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Crohn's Disease Forum » Books, Multimedia, Research & News » Research into MAP as the cause of Crohn's


 
02-06-2016, 11:44 AM   #91
JMC
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The Association of Mycobacterium avium subsp. paratuberculosis with Inflammatory Bowel Disease

http://journals.plos.org/plosone/art...l.pone.0148731

The association of Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) with Crohn’s disease is a controversial issue. M. paratuberculosis is detected by amplifying the IS900 gene, as microbial culture is unreliable from humans. We determined the presence of M. paratuberculosis in patients with Crohn’s disease (CD) (n = 22), ulcerative colitis (UC) (n = 20), aphthous ulcers (n = 21) and controls (n = 42) using PCR assays validated on bovine tissue. Culture from human tissue was also performed. M. paratuberculosis prevalence in the CD and UC groups was compared to the prevalence in age and sex matched non-inflammatory bowel disease controls. Patients and controls were determined to be M. paratuberculosis positive if all three PCR assays were positive. A significant association was found between M. paratuberculosis and Crohn’s disease (p = 0.02) that was not related to age, gender, place of birth, smoking or alcohol intake. No significant association was detected between M. paratuberculosis and UC or aphthous ulcers; however, one M. paratuberculosis isolate was successfully cultured from a patient with UC. We report the resistance of this isolate to ethambutol, rifampin, clofazamine and streptomycin. Interestingly this isolate could not only survive but could grow slowly at 5°C. We demonstrate a significant association between M. paratuberculosis and CD using multiple pre-validated PCR assays and that M. paratuberculosis can be isolated from patients with UC.
02-06-2016, 12:10 PM   #92
mf15
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JMC: Interesting paper,now perhaps raises more questions.
Only finding 29% MAP in the N=22 CD people.
What worse they raise the question of when is the MAP acquired, since they found
no MAP in the intestinal aphthous ulcer people.
They also found MAP in a few UC people.
I guess the GI community have looked at AIEC and intestinal aphthous ulcers.
We also know that crohn's people are dysbiotic from the start,dysbiosis can
be from inflammation, due to increased ROS/oxygen tension selecting more
facultative anaerobes,diet might also cause some dysbiosis.
If AIEC become virulent due say to a dietary component, will they
cause a general dysbiosis.
Also makes me wonder when do AIEC acquire virulence, and are they
causing the ulcers to form.
Old Mike

If I am reading this right it looks like AIEC and a few others might be there.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112894/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325296/
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Last edited by mf15; 02-06-2016 at 01:52 PM.
02-06-2016, 01:57 PM   #93
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JMC: Interesting paper,now perhaps raises more questions.
Only finding 29% MAP in the N=22 CD people.
Yes, it is interesting that they found a high correlation between CD and MAP and yet the actual incidence was very low in this case, certainly much lower than other studies.
02-06-2016, 02:03 PM   #94
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Also interesting that the one isolate they discuss had an amazing ability to adapt, and was resistant to all but clarithromycin.
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Past (failed) Treatments: Remicade, Humira, Prednisone, Pentasa, Azulfadine, Lialda, No gluten/dairy/sugar/coffee or processed food in general. Flagyl worked but not long term.
02-06-2016, 03:43 PM   #95
mf15
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Also of interest is the strain that likes to grow at 5 degrees C, that might
suggest a strain that has adapted to refrigeration.

But the real point of interest from the paper is that MAP may be a an after the fact bystander. I wonder if the MAP positive people had worse symptoms, or they were difficult to control with meds.

Old Mike
02-06-2016, 04:52 PM   #96
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JMC: Interesting paper,now perhaps raises more questions.
Only finding 29% MAP in the N=22 CD people.
One of the reasons for this is the stringent criteria they used demanding that all 3 PCR assays were positive. If on the other hand, your measure is that any of the tests were positive, then the result is 13/22 or about 59%.
02-06-2016, 05:05 PM   #97
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But the real point of interest from the paper is that MAP may be a an after the fact bystander.
Having read the paper very carefully, I don't think that is the point they are making.

I think you are referring to this statement:
Although it has been suggested that aphthous ulcers of the GI tract are precursors of CD, we found no evidence of M. paratuberculosis infection in any of our patients with aphthous ulcers. If aphthous ulcers are indeed a precursor of CD our results raise the question as to when M. paratuberculosis infection may occur. One possible scenario is that M. paratuberculosis may colonise only once inflammation has been initiated.

