Talk:Ulcerative colitis

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 Ulcerative colitis was a good article nominee, but did not meet the good article criteria at the time. There are suggestions below for improving the article. Once these are addressed, the article can be renominated. Editors may also seek a reassessment of the decision if they believe there was a mistake.

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Given this is still largely a mystery,does anyone know where cutting edge research is being done on it?Andycjp14/05/04.

This is a question for Steve Holland, M.D., Wikipedia's own gastroenterologist. Try his talk page. AFAIK there is cutting edge research being done everywhere. Steve will be able to give you more. JFW | T@lk 12:27, 14 May 2004 (UTC)

Somebody should add something about the recently established connection to sulfate-reducing bacteria and hydrogen sulfide in the colon. AxelBoldt 07:18, 19 Jun 2005 (UTC)

I agree, but i don't think it should be included in the "Causes" section, it is yet to be confirmed that this is a significant factor in the development of the disease. I think a new section should be added, something like "Current research" which would list all or at least some of the most interesting theories currently proposed. I'll remove the hydrogen sulfide paragraph from the causes section for now, but it should definately be included in a future expanded version of the article. IMHO it's too misleading in its current form.

Contents

[edit] Current research and alt treatments

The claims on alternative treatment claim great success. Such is not the case. They need deflating. Kd4ttc 03:52, 20 February 2006 (UTC)

Which alternative treatments are you refering to? --Dr.Gonzo 21:28, 21 February 2006 (UTC)
There were claims on the page about probiotics and other treatments holding great promise. I editied them down in tone and my comment above was that I had. None of the treatements in the research section have shown anything stunning. Why do you ask? Kd4ttc 22:42, 21 February 2006 (UTC)

[edit] Bravo Samir

Samir धर्म rewrote the article based on his expertise and making extensive use of citations. Well done!

I have reorganised the article according to the outline on Wikipedia:WikiProject Clinical medicine/Template for medical conditions. I hope this does not disrupt the intended flow of the article. It can be changed back if necessary.

I have also improved the intro a bit, added links, and delinked words in titles as per the WP:MOS. With a bit of luck, we can push this article up to featured status at some point. JFW | T@lk 17:27, 7 March 2006 (UTC)

Yeah, I like it, too. I modified the bit on colonoscopy in severe UC to reduce the fright factor. Steve Kd4ttc 20:06, 7 March 2006 (UTC)

Reorganized like a pro JFW! It flows very well. Will see if I can find more pics to bolster it for WP:FA. -- Samir धर्म 22:30, 7 March 2006 (UTC)
Oh my. Hate to rain on your parade guys, but you basically butchered the article. It had a much more natural flow before. Granted, a lot of very usefull information has been added, and I applaud Samir for this, but it is written in a way you would expect from a medical encyclopedia. Which is bad. Wikipedia is a general encyclopedia and you basically made the article inacessible to laymen. Now, granted, there was a lot of space for improvement, but this is not the way. While I think the technical part is now better then before, I noticed you deleted quite a bit of usefull info. For example - no mention of pancolitis? Why?
Ok, so tell you what. Let's try and make this article even better, the theme deserves it. Let's get down to the technical, throw in as much relevant data as is needed, invoke the expertise of resident GIs like Samir and when we're done let's try and make brilliant prose out of it. After all, you have to consider this - many patients will be checking this article out, no sense in burying them in technicalities and scaring them out of their wits. It shoud be explained that while all those sideffect are possible they are not very probable. A great deal of UC patients NEVER experience any of them. I guess it's proffesional deformation, but GIs tend to see the worst, while a vast number of patients actually do ok most of the time. In any case, I'm prepared to invest a large portion of my time to improving this article, and if others feel like helping we could make it really shine. Who knows, maybe even a featured article? We'll see ;) Comment, please. --Dr.Gonzo 23:12, 7 March 2006 (UTC)
Well, if technically accurate is butchering then I applaud the butcher. I'd hope to keep out additions based on anecdotal cases unless very clearly marked as such. Kd4ttc 23:23, 7 March 2006 (UTC)
I agree with you 100%, the fact of the matter is the previous version wasn't going anywhere for a long time. So change is good. However, I believe we are now presented with a diamond in the rough. It needs to be polished. And we need more GI specialist input. I can provide prose if you can provide facts. But lets try and remain open-minded shall we, in my experience, way to many proffesionals are actually limited by their training and can't seem to be able to step back and look at the big picture. For example, why shove the alternative treatments to the very end of the article and treat them like a neccesary annoyance, when there are studies that suggest over 60% of IBD patients use or have used alternative remedies? Traditional medicine doesn't have all the answers (which is more true in the case of IBD then elsewhere) and treatments that were considered alternative yesterday become basis for new knowledge tommorow. I am also against anecdotal cases presented as fact, and that's precisely why I want to make this article something we can all agree on, since this theme (UC) is still very much open for debate. --Dr.Gonzo 23:40, 7 March 2006 (UTC)

