some focus or b) a little of insanity or c) possibly both to get through it. If you do bother to download the PDF in its entirety, I recommend that you start looking at the early pages and skip over a few pages about a third through, then read again, then skip the DNA sequencing pages at the end - unless you are a molecular biologist or geneticist... then it will be more fun for you to read all of it.

[0006] These organisms are closely related and cause similar manifestations with multiple stages: an expanding rash at the site of the tick bite (erythema migrans), fever, lymphadenopathy, fatigue, and malaise; effects of disseminated infection, including carditis, meningoradiculitis, and polyarthritis; and chronic manifestations including arthritis and neurologic disorders. Lyme disease is often difficult to diagnose because of shared manifestations with other disorders, and it can also be refractory to treatment during late stages of the disease.

re·frac·to·ry (r-frkt-r)

adj.

1. Resistant to treatment, as a disease.

2. Unresponsive to stimuli, as a muscle or nerve fiber.

(Did anyone make a checklist out of reading the above symptoms and nod "yes" to them? I did...)

[0007] B. burgdorferi, the etiologic agent of Lyme disease, is able to persist for years in patients or animals despite the presence of an active immune response (Steere, 1989; Schutzer, 1992).

[0009] Lyme disease may be disabling (particularly in its chronic form), and thus there is a need for effective therapeutic and prophylactic treatment. (Noooo...  You think?)

[0010] However, animal studies indicate that OspA vaccination may not be effective against all strains of Lyme disease Borreliae. OspA is also not useful for immunodiagnosis, due to weak antibody responses to OspA in Lyme disease patients. (Wait... but... Lymerix... I thought you guys said you pulled it due to lack of sales? Oh shhhh... that's not what I heard...)

[0020] An important aspect of the invention is the recognition that Borrelia VMP-like sequences recombine at the vls site, with the result that antigenic variation is virtually limitless. Multiclonal populations therefore can exist in an infected patient so that immunological defenses are severely tested if not totally overwhelmed. Thus there is now the opportunity to develop more effective combinations of immunogens for protection against Borrelia infections or as preventative inoculations such as in the form of cocktails of multiple antigenic variants based on a base series of combinatorial VMP-like antigens.

[0127] The present work discloses the identification and characterization of an elaborate genetic system in the Lyme disease spirochete Borrelia burgdorferi that promotes extensive antigenic variation of a surface-exposed lipoprotein, vlsE. A 28-kilobase plasmid of B. burgdorferi B31 (pBB28La) was found to contain a vmp-like sequence (vls) locus that closely resembles the variable major protein (vmp) system for antigenic variation of relapsing fever organisms. Portions of several of the 15 non-expressed (silent) vls cassette sequences located upstream of vlsE recombined into the central vlsE cassette region during infection of C3H/HeN mice, resulting in antigenic variation of the expressed lipoprotein. The resulting combinatorial variation will potentially produce millions of unique antigenic variants and thereby contribute to immune system evasion, long-term survival, and pathogensis in the mammalian host.

(Note: C3H/HeN mice are reported to develop severe arthritis when infected with B. burgdorferi.)




These observations suggest that the vls locus may provide the Lyme disease Borreliae with the capability of antigenic variation analogous to the vmp system of B. hermsii (Barbour, 1993). The above similarities also indicate that the vlsE gene, silent vls cassettes, and large vmp genes of relapsing fever organisms, all evolved from a common ancestral gene. Their relatively high G+C compositions (e.g. 45% for vlsE and 37% for vmp17) when compared with Borrelia G+C content (~28%) are also consistent with this evolutionary relationship, and further suggest the possibility of lateral transfer from other organisms. (Okay, these are more "may" and "indicate" and "suggest" statements, but given the weight of the evidence so far... something to consider.)

[0130] Lastly, each phase of B. hermsii infection is caused predominantly by organisms expressing a single vmp allele (Meier et al. 1985; Plasterk et al. 1985), whereas a high degree of vlsE allele variation occurs among organisms isolated even from a small ear biopsy specimen during B. burgdorferi infection.