If aphthous ulcers have no relevance to the onset of Crohn's then there is no evidence that MAP infection comes before or after inflammation.

If aphthous ulcers are a precursor to Crohn's disease, the lack of MAP infection at this stage shows that it must come later, maybe absorbed through ulcers in the mouth from drinking milk. What is absent, is someone with aphthous ulcers who then develops Crohn's but is negative for MAP infection. Given the lack of firm evidence either way, I don't think you can draw any conclusions.
02-06-2016, 05:19 PM   #98
mf15
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All good points JMC, I will just leave it there until myself or someone else, comes up with more info on these pre crohn's ulcers.
Read the links I posted on these ulcers above may provide more insight.
I also suspect that this might be somewhat difficult to determine, since you don't know your sick until after the fact, but they do know about the ulcers prior to onset, so some info is out there.
Never the less this study might raise a lot of questions, in many doc's minds
as to whether MAP is causal.
Something more on AIEC
http://www.medscape.com/viewarticle/549397_4

one point from this paper
Moreover, we observed that in any given patient, healthy and ulcerated mucosa were colonized by E. coli strains having the same ribotype profile, which indicates that colonization is independent of the inflammatory state of the mucosa.

here is one more,perhaps they are righ,t or perhaps not concerning iron,
perhaps it is dietary iron that sets off the virulence, prior to inflammation, then the iron from the inflammation makes things much worse.

https://lifesciencesweek.missouri.ed...abstract&p=389

Old Mike

Last edited by mf15; 02-06-2016 at 08:14 PM.
02-06-2016, 10:30 PM   #99
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Another consideration - maybe their MAP detection techniques are faulty. Or possibly they're looking for MAP when it's really some other mycobacteria that's the culprit. Seems like the rate of positive samples in CDmpatients is quite low compared to other studies, as JMC noted. I'd be interested to see what the detection rates were if the samples were given to John Aitken. He seems to be able to grow these things quicker and more accurately than others.
02-07-2016, 06:19 AM   #100
mf15
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Irish:
Sure anything is possible with this type of work.
I have been a big believer the MAP connection, for years.
For me this study, invokes a somewhat different research path,
as to what is going on with crohn's and the pre crohn's ulcers.

this might be a clue
http://jn.nutrition.org/content/131/5/1452.full

One problem is the doc's don't even know for sure what causes mouth ulcers.

The last time I tried to quit smoking about 2 years ago, was basically cold turkey. Well I got about 10 mouth ulcers that were so deep and painful, I had to carry around a bottle of benzocaine so I could eat or talk. After a month, could not stand it any longer, started smoking again, ulcers gone in about 2 days. Anyhow the next time I try to quit, will be with a long taper, and load up with Zinc. I had found a study,which indicates this procedure to prevent mouth ulcers when quitting smoking.

Old Mike

Last edited by mf15; 02-07-2016 at 09:00 AM.
03-01-2016, 11:12 PM   #101
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It's rather semi official, but still..

Comment from one of the prof. John Hermon-Taylor's team member on the statement "MAP found in ~95% of Crohn's sufferers":

"The 95% is old data. Currently we are finding MAP (in varying degrees) in 100% of those tested, but need to complete the research before making that claim." (Original here)

Everything I can say on this is simply "WOW!". One hundred percent. No more, no less.
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03-02-2016, 12:07 PM   #102
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I see that there's a lot of excitement here about the vaccine in progress, but if I'm not mistaken there are other options that are currently available, reportedly effective in some patients, and cheap. I'm on a trial of Dapsone right now, a few days in. I'll let everyone know how it goes.
03-02-2016, 12:50 PM   #103
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medicaljohndoe, your updates would be appreciated.

About "cheap/expensive" issue - I think in fact it's not an issue for anyone of us, undoubtedly any sum will be sacrificed for the proven cure. This excitement is rather about overall progress with research of causativity of MAP, simply vaccine team with their cheap and simple MAP test came closest to the final solution.
03-08-2016, 02:30 PM   #104
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Everything I can say on this is simply "WOW!". One hundred percent. No more, no less.
Yes, but caution is needed. I have been tested twice by Prof John Hermon-Taylor, both times positive for MAP. Although the test design is very good and John is very confident of the results, it still needs to be properly validated to confirm that what it is detecting is MAP and not another similar but harmless bacteria.

