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david.crichton · Joined: 02 May 2008 Posts: 42

Negative Type-2 Association Enhances Type-1 Association.

Exploited, you'll be happy to see the suggested benefits of Vitamin D during mycobacterial infections (see reference 15, published in Science, one of the most prestigious journals with a high impact factor).

More reason for more government and private research funding.

http://www.ann-clinmicrob.com/content/7/1/9 click on "PDF(248KB)" to the right for full text download.

admin · Site Admin Joined: 06 Jan 2008 Posts: 45

Hi David
How are you doing these days? Thanks very much for your post. You know, all along I have believed that Map affects everyone, just in a different way. Every family has some disease in their family that they are more prone to than others. I believe that this predisposition manifests itself in different ways. An example is MS, Parkinsons, diabetes, autism etc. I think alot of these diseases are connected to Map in one way or the other. I can not believe that only people with crohns are the only ones affected. I have done many medical histories on people with crohns and through them I have seen how diabetes, heart disease, and other diseases are prevelent in their lineage. What do you think? Diane

david.crichton · Joined: 02 May 2008 Posts: 42

Hi Diane,
Doing very well thanks. Just finished undergrad and deciding what is next.

Yeah, my mom has wondered about childhood asthma because we know TB can affect both the lungs and intestines, and based on Dr. JHT's work we know that MAP may aerosolize, and that apparently one of the first signs of Crohn's in children is a chronic cough, so could some develop asthma instead of Crohn's based on genetic susceptibility and/or the method of transmission; doesn't sound too crazy to me. Also, in animals, MAP is throughout the entire body parasitizing the macrophages, so who knows what it could be doing.

Inhibition of phagosome maturation and survival of Mycobacterium avium subspecies paratuberculosis in polymorphonuclear leukocytes from Crohn's disease patients.

Rumsey J, Valentine JF, Naser SA.
Department of Molecular Biology and Microbiology and Biomolecular Science Center, Burnett College of Biomedical Sciences. University of Central Florida, Orlando, FL 32816, USA.

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) is an intracellular pathogen that is known to parasitize macrophages. MAP is the known etiological agent of Johne's disease and implicated in the etiology of Crohn's disease. MATERIAL/METHODS: In this study, the survival of human-derived MAP isolate following phagocytosis was evaluated using murine macrophage cell line J774A.1 and polymorphonuclear cells (PMNC's) from six Crohn's disease patients. PMNC's from five healthy individuals and four ulcerative colitis patients, as well as Escherichia coli and Mycobacterium tuberculosis, were included as controls (MOI 10:1). Maturation of the phagosome was determined by evaluating the presence of stage specific markers on the surface of the phagosomal membrane. The endosomal protein, transferrin receptor, and the lysosomal protein, Lamp-1, were then immunostained with Cy-5 conjugated secondary antibodies, and colocalization of bacteria with each marker was evaluated separately using confocal scanning laser microscopy (CSLM). RESULTS: In both models, colocalization of viable MAP and M. tuberculosis with the early endosomal marker occurred with a higher frequency than did association with the late lysosomal marker, as compared to live E. coli, and all dead bacterial species. Using differential live/dead staining and fluorescent microscopy, survival of M. tuberculosis and MAP was calculated to be 85% and 79%, respectively compared to only 14% for E. coli. CONCLUSIONS: Overall, MAP survival in murine macrophages and human PMNCs appears to mimic M. tuberculosis, suggesting the ability of this microorganism to resist phagolysosome fusion, by maintaining association with the early endosomes. The data supports MAP virulence in humans.

PMID: 16572045 [PubMed - indexed for MEDLINE]

So something is happening because of MAP itself or something in the cell which prevents the cell from continuing the 'eating process' and killing the MAP with the lysosome

So based on the above and that host and pathogen interactions can determine the phenotype of disease, maybe MAP does cause a variety of diseases.

david.crichton · Joined: 02 May 2008 Posts: 42

MAP as cause of Type-1 Diabetes and other "autoimmune" diseases.

