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Crohn's Disease Forum » Books, Multimedia, Research & News » Etiology of inflammatory bowel disease: A unified hypothesis


 
07-28-2012, 11:21 PM   #31
kiny
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here's a map of Europe 2007 with crohn indices

I have lived in Belgium, France, Spain and Switzerland. Habit wise, outside of people in spain and southern france sleeping during the day because it's so hot in the summer, there is no difference. Food is very similar, brands are very similar.

The North-South crohn gradient theory about climate does not make a lot of sense on this map, Eastern Europe has a very low crohn indice and it's damn cold there. This map is a reply that questioned the North-South grade study because it didn't include Easter Europe, once Eastern Europe is included the North-South theory stops making sense.

The study and many people say "Westernisation", which makes sense on that map until you look at croatia, is one of the least westernised country on that map and it's bright green.

I notice that all the countries with high crohn are clustered together. There isn't one country that pops out or is wrong, there is a real gradient running over that map.

I don't think it has much to do with underdiagnosis either, Eastern Europe might have that issue but Greece is yellow on that map too and it's almost 100 times as low than Western Europe. I've lived in Greece and Krete a while, their hospitals are not that bad that they would miss a 100 cases for every 1 case rightly diagnosed in Western Europe.

I think Europe is a much more interesting case than looking at the US, because Europe up until a few years ago, did not have the same free trade and movement of populous as the US has had for decades, whatever differences and clues there are, it will be much more pronounced in Europe.

All I know is if you showed a map to someone like this, and you did not tell them what disease it was, the first thing they would say is infectious disease / epidemic. Why are all those countries clustered together? What else is there that explains clustering like that outside of infection?

Genes don't explain crohn at all anymore. Many many people with CD don't have a genetic predisposition, man y in Asia with crohn have none of the genetic markers. Ireland rising by 90% in 10 years can't be explained by genes either. Genetic predisposition is all I believe in.

Last edited by kiny; 07-29-2012 at 12:21 AM.
08-04-2012, 11:49 AM   #32
wildbill_52280
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here's a map of Europe 2007 with crohn indices

I have lived in Belgium, France, Spain and Switzerland. Habit wise, outside of people in spain and southern france sleeping during the day because it's so hot in the summer, there is no difference. Food is very similar, brands are very similar.

The North-South crohn gradient theory about climate does not make a lot of sense on this map, Eastern Europe has a very low crohn indice and it's damn cold there. This map is a reply that questioned the North-South grade study because it didn't include Easter Europe, once Eastern Europe is included the North-South theory stops making sense.

The study and many people say "Westernisation", which makes sense on that map until you look at croatia, is one of the least westernised country on that map and it's bright green.

I notice that all the countries with high crohn are clustered together. There isn't one country that pops out or is wrong, there is a real gradient running over that map.

I don't think it has much to do with underdiagnosis either, Eastern Europe might have that issue but Greece is yellow on that map too and it's almost 100 times as low than Western Europe. I've lived in Greece and Krete a while, their hospitals are not that bad that they would miss a 100 cases for every 1 case rightly diagnosed in Western Europe.

I think Europe is a much more interesting case than looking at the US, because Europe up until a few years ago, did not have the same free trade and movement of populous as the US has had for decades, whatever differences and clues there are, it will be much more pronounced in Europe.

All I know is if you showed a map to someone like this, and you did not tell them what disease it was, the first thing they would say is infectious disease / epidemic. Why are all those countries clustered together? What else is there that explains clustering like that outside of infection?

Genes don't explain crohn at all anymore. Many many people with CD don't have a genetic predisposition, man y in Asia with crohn have none of the genetic markers. Ireland rising by 90% in 10 years can't be explained by genes either. Genetic predisposition is all I believe in.

the north south gradient is more evident on a North american map, as the european equivalent to "south" is not land.
08-05-2012, 04:32 PM   #33
Xiaofa Qin
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Thanks kiny for posting this informative map on CD. This map clearly showed that Sweden were among countries with the highest incidence of CD, which was higher than countries like Germany, despite that Sweden are almost free of MAP while some parts of Germany may have as high as 84.7% of MAP positive in dairy herds (Khol JL, et al. Examples and suggestions for the control of paratuberculosis in European cattle. Jpn J Vet Res. 2012 Feb;60 Suppl:S1-7. http://eprints.lib.hokudai.ac.jp/dsp...20Suppl.-1.pdf). This would a strong indication that the development of CD is indeed unnecessarily related to MAP.

It seems inaccurate to say Dr. Van Kruiningen never finds MAP. In fact, he had been a key author of the first report of finding MAP in gut tissues from CD patients (Chiodini RJ, Van Kruiningen HJ, Thayer WR, Merkal RS, Coutu JA. Possible role of mycobacteria in inflammatory bowel disease. I. An unclassified Mycobacterium species isolated from patients with Crohn's disease. Dig Dis Sci 1984;29:1073–9), which had been just the study that refreshed the interest and kindled the extensive study on the possible link between MAP and CD in the last several decades. He had also been the key author for the report of the possible existence of spheroplastic phase of mycobacteria in CD patients (Chiodini RJ, Van Kruiningen HJ, Thayer WR, Coutu JA. Spheroplastic phase of mycobacteria isolated from patients with Crohn's disease. J Clin Microbiol. 1986 Sep;24(3):357-63). He seemed to be an expert in this area with thorough and detailed information for both sides of the MAP controversy. It would need great courage to acknowledge that these glorious studies that he authored and have been “verified” by many followers as a possible contamination, and the change in his believe over time and along with the accumulation of knowledge would not be arbitrary. It was not Dr. Van Kruiningen but rather multiple other researchers such as Drs Hugh Freeman and Michael Noble from University of British Columbia, Canada (Freeman H, Noble M. Lack of evidence for Mycobacterium avium subspecies paratuberculosis in Crohn's disease. Inflamm Bowel Dis. 2005 Aug;11(8):782-3) and Nicole M.Parrish et al from John Hopkins (Parrish NM, et al. Absence of mycobacterium avium subsp. paratuberculosis in Crohn's patients. Inflamm Bowel Dis. 2009 Apr;15(4):558-65) that failed to repeat the crucial finding of the existence of MAP in the blood of CD patients.