This is why fund raising for the MAP Test is still on-going as is the research work. So, I would advise people to wait for the patent to be granted and the paper to be published in a refereed journal before cracking open the champagne, which hopefully should be some time this year. :-)
03-09-2016, 12:23 PM   #105
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Agree with JMC
95-100% of what sample size and what exclusion criteria etc
Any data needs validation especially new testing .
Good luck
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03-18-2016, 08:06 PM   #106
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Oxidative stress due to Mycobacterium avium subspecies paratuberculosis (MAP) infection upregulates selenium-dependent GPx activity

http://gutpathogens.biomedcentral.co...099-016-0090-8

Conclusion
This study demonstrated a strong correlation between MAP and the elevation of GPx activity. This was especially evident in Crohn’s patients, which further supports the association of MAP and Crohn’s disease. GPx activity may also be used to predict MAP infection status and to show that Crohn’s disease patients who are infected with MAP have higher tendency to develop oxidative stress than Crohn’s disease patients who are negative for the bacteria.
03-20-2016, 03:23 AM   #107
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I've been on Dapsone now for three weeks. I started at 100mg/day but had to stop after a week due to side effects, namely clear signs of hemolytic anemia. After a few days to let my bone marrow regenerate red blood cells, I started again at 50mg/day. At the lower dose, I've had almost no notable side effects. (I weigh about 150lbs for reference--I know I'm going to have GI problems when my weight goes above 152lbs.) When I started at the lower dose, I also added a multivitamin supplement (Centrum), a 400mcg folic acid supplement, and 4000IU Vitamin D-3.

My GI symptoms have not been perfect--there have been two or three days when I have felt bloated, and I had one episode that reminded me of what things were like before my diagnosis. However, on average I'd say that I generally feel far better. On most of the days I've felt completely normal, with no GI symptoms at all. The one episode that took place also seemed less severe than previous ones. I have also noticed that I have gotten more work done in the past few days than I probably got done in the past three months, simply because I have more energy and can focus more.

My skin symptoms are not gone, but they have also improved. The most important point is that the constant itching that used to plague me is basically gone (a known effect of Dapsone), and the flaking is not nearly as bad as before. The inflammation has largely, but not completely, subsided in the few psoriatic lesions that I have. My skin is still pink, but not angry red like it was before.

In the last few months many of my facial hairs and hair along my temples have turned gray--not totally impossible since I'm 32--and most have remained that way, but one has started growing back in black. I saw this in a few other hairs previously after starting to take the multivitamin more regularly. I suspect it's related to the folic acid supplement, though I now also wonder if perhaps I should be taking additional amounts of B-12.

Overall I would suggest inquiring about Dapsone (and folic acid or other Vitamin B supplementation) as possible treatment options, especially for those with skin manifestations of IBD.
03-20-2016, 12:41 PM   #108
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Medicaljohndoe what skin manifestations do you have ???
03-20-2016, 04:07 PM   #109
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Psoriasis, and various minor non-flaking non-itching rashes which have thankfully disappeared.
03-20-2016, 06:14 PM   #110
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Thanks
Ds is currently being checked for sweets syndrome and one of the drugs is dapsone
Still waiting on biopsy results
03-22-2016, 05:56 AM   #111
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Yes, but caution is needed. I have been tested twice by Prof John Hermon-Taylor, both times positive for MAP. Although the test design is very good and John is very confident of the results, it still needs to be properly validated to confirm that what it is detecting is MAP and not another similar but harmless bacteria.