[0137] Variation of B. burgdorferi surface proteins such as VlsE may also effect the organism's virulence and its ability to adapt to different micro-environments during infection of the mammalian host. Recent studies of a Borrelia turicatae mouse infection model that resembles Lyme disease showed that one serotype expressing VmpB exhibited more severe arthritic manifestations, whereas another expressing VmpA had more severe central nervous system involvement (Cadavid et al, 1994). The numbers of Borreliae present in the joints and blood of serotype B-infected mice were much higher than those of mice infected with serotype A, consistent with a relationship between Vmp serotype and disease severity (Pennington et al, 1997). (And? Where was the Borreliae present in mice in serotype A? Hm?)
[0138] The importance of the vls-containing plasmid, pBB28La, during infection is supported by the following evidence: (i) all high-infectivity clones and strains tested thus far contain the vls-containing plasmid pBB28LA and loss of this plasmid correlates with a decrease in infectivity; (ii) pBB28La was maintained in all animal isolates tested thus far, and (iii) the vls sequences are preserved among three Lyme genospecies despite their genetic heterogeneity (Casjens et al, 1995).

[0139] VlsE (or, potentially, other genes encoded by pBB28La) appears to have another important but undefined function which is unrelated to antigenic variation. Low-infectivity clones lacking the vls-encoding plasmid pBB28La do not propagate in severe combined immunodeficiency (SCID) mice, indicating that the required factor(s) provides an important function unrelated to evasion of the adaptive immune system.

Also, in vivo selection against Bb clones lacking pBB28La appears to occur early in infection (within the first week), before the adaptive immune response would be expected to exert significant selection pressure. Therefore, it is likely that vlsE plays an important role in some aspect of infection (e.g. colonization, dissemination, adherence, extravasation, evasion of innate immune mechanisms, or nutrient acquisition), and that antigenic variation merely permits surface expression of this protein without leading to elimination of bacteria by the host's immune response.

[1041]  A genetic locus (called vmp-like sequence or vls) has been identified and characterized in B. burgdorferi that surprisingly resembles the vmp system of B. hermsii. [...] Examination of ear and blood isolates from C3H/HeN mice infected 4 weeks previously with B31 clone 5A3 demonstrated the occurrence of promiscuous recombination at the vlsE site, such that each of B. burgdorferi clones examined was unique and appeared to have undergone multiple recombination events with portions of the silent vls cassettes. The resultant vlsE variants exhibited a decreased reactivity to antiserum directed against the parental Vls1 cassette region. This elaborate genetic system permits combinatorial antigenic variation of vlsE in the mammalian host, thereby contributing to evasion of the immune response and long-term survival in the mammalian host.

Etc...

[0145] This mechanism of genetic switching appears to be different from any other antigenic variation mechanism described in bacteria or protozoa and has important implications in Lyme disease. By combining different regions of the silent vls cassettes, it is possible for many different vlsE serotypes to coexist the same patient. It may be impossible for the host to mount a protective response against any one of these clonal populations, because of the small number of each type. Even mounting a response against one serotype would not protect against rapidly evolving, new serotypes. The fact that B. burgdorferi has evolved such an elaborate mechanism for varying the sequence of VlsE indicates the importance of the protein in pathogenesis and/or immune evasion.

[0294] Since the C3H/HeN mice were infected with a large number (10⁵)  of the organisms, it was possible that the antibody response against vlsE had resulted from the intial inocolum. To test this possibility, sera from the white-footed mice (Peromyscus leucopus) infected with B. burgdorferi B31 via tick bite and from human Lyme disease patients were used to react with the similar immunoblots. The representative results depicted showed that tick-infested Peromyscus leucopus mice also had strong reactivity to the VlsE protein of B. burgdorferi B31-5A3 and GST-Vsl fusion protein but not with GST alone. These results were further confirmed with sera from Lyme disease patients. [...] These results indicate that VlsE is expressed and is highly immunogenic in the mammalian host, but that genetic variation may generate unique VlsE variants which are no longer fully recognized by the immune response against the parental vlsE. They also indicate that antibodies generated against VlsE may be useful in immunodiagnosis of Lyme disease. (Got new tests, anybody? I hope this is a good thing!)

[0295] (Contains test data that just confirms more of what was said further upstream, but thought I'd add it here...)

Seriously, this is fascinating stuff, and I really hope that the knowledge about vlsE can be put to good use. My immediate thoughts, of course, are to ask how this can be used to create new treatments for Lyme disease and improve testing - as well as if a safe and effective vaccine can be developed. The vaccine issue - as always - is touchy, and is no different in this case... especially when they are proposing multiple shots will be needed over time. Also, there is more detailed information in the remainder of the patent describing ways of using bacteriophage therapy or attaching DNA to recombinant adenoviruses for  gene therapy treatment.