Hope the Crohn's Disease Initiative, led by Dr. Chiodini who had first isolated M. paratuberculosis from a CD patient and initiated the MAP controversy, will also bring an end to this controversy. I found their site has a fairly detailed description for the history of the MAP controversy and the formation of the two camps (http://www.thecrohnsdiseaseinitiative.com/index.php). As stated there, there are some critical questions we will have to answer. For instance, large amounts of MAP can been found in gut tissue and feces of cattle with Johne’s disease, while most positive findings of MAP in CD patients was detected by methods like PCR, after more than 30 cycles of doubling (billions of times of amplification), along with the increased possibility of false-positive. How come such a trance amount of MAP, hidden deeply inside the cell, may have caused the much severe and extensive damage of the gut and other tissues as seen in the CD patients than Johne’s disease. As even a combination of the well tested anti-mycobacterial drugs such as clarithromycin, rifabutin and clofazimine failed to show a sustained effect on CD patients, the anti-TNF (like infliximab) and immune suppression agents would more likely exert their effect on CD through a direct inhibition of inflammation rather than MAP. As described in the paper discussed here, I personally suspect that factors like the digestive proteases produced by us to digest the food rather than pathogens like MAP, Helicobacter pylori, invasive E. coli, etc might be the primary cause for gut damage. However, this remains a hypothesis awaiting further tests.
08-05-2012, 05:15 PM   #34
kiny
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nm, I get way too worked up about this because it affects me

thanks for your info Xiofa

Last edited by kiny; 08-05-2012 at 09:51 PM.
08-05-2012, 05:49 PM   #35
Moe.
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But if it is MAP. Then we can kill it. Otherwise they will look around for
Another hundred years to what causes. Hence no cure.
08-05-2012, 08:41 PM   #36
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nikimazur-

Your right better technology means a rise in the diagnosis of CD and UC. Just as better fetal monitoring has given a higher c-section rate.

I think UC and CD are just that- disease we are "lucky" enough to have. Some groups are predispossed to it and others aren't. Just as some groups are predispossed to diseases we don't get.

I dont think the artificial sweetners are the cause- my mom never used them and neither have I. ( I have had this my whole life ) I don't think antibioitcs "cause" IBD. There are certinly antibiotics can bring on a "flare" up. I didnt use them as a child and my mom didnt take them during her pregnency. Likewise my three kids had chronic cases of ear infections and strep throat. And none of them have Crohns.


Lauren
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Diagnosed= 1992 and again Feb 2012 Confirmed with
CT enterography May 2015 !!


Waiting for the ok from my Ins company to restart Remicade. Will also start Imuron to get into remission!
I know it's out there somewhere and I WILL find it!


:


Ok, my family Dr told me to cut down on the stress- a husband, 3 kids, and 3 dogs!
08-06-2012, 06:36 PM   #37
Mark in Seattle
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Having read many research reports over the years, I've read little that speaks to the question of why CD tends to occur so frequently at the terminal ileum. Having spent the last few years sleeping on my left side due to severe GERD (look at the shape of the curvature of the stomach/ GE valve to see why sleeping on left side prevents food/acid from escaping from the stomach while lying down), and having recently developed severe CD on my left side of my intestines somewhere for the first time in my 30 years of suffering with CD, I have come to suspect that CD occurs when food/chyme comes in contact with the intestines for a prolonged period. I guess that for most people, terminal ileum is where the food contacts the intestine for the longest time period, as it awaits opening of the ileocecal valve. And for me, the food undoubtedly comes to rest at night somewhere on my left side since I lie on my left. I'm not exactly sold on the notion of sweeteners, but the notion of bile burning the mucosa if it comes to rest at the terminal ileum is an idea I would not dismiss, unless someone could argue why it doesn't make sense. I've also noticed that when I eat a fibrous meal, such as a burrito with some beans, it slows the transit of the food, and at the same time causes more burning pain as a result of the increased time in my guts. So there is clearly something there that my gut does not like to be in contact with. Or perhaps the tissue is inflamed for some other reason and simply does not like to be in contact with anything, even something inert perhaps.

Another thing I've noticed is that if I take a proton pump inhibitor medication 2 days in a row (omeprazole) then my CD flares/burns badly. Same thing if I try to take an antibiotic - can't do it, it hurts me too bad. These two things suggest in my mind that there is some problem with bacteria doing battle in my guts. The ppi meds I suppose let some bacteria come in, more than usual, while the antibiotic perhaps wipes out the minority of good bacteria, leaving only the majority dwellers which are probably pro-inflammatory bacteria. So at least in my mind, I'm picturing a messed up configuration/distribution of bacteria as causing alot of the problem somehow.

Anyhow, Xiaofa, how would you propose to test the hypothesis that unconjugated bile acids & such are causing the damage, not to mention the hypothesis about the sweeteners?
08-06-2012, 11:04 PM   #38
Xiaofa Qin
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Thanks tots for sharing the story. There would be definitely other causes of IBD other than saccharin and sucralose. I personally believe anything that caused a prolonged and sustained damage and inflammation of gut may increase the risk for IBD.

Thanks Mark in Seattle for the interest in my opinion. More accurately, I suspected that the impaired deconjugation of conjugated biliary bilirubin (rather than bile acids) had caused a poor inactivation of the digestive proteases and further damage of the gut. As this deconjugation depends on an enzyme called beta-glucuronidase enriched in gut bacteria, I had suggested in my grant application to give animals some inhibitors of the enzyme such as 1,4-saccharolactone to see how the deconjugation of bilirubin, the inactivation of digestive proteases and gut damage correlate with each other, but it never got funded. Months ago, Old Mike (mf15, see some posts by him in the same thread) had discussed with me via email his suspecting that glucaric acid existed in some vegetables, fruits and other foods may have contributed to IBD by its inhibition on beta-glucuronidase. I was very impressed by his great efforts and knowledge. In fact, 1,4-saccharolactone is just another name for glucaric acid.