This is why fund raising for the MAP Test is still on-going as is the research work. So, I would advise people to wait for the patent to be granted and the paper to be published in a refereed journal before cracking open the champagne, which hopefully should be some time this year. :-)
I really hope you are right about it being this year. Thank you for the updates
04-01-2016, 02:50 PM   #112
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Not directly CD related and 14 years old paper, but still extremely interesting:

"This report suggests a pathogenic role of MAP for immunocompromised patients, raising the question of whether this strain so far has not been detected because of its limited growth, whether it has been misidentified as M. avium, or whether its occurrence in infections is low. However, herd prevalence of bovine paratuberculosis has been reported to range from 7% to 55% in Europe and to reach approximately 40% in stocks of >300 animals in the United States (4). Thus, consumption of inadequately pasteurized dairy products may be a possible risk for infection, especially for immunocompromised patients."

http://wwwnc.cdc.gov/eid/article/8/7/01-0388_article
04-03-2016, 01:49 PM   #113
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Does anyone know what the time frame is for drugs to be approved for prescription following phase 3 clinical trials? I am interested to know for the ongoing MAP antibiotic trial going on around the world. If the results are good when can we get prescribed this drug?
04-04-2016, 08:28 AM   #114
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Does anyone know what the time frame is for drugs to be approved for prescription following phase 3 clinical trials? I am interested to know for the ongoing MAP antibiotic trial going on around the world. If the results are good when can we get prescribed this drug?
My guess, 2018/2019.

Here I'm speaking about the FDA process, and not the European.

Typically the Phase III stage takes 3 years to complete, and if the drug is safe and effective, then another 2 years for it to go through new drug application stage for final approval. This process may be sped up if the company had received fast-track designation at the time of their application.

As far as I can tell, the RedHill RHB-104 trials still have a ways to go. They recently finished enrolling half of the patients and once those complete 26 weeks of therapy, the company will release preliminary results, expected in second half of this year. They're probably continuing to recruit the second half of their patients and then those will need to complete their 26 week course. At the current rate that'll probably wrap up mid-2017. Then the NDA and hopefully approval.

RedHill is probably pretty motivated to get the drug to market; by all indications, they'll only have patent cover until 2029.
04-04-2016, 02:11 PM   #115
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and if the drug is safe and effective, then another 2 years for it to go through new drug application stage for final approval.
Stop and think for one minute, what are they actually doing for 2 whole years to get final approval? The sluggishness of these processes drives me crazy! I bet you could do it in a couple of days with proper focus!
04-04-2016, 02:38 PM   #116
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Stop and think for one minute, what are they actually doing for 2 whole years to get final approval? The sluggishness of these processes drives me crazy! I bet you could do it in a couple of days with proper focus!
This FDA article gives a pretty good run-down. In the application, they're looking at pre-clinical (animal studies), phase I-III data, safety and effectiveness results, inspecting manufacturing facilities, etc. I have read other places they may be reviewing as much as 100,000 pages of supporting documents. It's a laborious process.

I'm not rationalizing the long approval times, but can understand why, as they are generally responsible for public health, including veterinary medicine, our food supply, tobacco, cosmetics, etc. Out of their $4.7B budget, about $1.3B is allocated toward human drugs, with another $300M to biologics.

And, it's a bureaucracy.
04-04-2016, 02:48 PM   #117
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So, Xeridea, Prof JHT's vaccine which is due to start phase 1 trials this year, and phase 2 next year, will probably not be available, if all goes well, until 2020 at the earliest by this reckoning?
04-04-2016, 05:17 PM   #118
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Maybe longer depending on a number of factors on both sides of the coin.
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04-04-2016, 05:35 PM   #119
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So, Xeridea, Prof JHT's vaccine which is due to start phase 1 trials this year, and phase 2 next year, will probably not be available, if all goes well, until 2020 at the earliest by this reckoning?
I don't know Mattie, and will defer to someone more closely tied to the CMV effort to respond.
04-05-2016, 12:34 PM   #120
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I don't know Mattie, and will defer to someone more closely tied to the CMV effort to respond.
According to the "crohn's MAP vaccine" website access to the vaccine should be granted to the most severely ill patients in the end of 2017:
"As soon as there is evidence of safety and efficacy, we can apply for use of the vaccine on compassionate grounds; this will enable people who wish to have the vaccine but are unable to be part of the trial to access it on a named-patient basis outside of the trial.

Indeed, under the newly proposed ‘Early Access to Medicines’ scheme in the UK, severely ill patients who have failed existing treatments may be granted access to new medicines that are proven to be safe, even before efficacy has been fully established.

This means that the earliest the vaccine could be made available to patients on a named-patient basis would be late 2017.
"
So, in advance: happy new year 2018! =)
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