But the take home point I'm making here by sharing portions of this patent (and it is a multipage document, with lots of pages of data and genetic sequencing that most people will not want to plow through) is that Lyme diseases's Borrelia burgdorferi is unique, and closely related to relapsing fever, and has genetic behavior which is similar to - yet different from - relapsing fever.

Borrelia burgdorferi is highly complex in its presentation, multiple sources have stated that it can be refractory to treatment, and it has a chronic manifestation. It's all right here.

"This mechanism of genetic switching appears to be different from any other antigenic variation mechanism described in bacteria or protozoa and has important implications in Lyme disease. By combining different regions of the silent vls cassettes, it is possible for many different vlsE serotypes to coexist the same patient. It may be impossible for the host to mount a protective response against any one of these clonal populations, because of the small number of each type. Even mounting a response against one serotype would not protect against rapidly evolving, new serotypes."

We can't ignore this. The scientific truth isn't going to go away, whether it is posted in this patent or in the papers to which it refers.

ADDENDUM

There are more entries posted here related to this one. If you were interested in this post, check out these  - especially the one on the vlsE test kit package insert:
http://campother.blogspot.com/2011/02/more-on-that-vmp-like-sequence-aka-vlse.html
http://campother.blogspot.com/2011/02/package-insert-excerpt-athena-multi.html
http://campother.blogspot.com/2011/02/history-of-antigenic-variation-in.html

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2 It almost always ends with scotch...

Who would want to live this way by choice?

Did I miss anything, folks?

This work by Camp Other is licensed under a Creative Commons
Attribution-NonCommercial-ShareAlike 3.0 Unported License.

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0 TED Talk: Aiding the immune system to fight infection

I caught this talk recently on TED that was more of a teaser for me. I found it interesting and wanted to share here.

About this TED Talk

Drug-resistant bacteria kills, even in top hospitals. But now tough infections like staph and anthrax may be in for a surprise. Nobel-winning chemist Kary Mullis, who watched a friend die when powerful antibiotics failed, unveils a radical new cure that shows extraordinary promise.(Recorded at TED 2009, February 2009 in Long Beach, California. Duration: 4:35)



[ More here, in an interview with Kary Mullis. ]

So, in case you didn't know, in the early 1980s, Kary Mullis developed the polymerase chain reaction (PCR), which is a way of making copies of a DNA strand using the enzyme polymerase and some basic DNA "building blocks." Mullis shared the 1993 Nobel Prize in Chemistry for developing this technique.

But Mullis has moved on to doing research on chemically programmable immunity using Altermune technology.

Altermune, LLC, in collaboration with Ron Cook of Biosearch in Novato, CA, re-directed antibodies whose job used to be binding to something called the alpha-Gal epitope or galactose-alpha-1,3-galactosyl-beta-1,4-N0-acetyl glucosamine (now say that three times fast, I dare you) to influenza using DNA aptamers attached to the alpha-Gal epitope.

These linkers can grab influenza virion and turn it over to a human macrophage, which gobbles it up. Testing was done using a drug that can be inhaled.

Altermune is currently focusing on Influenza A and drug resistant Staphylococcus aureus.

This is fascinating.

Programming your own immune system to more effectively fight infections.

I've been wondering what other technologies we could use to combat infection and avoid the issue of antibiotic resistance, which is becoming more crucial as there has been little in the way of new antibiotic research and development during the past decade.

If Kary Mullis can help us use our own immune systems to effectively fight infection, maybe we can not only avoid resistance - but the side effects of many antibiotics and antiviral medications as well.

I'm sure there are some drawbacks and kinks to work out. I'm wondering, for example, how this technology handles transfections. I need to replay the entire TED talk and watch it again, and read the research.

In the meantime, if you are up to the task, here is a more technical Powerpoint presentation on Altermune I have found online:

www.bibalex.org/supercourse/supercoursePPT/37011-38001/38071.ppt

Note of bizarreness: Read the comments on the original TED post. Apparently Mullis is an AIDS denialist? Does anyone know about that?

Dig out your googling chops... the more you learn about Mullis, the more bizarre his story becomes.

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