It has been well documented that damage of the gut in IBD indeed related to luminal contents, which is demonstrated by facts that diversion of luminal contents resulted in remission and relapse occurred after re-introduction, and the damage of gut mostly occurred in areas with prolonged retention of the luminal contents.

Last edited by Xiaofa Qin; 08-06-2012 at 11:20 PM.
08-07-2012, 12:07 AM   #39
Mark in Seattle
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Thanks Xiaofa. Sorry I messed up a bit on the terminology (digestive proteases, etc.) -not my specialty.

So I'm still curious about your animal proposal. Any particular kind of animal? Would you have a means of measuring/correlating the deconjugation, the inactivation of proteases, and damage done to the intestines? I can envision being able to measure the damage that is done or not done relative to control animals, but I wonder how you would measure the deconjugation of bilirubin and the inactivation of proteases. I'm guessing you'd have to kill the animal and lavage the intestines sometime before the meal is excreted, is that about right? And do the same for control animals?

Do you know how much such an animal study would cost?

Regarding glucaric acid, as I check this web site,

http://www.livestrong.com/article/33...glucaric-acid/

it appears that there are a great many fruits & veggies high in glucaric acid. I don't know what to make of that. I would guess that the glucaric acid in those many food items must not have the ability to significantly disrupt the bilirubin/proteases/etc. Otherwise I would think everyone would get a gut ache when eating those things.
08-07-2012, 12:31 AM   #40
Mark in Seattle
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[QUOTE=kiny;479340]

croatia, is one of the least westernised country on that map and it's bright green.

[QUOTE]

http://www.ncbi.nlm.nih.gov/pubmed/10377694

Apparently Croatia saw a 10-fold increase in CD incidence from 1973 to 1994. Something must have happened during that time period.

Interesting when I check wikipedia about their foods, it sounds like they stick to real food, not so much to processed food. I'm guessing though that this all has something to do with the processed food industry. I basically think there is some problem with the processed food industry. Processed foods are so filled with chemicals.
08-07-2012, 07:55 AM   #41
Xiaofa Qin
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Thanks Mark in Seattle for interest in the proposed research. For this kind of study, the commonly used laboratory animals like mice and rats may be used. Deconjugation of bilirubin and inactivation of digestive proteases can be assessed by measuring the amount of conjugated bilirubin and protease activity in the luminal contents collected from the animals. These assays are actually easier than scoring gut damage. The reagents and materials are pretty cheap. The main cost would be the labor and animals, and the scale of the study may be adjusted according to the resources.

Large amounts of digestive proteases can be found in animals or people treated with antibiotics but not under normal condition, suggesting the components in diet just had minimal effect compared to a change in gut bacteria. Glucaric acid is readily absorbed through the intestine, thus a fairly large amount would be needed to reach the lower intestine and exert a significant effect on beta-glucuronidase enriched in gut bacteria. An accurate evaluation would need more study in this area.
08-11-2012, 09:51 AM   #42
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This paper suggested that ulcerative colitis (UC) and Crohn’s disease (CD) are just two phenomena of the same disease rather than two different diseases. This notion came to my mind when I saw the consecutive shift of CD from the small to large intestine over time, and thus likely a shift from UC to Crohn’s colitis. The many case of Crohn’s colitis today would be just diagnosed by Dr. Crohn and colleagues as UC but not CD, the so called regional ileitis at that time (Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. 1932. Mt Sinai J Med. 2000 May;67(3):263-8). I knew this notion would be very difficult to be accepted by many people. However, I took it as a crucial part in this unified hypothesis. I realized that it is against the current main stream of thoughts and efforts, trying to divide UC and CD into multiple subtypes with each corresponding to a specific cause. This would be no surprising, as it is just what people usually do in facing the many perplex phenomena without a reasonable explanation.

In deed, strictly to say, each IBD patient is different from the others: each one has a unique set of genes, and even identical twins may have different diet, different sanitary habit, and thus different spectrums of bacteria (microbiome) in the gut. However, time and again, the overwhelmingly perplexed phenomena were usually fallen into some simple explanation. A couple of decades ago, when I was a postgraduate student, I wrote a paper entitled “the phenomenal diversity and complexity and the essential simplicity and unity upon life” that was published in Philosophy and Medicine. I hold this philosophy and belief then and also now. We definitely should realize and explore the diversity and complexity of things. However, we should also put more efforts to find out the principles and laws behind them, which are usually characterized by simplicity and unity. There are numerous different forms and species of life on earth, with a constant disappearance of some old ones and the emergence of some new ones, but we now know all the differences are just governed by the different sequences of base-pairs in DNA.

CD and UC have many similarities in clinical, pathological and epidemiological features. People may easily attribute this to the gene. However, this notion would be immediately embarrassed by the fact that the NOD2/Card15, also called IBD1 gene, is shared by Crohn’s disease with diseases other than IBD such as the Blau’s syndrome and early onset sarcoidosis, but not with UC, its twin brother of IBD. As we know, there are always some IBD patients that cannot be classified to either UC or CD, the misclassification between UC and CD frequently occurred. Pet dogs and cats are also just diagnosed as IBD without further classification. This misclassification or the lump up of UC and CD seems without big consequences for the treatment. These suggested the great similarity in nature between UC and CD. All hypotheses would have to address this close relationship between them and the dynamically changed faces of UC and CD. Otherwise, the theory would likely bear some fatal defects or at least some potentially severe flaws. The great efforts of a century long extensive research on IBD had generated a vast amount of information. Some of them may somehow reflect the true nature of the disease, but many of them may be superficial, erroneous and misleading, as demonstrated by the many totally opposite or conflicting evidences (such as those regarding MAP). To get to the nature of IBD, we may need more in-depth, insightful, thorough and critical thoughts.
08-19-2012, 07:53 PM   #43
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This is the era of genome. We all expect research on genes may solve the big problems, and this is indeed where we have put the greatest enthusiasm, attention, hope, trust and belief as well as the energy, efforts and resource. However, it seems not that easy to get the miracle.