Taken from the International Association for Paratuberculosis website:
http://www.paratuberculosis.org/pubs/proc9/abst181f_o3.htm

Association of Mycobacterium avium subsp. paratuberculosis with Type-1 diabetes, a possible trigger
Sechi LA, Rosu V, Paccagnini D, Salza S, Pacifico A, Ahmed N, Zanetti A.
Mycobacterium avium subspecies paratuberculosis (Map) is a zoonotic pathogen whose association with Crohn's disease in humans is under scrutiny. To investigate its association with other chronic diseases where the involvement of a persistent pathogen as Map could be the trigger

Forty-six diabetic patients were recruited along with 50 healthy people as control. Map was searched in the PMBC by a specific PCR targeting IS900. Sequence product confirmed identity by sequencing. Also, all the diabetic patients revealed significant humoral immune responses to two recombinant Map antigens and the whole cell lysate of the Map bacilli.

A total of 29 blood samples out of 46 were found to be positive for Map specific PCR (63%) whereas only 8 out of the 50 healthy control samples (16%) generated a positive signal. Extremely significant humoral responses to recombinant HbHA and GSD proteins and the whole cell lysates of the Map bacilli were recorded in T1DM patients as compared to healthy controls.

We report presence of Map DNA and Map specific antibodies in the blood of Type1 Diabetes Mellitus (T1DM) patients in an endemic setting like Sardinia. Finding evidence of Map involvement in T1DM is perhaps a novel finding that might serve as a foundation stone in establishing an infectious aetiology for T1DM.

AND: http://www.paratuberculosis.org/pubs/proc9/abst185f_o4.htm

Is M. avium subspecies paratuberculosis (MAP) the cause of multiple "autoimmune" and "inflammatory" diseases in man? Inferences from the anti-MAP activity of methotrexate, 6-MP, 5-ASA and thalidomide, on MAP in culture.
Greenstein RJ, Su L, Brown ST.

BACKGROUND:
We have shown that the "immuno-modulators" methotrexate and 6-MP and the "anti-inflammatory" 5-ASA inhibit MAP growth (www.PLoSONE.org) and concluded that their most plausible mechanism of action in several idiopathic diseases is as antiMAP antibiotics. Thalidomide is an "immunomodulator" used in multiple "auto-immune" and "inflammatory" diseases and the mycobacterial diseases leprosy and tuberculosis. We now test the hypothesis that thalidomide inhibits MAP growth.

METHODS
Thalidomide (±) and (+) and (-) and its two components, phthalimide and 1-hydroxy 2,6 piperidine dione (HPD) were evaluated in culture of two strains each of MAP (ATCC 19698 [bovine] & Dominic [human]) and M. avium subspecies avium (ATCC 25291 & 101.) We used a radiometric (14CO2 Bactec®) detection system. Inhibition is indicated by "percent decrease in cumulative Growth Index" (%-DcGI) from control.

RESULTS:
Phthalimide has no dose dependent inhibition on any strain. There was no dose dependent inhibition on either M. avium strain with thalidomide or its components. With the two MAP strains, there is dose dependent inhibition with thalidomide (±); Dominic (31%-DcGI) and ATCC 19698 (26%-DcGI) at 64µg/ml. Thalidomide (+) is more inhibitory than (-). HPD is, on a weight for weight basis, the most inhibitory agent evaluated; Dominic (46%-DcGI) and ATCC 19698 (44%-DcGI at 64µg/ml)

CONCLUSIONS:
We show in vitro heretofore-undescribed inhibition of MAP growth by racaemic thalidomide. Thalidomide (+) is more potent than (-). Of thalidomide's two moieties, phthalimide has no antiMAP activity and HPD is the active component in inhibiting MAP growth. We suggest that since 1942, initially with 5-ASA, the medical profession has unknowingly been treating MAP infections. These data are compatible with our concern that MAP is zoonotic. We conclude that all idiopathic "autoimmune" and "inflammatory" diseases, empirically treated with medications that we show are active against MAP, should now be evaluated for MAP as the etiological agent.

billyfish · Joined: 07 Jan 2008 Posts: 30

Its a bit of a shock that this horrific form of diabetes might be a cousin of crohns. I had not heard of this before.

I have looked it up and yes, it is doubling every 20 years, it is associated with drinking milk and there are 230,000 victims ijn the uk, roughly the same number as crohns.

There are families where someone gets crohns and another gets diabetes.

I have not been able to find anyone campaigning to get MAP out of food because of the diabetes risk. If this study is confirmed I am confident that there will be substantial pressure to get MAP out of food.

Diabetes is a very emotive subject that all too often gets blamed on the patient. Its a lot easier to understand than crohns and there is a more definite risk of death, especially in young people.

Thanks for finding this article, there are more questions to be answered now?