I found the possible link between saccharin and IBD in 2001, about the same time people hailed the finding of the first IBD gene, NOD2/Card15, also called IBD1, associated with the Crohn’s disease. In the May 31 issue of Nature, three papers were published: two research articles and one commentary. At that same moment, I thought I probably had found an important causative factor in the environment and thus would also draw some attention, as the emergence and dramatic increase of IBD clearly suggested IBD being caused by changes in the environment rather than the genes. However, the manuscript I wrote with the evidence suggesting the possible link between saccharin and IBD was rejected by journals even specialized in gastroenterology. Finally, I found the previously unknown journal named Medical Hypotheses, and the paper was eventually published there.

A decade later, we can see the paper published in Nature was cited thousands of times and NOD2 was studied again and again by many researchers. In contrast, my paper was hardly mentioned or cited by any of the dozes of thousands of paper even in IBD area.

Failed to raise any action and get any grant, I had to continue the pursuit by myself and the paper discussed here is just the result of the decade-long effort during my spare time. Although it is still hypothetical in nature, at least it constituted a tangible unified theory that provided cohesive and comprehensive explanations for many puzzles in IBD. For me, I felt IBD no more a mystery.

On the other hand, multiple millions, if not billions, had been spent on mostly gene related research on IBD (NIH alone funded 113 million on IBD research in 2011). However, despite of the more than a decade extensive research, we still do not know exactly how NOD2 related to IBD. It is speculated that mutation in NOD2 (and also autophage genes like ATG16L) may caused IBD as the result of the impaired clearance of gut bacteria, but why IBD is lower before modernization with poor hygiene condition, and is more closely related to CD in the small intestine rather than CD in large intestine or UC, where there would be more bacteria in the gut.

With the many puzzles regarding NOD2 awaiting to be solved, the great effort in last decade have lead to the hailed achievements of finding further about a hundred more genes related to IBD, with more to be discovered along with the ongoing endeavor on both the host and gut bacteria. As the relationship of these genes with IBD would be more remote, ambiguous, and perplex, it would be likely more difficult and take more time to decode. We still do not know how and when a united hypothesis on the etiology of IBD would be constructed based on these genetic findings that, according to the main stream of thought, would take into consideration not only the interaction among these genes but also their interaction with the environment, the gut microbiota and the immune system. Nevertheless, one thing would be sure: it will generate many fantastic theories, remarkable achievements, momentous new advances, and magnificent scientific articles published in the renowned journals along this process.

One day the history would make a judgment as whether the establishment of this unified hypothesis discussed here or the finding of the more than 100 IBD genes would make us more closer to a final solution of IBD. I personally felt we should put more efforts to find out the causative factor(s) of IBD in the environment and thus the root mechanism (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315). We now know that 90% of lung cancer is caused by smoking and only about 1% is caused by air pollution, thus a big reduction in lung cancer should largely rely on stopping smoking rather than stopping driving the car. This kind of knowledge can only be got by epidemiological studies rather than research on genes, thus I think we should realize the importance of both studies and treat them with balanced enthusiasm, attention, appreciation and efforts.
10-03-2012, 09:58 PM   #44
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Thank you for your interest in IBD research and the great long post!
I believe the causes and effects of IBD are so complex that investigation must occur from multiple different avenues. The interaction of causal factors and the individualized nature of symptoms under the broad umbrella of Crohn's / IBD indicates that this disease does not have just one answer.

I fully support and appreciate any and all research into Crohn's Disease and hope one day we can piece it together for more effective treatments - and a cure!

Thank you for all of your hard work in adding to piecing together the puzzle of Crohn's Disease.
10-14-2012, 07:13 PM   #45
Xiaofa Qin
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Thanks Judith for the comments. IBD indeed seems very complex, as suggested by the many articles published in some of the most renowned journals. However, time and again, this kind of overwhelmingly bewildering complexity may largely due to the failure of knowing its cause. For instance, infection of the gut by Mycobacterium Tuberculosis can exhibit many symptoms virtually indistinguishable from Crohn’s disease. In addition, this bacteria can also infect many other organs like the lung, brain, liver, kidney, spleen, and bone, with much more complex spectrums of symptoms different greatly among individuals. Despite that, all these can be cured by eradicating the bacteria using some antibiotics.

As stated in the paper, I totally agree with the notion that the development of IBD must involve multiple factors, just like there are many risk factors for tuberculosis such as overcrowding, malnutrition, alcoholism, smoking, HIV, diabetes, silicosis, corticosteroids, anti-αTNF antibodies like infliximab, and genes like HLA-DR, INF-γ, SLC11A1, VDR, MAL/TIRAP, and CCL2 (http://en.wikipedia.org/wiki/Tuberculosis#Risk_factors). However, we should realize that many of these factors are affecting factors but not the key causative factor, and we should not be confused and intimidate by them. The prompt ups and downs of IBD even in the developed countries in the west would strongly suggest there might also be some key causative environmental factors for IBD. As stated in the previous posts and illustrated in the paper, I suspect saccharin and sucralose could be just this kind of causative factors that should be checked out, but this does not exclude the possible existence of other important causative factors that need to be found.

As for the cure, I believe the cure, as well as effective prevention, of IBD would largely depend on finding out the main cause and thus the root mechanism. I found a thread in this forum started by David with wonderful detailed descriptions regarding the strong relationship between the mucosal healing and the long-term prognosis of IBD (http://www.crohnsforum.com/showthread.php?t=36253). A more recent paper on this topic can be found in Gut (Neurath MF and Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut. 2012 Nov;61(11):1619-35; http://www.ncbi.nlm.nih.gov/pubmed/22842618). It becomes more and more clear that the long term remission and prognosis of IBD are most strongly related to mucosal healing as judged by the appearance and integrate of the gut surface observed with the naked eye through an endoscope, but rather than the set of genes the patients being baring, the amount and type of inflammatory cells aggregated in the mucosa, the amounts and type of bacteria hide in the macrophages, the type and strength of antibodies in the blood, the feelings and symptoms of the patients, and even those gold standards of clinical remission. Doctors and IBD professionals seem still greatly puzzled by this phenomenon and wondering this mucosal healing is indeed essential or just cosmetics. However, this close relationship is not surprising to me. If you read through my paper, you may find that this hypothesis simply suggested that the weakening of the gut barrier as the result of over digestion of the mucus layer and underlying gut tissue by the poorly inactivated digestive proteases have been the primary cause of IBD. The many changes of the immune system, which may be greatly affected by genes and many other factors, might be just a natural response to the increased infiltration of bacteria or dietary components. It suggested the close relationship between mucosal healing and prognosis had actually reflected the root mechanism of IBD and a cure may largely depend on a full restoration of the function of gut barrier. This may just like a group of bandit sneaked into a well-built castle through a small leftover opening of the gate. They were found by the well-trained guards and the fighting between the guards and the intruders caused some turmoil. To solve the problem, some people tried hard to find out the defects of the castle and would like to rebuild it. Other authorities put a great effort to disarm and disable the guards loyal to their duty, and the temporary peace thus achieved made many people believe this would be the wonderful approach. However, there might be a more easy and complete solution, i.e., to close the door tightly.
10-14-2012, 07:44 PM   #46
mf15
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Xiaofa Qin:I agree the immune system is attacking someting that is leaking through
the barrier,bacteria/endotoxin. The immune system is not stupid.
The question is why the leak.
We have to start around 1920 perhaps to figure this out.
One thing that might be implicated is all the synthetic surfactants and detergents we ingest,if some of them get to the colon then they will reduce the integrity of the hydrophobic mucus barrier,also the wrong type of bile acids,which can act as surfactants,or their non activation.
I also believe that over fortification of food with iron and B6 are involved.
I am starting a new thread that might be of interest,
which is some older and some new material.
Please see Radical Induction Theory.
Old Mike

Last edited by mf15; 10-15-2012 at 08:55 PM.
10-14-2012, 07:49 PM   #47
Moe.
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Interesting.
Could you answer this question please?
Qu biologics made a ssi vaccine for crohns (YouTube ssi vaccine crohns)
It put the individual in remission. The vaccine was to stop a certain strain of e.coli. Why would something like this work? Is it stopping the gut being infected by this bacteria? Very confusing because it seems that there is a different cause to everyone's ibd. Hence different response to treatment.?
I'm probably guessing but ill link tonight a Saudi woman had tuberculosis which caused ibd, in Saudi it's .94 out of 100,000 people have ibd which is very small.
Anyhow ill link it up later tonight and have a read and tell me what u think.
10-15-2012, 08:50 PM   #48
Xiaofa Qin
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Thanks Old Mike and Moe for sharing the thoughts and info.

Yes, there are so many possibilities for IBD. It would be better we can sort them out and make some kind of quantitative assessment. Free radicals have been the weapon of white blood cells to fight bacteria. They definitely can cause damage to the tissue, and antioxidants may help reducing the inflammation. As for the anti E. coli vaccine, I do not know the detail. If it indeed work, one simple explanation I can think of would be also its fighting against the infiltrated bacteria, as E. coli is one of the most abundant bacteria in the gut. But the producer may have more sophisticated and profound explanation.
10-17-2012, 03:17 AM   #49
Moe.
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BMJ Case Reports 2012; doi:10.1136/bcr.01.2012.5620

Reminder of important clinical lesson

Crohn’s disease or TB – the perennial question and diagnostic pitfalls

Rudra Krishna Maitra1,
Tim Bowling2,
Pradhib Venkatesan3,
Charles Maxwell-Armstrong1

+ Author Affiliations

1Surgery Department, Queens Medical Centre, Nottingham University Hospitals, Nottingham, UK
2Gastroenterology Department, Queens Medical Centre, Nottingham University Hospitals, Nottingham, UK
3Infectious Diseases Department, City Hospital, Nottingham University Hospitals, Nottingham, UK

Correspondence to Mr Rudra Krishna Maitra, [email protected]

Summary

A previously healthy 28-year old lady from Saudi Arabia presented with recurrent peri-anal abscesses progressing to fistula-in-ano. These were treated with incision and drainages and with setonisation of the fistula. Multiple biopsy and culture specimens were taken to rule out tuberculosis (TB) or Crohn’s disease – all showed granulomatous disease suggestive of either Crohn’s or TB, no mycobacteria were grown. MRI scanning also suggested either TB or Crohn’s disease. Tuberculin skin test was inconclusive and Quantiferon Gold test was negative. Treatment for Crohn’s was started with oral prednisolone – the patient deteriorated and adalimumab (tumour necrosis factor α antagonist) was commenced. With continued deterioration in the absence of intra-abdominal abscesses, a clinical diagnosis of TB was made, Crohn’s treatment suspended and quadruple therapy for TB was initiated. The patient rapidly improved and a delayed re-look histological specimen identified an isolated mycobacterium. Subsequent cultures confirmed drug-sensitive TB. The lady is currently well on TB eradication regimen.
Background

In the UK, Crohn’s disease (CD) has an incidence of 8.3 per 100 000 of population and is a common cause of recurrent peri-anal abscesses and fistulation. Tuberculosis (TB) is uncommon in the UK with a prevalence of 15 per 100 000 of the population (2009) of which only a small fraction present as intestinal TB; prevalence is significantly higher in developing countries.1 2 Diagnosing TB is difficult with no test providing 100% sensitivity and specificity. Delayed diagnoses can result in serious morbidity. Extra-pulmonary manifestations of TB accounted for 47% of cases in the UK (2009), more commonly in foreign-born individuals who account for the majority of cases.2 Intestinal TB presents with clinical features resembling CD and must be distinguished from it.

In the following case, TB was suspected as a differential for CD from the outset but all tests proved negative for TB. TB was correctly diagnosed after clinical deterioration following initiation of treatment for CD. This case highlights the difficulty of distinguishing intestinal TB and CD and the need for constant re-evaluation of the diagnosis in the face of deterioration.
Case presentation

A previously well 28-year-old lady from Saudi Arabia presented with a left-sided peri-anal abscess. She had BCG immunisation as a child and gave no personal, family or contact history of TB. In Saudi Arabia she did not drink any unpasteurised milk. She had a history of a previous peri-anal abscess. She was systemically well. An incision and drainage of the abscess was performed. Microbiology samples grew Escherichia coli and Enterococcus, both sensitive to co-amoxiclav, with which she was treated.

She returned 5 months later with a slow healing wound and discharge from the opposite side.
Investigations

MRI showed a fistula tract, thickened small bowel loops with a small quantity of fluid in the pelvis (figure 1). The MRI report suggested CD. A barium follow-through showed a dilated distal ileum and narrowing in multiple parts of the colon. Colonoscopy showed significant inflammation in the ascending colon. Biopsies were sent for histology but not for culture. Histology showed non-caseating granulomata, with no acid fast bacilli (AFB), consistent with CD but a differential of TB could not be ruled out. A CT scan showed some subcentimetre intra-abdominal lymph nodes, not amenable to percutaneous biopsy. A chest x-ray was clear.
Figure 1
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Figure 1

Initial MRI showing fistula tract and thickened small bowel loops with fluid in pelvis.
Differential diagnosis

TB and CD were the principle differential diagnoses. In the absence of any mycobacterial growth or evidence of TB on histology, a provisional diagnosis of CD was made.
Treatment

Treatment for CD was started with prednisolone while a seton suture was inserted in the persistent peri-anal fistula. The patient did not improve and re-presented with an ischio-rectal abscess on the opposite side. This was incised, tissue was sent for histology and swabs were sent for culture. The histology showed florid granulomatous inflammation. A second colonoscopy was performed to assess the need for an antitumour necrosis factor (TNF) α agent, namely adalimumab. Colonoscopy showed continuing active inflammation. No further samples were taken for histology or culture. Before commencing adalimumab a tuberculin skin test (TST) showed a 16 mm response and a Quantiferon Gold IT interferon γ release assay (IGRA) was negative. Within 1 month of starting adalimumab she presented with fever, rigors, diarrhoea and lethargy. A CT scan showed no abscesses, but found intra-abdominal fluid and multiple enlarged mesenteric lymph nodes. Adalimumab was immediately stopped. Her fever continued despite intravenous tazocin. Ascitic fluid was sent for culture (including for AFB) and all her previous samples were re-evaluated. At this point, an isolated acid fast bacillus was discovered on re-sectioning her first colonoscopic biopsy taken 8 months previously. She was commenced on quadruple therapy for TB (rifampicin, isoniazid, pyrazinamide and ethambutol).
Outcome and follow-up

On commencement of anti-TB therapy, she improved dramatically. Fully sensitive Mycobacterium tuberculosis subsequently grew from ascitic fluid. An HIV test was negative. She was discharged from hospital 1 week later and is currently well on treatment.
Discussion

The phenomenon of mycobacterial infection revealed by the use of anti-TNF α agents is well recognised.3 Guidance exists on assessment for latent or active TB infection before the use of such agents.4 5 When screening for latent TB, a chest x-ray and TST or IGRA are performed. Our patient had a normal chest x-ray and a positive TST. The latter could have been due to either mycobacterial exposure or prior BCG. If this had been interpreted as a marker of latent TB infection one possible option might have been to prescribe isoniazid chemoprophylaxis and continue with anti-TNF α therapy. A risk from this course of action arises when active TB, rather than latent TB, is present, isoniazid monotherapy is insufficient to treat the higher mycobacterial burdens of active TB and will eventually select for isoniazid resistance, although a false sense of clinical response may occur initially as isoniazid kills sensitive organisms. Our patient had an IGRA Quantiferon Gold IT, in addition to a TST. BCG would not have affected an IGRA, given the specificity of this test for M tuberculosis infection. Her positive TST with a negative IGRA could have been interpreted as a false positive TST due to her prior BCG, but this was in fact a false negative IGRA.

Our patient gave no clear exposure history to TB, had a clear CXR and had had BCG as a child. Although taking a BCG vaccination history is routine, its value in reducing the probability of a TB diagnosis is uncertain. The efficacy of BCG varies between populations, may wane with time and some argue may apply more to reactivation of latent infection than new exposure to TB.6 7 In some patients for example, with established rheumatoid arthritis, there may be no additional clinical considerations before starting anti-TNF. However in our patient there was the added complexity that active TB was a possibility.

The UK NICE guidelines do not advocate the use of IGRAs or tuberculin skin tests for the diagnosis of active TB.8 These tests do not have sufficient sensitivity to exclude disease when results are negative and lack the specificity to distinguish latent from active disease when results are positive.9 The diagnosis of active TB depends on clinical suspicion and sampling for culture. The clinical pictures of intestinal TB and CD can be very similar, although some differences have been reported.10 At colonoscopy and on histology TB can cause superficial, transverse ulcers which do not penetrate beyond the muscularis mucosa. In CD, ulcers can be longitudinal and serpiginous. Granulomas in the intestine or local lymph nodes can be non-caseating with either diagnosis, but only caseating with TB and some other infections. Mycobacterial culture of suitable samples (lymph node, intestinal tissue, fluid or pus) not placed in formalin is key to the diagnosis of TB. Swabs are not suitable for mycobacterial culture. Staining for AFB may occasionally be misleading as atypical mycobacteria may be found in the intestine. In coming years new PCR methodologies will augment diagnostic rates.11

The diagnosis of active TB depends on clinical suspicion and sampling for culture. The clinical pictures of intestinal TB and CD can be very similar, although some differences have been reported.10

Clinical suspicion is influenced by epidemiological knowledge. CD is uncommon in Saudi Arabia with a reported incidence of 0.94 per 100 000, compared with 8.3 per 100 000 in the UK.12 13 The prevalence of TB in Saudi Arabia is 22 per 100 000 and not that much higher than the overall prevalence in the UK.1 However, in the UK in 2009 the prevalence of all forms of TB ranged from 7 per 100 000 (only a fraction of which would be intestinal TB) in Caucasians to 273 per 100 000 in Black Africans.2
10-17-2012, 03:18 AM   #50
Moe.
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Join Date: Aug 2012
Location: sydney, New South Wales, Australia
Direct website with refrences

http://casereports.bmj.com/content/2...2012.5620.full
10-17-2012, 06:54 PM   #51
Xiaofa Qin
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Join Date: Jul 2012
Location: New Jersey
Thanks Moe for sharing the info. This is really a very interesting case that demonstrated the difficulty to distinguish between intestinal tuberculosis and Crohn’s disease on symptoms.

It would be also very interesting for the very low Crohn’s disease in Saudi Arabia. We can see a thread in this forum with fervent discussion regarding the relationship between less sunshine and low vitamin D level and Crohn’s disease (http://www.crohnsforum.com/showthread.php?t=23826). Studies have shown that vitamin D deficiency and insufficiency occurred in as high as 80 – 90% of Saudi Arabian men (Ardawi MS, et al. High prevalence of vitamin D deficiency among healthy Saudi Arabian men: relationship to bone mineral density, parathyroid hormone, bone turnover markers, and lifestyle factors. Osteoporos Int. 2012 Feb;23(2):675-86. http://www.ncbi.nlm.nih.gov/pubmed/21625888) and women (Ardawi MS, et al. Vitamin D status in relation to obesity, bone mineral density, bone turnover markers and vitamin D receptor genotypes in healthy Saudi pre- and postmenopausal women. Osteoporos Int. 2011 Feb;22(2):463-75. http://www.ncbi.nlm.nih.gov/pubmed/20431993). If vitamin D is really so important, we would expect to see extremely high incidence of Crohn’s disease in this country. Why not?
10-18-2012, 03:39 AM   #52
Moe.
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Join Date: Aug 2012
Location: sydney, New South Wales, Australia
Well then in this case we can rule out Vitaman D??? possibly vitamin D?
Could crohns be a mutated form of intestinal tuberculosis?
Only way we will find out is if a doctor has the balls to infect himself with MAP and go from there
10-18-2012, 03:51 AM   #53
Moe.
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Join Date: Aug 2012
Location: sydney, New South Wales, Australia
Also would just like to add. For MAP wasnt the Koschs postulates accepted. Im not 100% what it means. But what I understood is this ;
Take MAP from the Cow infect a Goat,Sheep,Any animal and its gets Johnes Disease. Has this been done by purposely infecting a Human? If so why not? Wouldn't an answer lay there.
11-15-2012, 02:24 PM   #54
MiciCom
 
Join Date: Nov 2012
Location: France
Hello

Thanks for your great job Xiaofa Qin !

I don't see C. albicans in your document, I think that its proliferation in the digestive tract and buccal microbiota has a role determining with the apparation of saccharin and aetiology IBD, Crohn's disease, I know better than the UC, and that is linked (I summarizes...) to an overconsumption and bad decomposition of sugars (MAP linked to mannose, etc The foods additives such as starches, the cereal lectins, etc and of course saccharin, aspartam etc., medications such as saccharose ingredients, lactose, maltodextrin, toothpastes with what is known, etc. etc. These links is actually etablished between Crohn's and C. albicans. I would like to put links about the publications on this subject but the system of protection of the forum does me not, do I actually post 10 posts to get there?

Have you done research on these links between c. albicans and your work on saccharin Xiaofa Qin?

Greetings from France
Sorry for my English vocabulary, thanks to google trad
11-15-2012, 03:02 PM   #55
wildbill_52280
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Join Date: Sep 2009
If vitamin D is really so important, we would expect to see extremely high incidence of Crohn’s disease in this country. Why not?
i suggest, that there is no major direct causative connection between vitamin d and crohns disease, it is merely an association the simply occurs together, it doesnt guarauntee anyone will develop crohns disease or ibd its not an absolute predictor.

I theorize that the proposed vitamin d connection is only in relation to vitamin d's larger role in respiratory infections, which are treated with antibiotics. it is the antibiotics that have a more direct connection to crohn's and ibd. this theory will become stronger when you compare rates of crohns disease with industrialized and non industrialized countries rates of ibd. with the concept of industrialization almost synonomous with westernization, such as western medicine opposed to older traditional medicinal systems. between the lowest recorded rates(non-industrialized) and the highest rates which are always more developed countries, the difference is up to 70x higher in developed countries. that is a huge difference. the #1 one environmental risk for ibd i believe, is antibiotics. many other substances in our environment may contribute, but taking lots of antibiotics is the fastest route to ibd.
11-17-2012, 07:52 PM   #56
Xiaofa Qin
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Location: New Jersey
Thanks Moe, MiciCom and wildbill_52280 for sharing the thoughts and info. Here I attached a link to a review article regarding the controversy on the possible link between MAP and Crohn’s disease, as well as some information on Koch’s postulation (Rosenfeld G, Bressler B. Mycobacterium avium paratuberculosis and the etiology of Crohn's disease: a review of the controversy from the clinician's perspective. Can J Gastroenterol. 2010 Oct;24(10):619-24; http://www.ncbi.nlm.nih.gov/pmc/arti...f/cjg24619.pdf ). According to Koch’s postulation, MAP should be isolated from the patients and be capable of transmitting the disease to others. However, the MAP controversy largely attributed to the extremely low MAP in CD patients and the fact that there is no evidence suggesting IBD is contagious. The MAP controversy will likely continue, as the extreme complexity of our body made it difficult to completely turn down an argument, no matter how unlikely it would be. In facing such a big controversy we would have to think deep and thorough to make a judgment. I feel a really breaking through in the etiology of CD would rather rely on finding out the answer as what caused the high incidence of IBD in countries like Sweden where MAP is extremely low, or identify agents other than MAP as the main cause of IBD.

I have not realized any causative role of C. albicans in IBD and would appreciate MiciCom to share more info on this.

As for antibiotics, multiple large-scale studies such as the nationwide study in Denmark (Hviid A, et al. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54; http://www.ncbi.nlm.nih.gov/pubmed/20966024 ) have clearly demonstrated the increased risk of IBD. However, the recent increase in IBD in the developed countries seems difficult to be explained by the increased use of antibiotics. In fact, antibiotics are more widely used in countries like China than the western countries, despite that both CD and UC are still very low in China. Here is a link to an article regarding the antibiotics abuse in China (http://www.wanchuanlin.org/papers/An...in%20China.pdf). According to the paper, 90% of inpatients and 80% of outpatients in China are prescribed antibiotics, compared to only 30% of inpatients and 20% of outpatients in the West. As discussed in my paper, I suspected that dietary chemicals may have imposed much more strong impact on the gut bacteria and IBD in the general population than antibiotics simply because of their wide use.

The great efforts in the last century have suspected numerous agents as the cause of IBD. However, many of them were largely based on some pieces of evidence with the ignorance of some other key facts. Currently the cause of IBD remains regarded as unknown, as none can fit into the many features of IBD. When I found the possible link between saccharin and IBD a decade ago, I also wondered how valid and how important such a link might be. This drove me digging hard piece by piece into the origin and history of both saccharin and IBD, with many references being published a century ago. The more information I got, the more evidence seemed to support the primary hypothesis rather than denied it. The paper discussed here is virtually the result of this decade-long efforts. Although it remained a hypothesis, I still strongly recommend checking out dietary chemicals like saccharin and sucralose as the possible main cause of IBD.
11-17-2012, 09:08 PM   #57
wildbill_52280
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Join Date: Sep 2009

As for antibiotics, multiple large-scale studies such as the nationwide study in Denmark (Hviid A, et al. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54; http://www.ncbi.nlm.nih.gov/pubmed/20966024 ) have clearly demonstrated the increased risk of IBD. However, the recent increase in IBD in the developed countries seems difficult to be explained by the increased use of antibiotics. In fact, antibiotics are more widely used in countries like China than the western countries, despite that both CD and UC are still very low in China. Here is a link to an article regarding the antibiotics abuse in China (http://www.wanchuanlin.org/papers/An...in%20China.pdf). According to the paper, 90% of inpatients and 80% of outpatients in China are prescribed antibiotics, compared to only 30% of inpatients and 20% of outpatients in the West. As discussed in my paper, I suspected that dietary chemicals may have imposed much more strong impact on the gut bacteria and IBD in the general population than antibiotics simply because of their wide use.

thanks for the article on antibiotic use in china, yet this article does not say how may people in china utilize western medicine as whole, and this distinction must be made to explain the still low but rising rates of ibd in china. certainly within the community that does utilize western medicine, they may be exposed to antibiotics more then a similar amount of people in america, but there is way more people in china then america.

here is where i got the data on ibd rates and when comparing the lowest rate occuring in china with the highest rate recorded in nova scotia, ibd is around 70X higher in nova scotia.
http://biologie.univ-mrs.fr/upload/p87/Economou.pdf

i wish i had more time to get back with more references, but i did find some studys on chinas utilization of western medicine compared to traditional system, and their transition from traditional medicine has been very slow. This fact may explain the current low rates of ibd, despite high rates of antibiotic prescriptions.

i hope i am reading all this correctly, but at least for now, that is my take on it. I certainly want to avoid defending my position at all costs to avoid my own bias, if you disagree for any good reason, let me know, but it still seems like there is a possibility antibiotics can explain some of these patterns in ibd rates. it certainly cannot explain all cases, im aware of this.

Last edited by wildbill_52280; 11-17-2012 at 09:40 PM.
11-17-2012, 10:52 PM   #58
Xiaofa Qin
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Join Date: Jul 2012
Location: New Jersey
Antibiotics are indeed heavily abused in China. Here is a link to an article published in Jan. 5, 2012 with some information ( http://www.time.com/time/world/artic...103733,00.html ). It stated that “Last month, the country (China)'s Ministry of Health revealed that on average each Chinese person consumes 138 g of antibiotics per year — 10 times the amount consumed per capita in the U.S.” This suggests that even if antibiotics played some role in IBD as shown in some big-scale studies, something else have played a much, much big role. We need to find out what’s that.
11-18-2012, 03:14 PM   #59
wildbill_52280
Senior Member
 
Join Date: Sep 2009
Antibiotics are indeed heavily abused in China. Here is a link to an article published in Jan. 5, 2012 with some information ( http://www.time.com/time/world/artic...103733,00.html ). It stated that “Last month, the country (China)'s Ministry of Health revealed that on average each Chinese person consumes 138 g of antibiotics per year — 10 times the amount consumed per capita in the U.S.” This suggests that even if antibiotics played some role in IBD as shown in some big-scale studies, something else have played a much, much big role. We need to find out what’s that.
this is interesting information indeed, but i think the information we need on china is how many people are utilizing western medicine compared to traditional medicines over the course of say the last thirty years. i recall reading some good studies on this saying that the chinese were very reluctant to embrace western medicine, and only recently have the trends been on an upswing, recently meaning the last 10-15 years.


to say that on average chinese consume 10x more antibiotics then the U.S., we must see how they chose a representative sample. by unintentionally cherry picking only people that use western medicine, it may appear that the rate of antibiotic use is 10 times higher then the U.S. To draw more certain conclusions, we would have to see how they came up with this data.

thats all the brain power i have for now.
11-18-2012, 03:22 PM   #60
wildbill_52280
Senior Member
 
Join Date: Sep 2009
Here is what we need, not sure if the full article is available though.
http://www.deepdyve.com/lp/elsevier/...-in-JUK9sYSual
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