[edit] Changes

Dr. Gonzo, I appreciate your comments, as usual. To tell you the truth, I wasn't a big fan of the previous article, and really wanted to add more on epidemiology and causes, add references, and cut out a lot of the redundancy in the article. There was a lot in the old article that was unsubstantiated (fistula formation, "fibrostenotic" UC, incorrect definition for pancolitis), a Medscape copyvio, and limited references. I do agree that physicians can sometimes get caught up in jargon when making general articles, but is it really that unaccessible to laymen? I had my UC patients in the clinic today look at the article in the waiting room computer, and feedback was pretty good as far as comprehension goes. They blue-linked the words they didn't follow and got descriptors. But that's WP:OR... -- Samir ∙ T C 09:55, 8 March 2006 (UTC)

I like the way you made the article more professional and accurate, and I think there is definately no going back now. You need to consider, however, that your UC patients may not be able to objectively grade the article for two reasons - 1.) you're their doctor after all so they have more confidence in your judgement 2.) more importantly, they are already quite familiar with terminology and subject. A Wikipedia article should ideally be oriented towards readers who encounter the subject for the very first time. So, from that perspective, this version can be quite confusing. IMO, we need a very consise brief at the top of the article and elaborate further in the segments below. A few more pictures would be great, and if you can provide them it would really help. They also need to be moved around a bit. In regard to fistula - I don't understand, are you saying they should not be included or that description was somewhat lacking in the previous article? Also, I don't think that clubbing picture should really be in this article, it's already included in the clubbing article, so it's somewhat redundant.
I'm basically proposing some touch ups to the flow of the article, some more prose (and not just dry terminology), and more imagery, one thing that was really lacking from the previous version of the article. For example, a nice big diagram of the intestine with different coloration for parts of the intestine that can be affected and the parts that are most often affected. We already have the endoscopy picture you provided, but it would be great if you could provide one with higher resolution. A picture of the healty colon endoscopy would also be most helpful. You could also add irigographic x-ray images showing characteristic colon de-haustration. Some sonography images showing toxic megacolon would also be great. There's a lot that can be improved, and I suggest, since you already did such a fine job, let's do it all the way, let's make this a featured article quality. --Dr.Gonzo 20:49, 8 March 2006 (UTC)
Sure, more pictures are a good idea. I can help in that regard. I agree that the clubbing picture probably can go. Wish I had a dehaustration picture; I'm sure Steve will agree that we really don't do many barium enemas in UC anymore. I can work on a diagram to show proctitis vs. L sided disease vs. extensive colitis vs. pancolitis.
I like the way that JFW made it fit with the WP:MOS. My worry is that the article will devolve into a lengthy narration of unsubstantiated information, like the previous one. I don't think that's in anyone's interest. -- Samir ∙ T C 22:02, 8 March 2006 (UTC)
Ok, so that's a good start. Let's get those pictures first and then we can start tweaking the article. I'll submit to your expertise on the traditional side, but I can contribute on the new and alternative treatments segment. I would like to add HBOT therapy info, some herbal remedies, some alternative diets (like SCD), and a few more "futuristic" ones like that dialysis-like treatment the Japanese have been experimenting for some time. I think it's important to include them because many patients who visit Wikipedia may come in contact with these ideas for the first time, and some of them may actually benefit from it. I actually don't agree with JFWs categorisation of alternatives as a sort of "necessary evil" because, unlike some other conditions, some of the alternative treatments for UC really do have verifiable effect on the course of the disease and length of remission. And including them in this article is a HUGE favour to patients and physicians alike because it gives them a neat overview and a lot more options to consider. As i said, traditional medicine, at least at this time, has its limitations. Of course, if included, everything needs to be backed by references from reputable sources. Concerning the images - I think the dehaustration x-ray would be one of the more informative ones, so let's try and make it a priority. It doesn't have to be original, an old encyclopedia image will do fine, just cite the source. I share your concern about the article devolving into a lengthy narration, but if you look at some of the featured articles they are quite long but not boring or uninformative. So I guess it's a matter of style and being to-the-point. Some things that are not explained elsewhere on Wikipedia need to be elaborated on, but many others do not. If a subject has it's own Wikipedia article just blue-link it and that's that. In any case, if someone is not satisfied with new aditions or elaborations we can always discuss and come to a compromise here. --Dr.Gonzo 22:54, 8 March 2006 (UTC)

Just a few points: unsubstantiated material can be safely removed if it is noncompliant with WP:NOR and WP:CITE. We all know this, and Wikipedia is influential enough to warrant reliable information.

The alternative treatments go at the end out of necessity: many patients use them, but the whole entity of UC is principally the domain of mainstream medicine. If a patient depended on alternative practicioners only, nobody would have a colonoscopy! I think the present arrangement is fine, and I don't think we need CAM apologetics.

I agree more images would be good, but healthy organs are our last concern (unless they are next to abnormal ones for comparison). A plain X-ray of toxic megacolon is just what the doctor ordered. JFW | T@lk 22:23, 8 March 2006 (UTC)

To use a rather corny line - "We agree to disagree" ;) It's good that we're talking about it at least, and the changes that I'm suggesting are little more than trivial at best so I think we can all come to a consensus very easily here. What I don't want is this article to become a dry, strictly "doctor lingo" assortment of blue-links that don't benefit anyone. Let's make it as informative and as approachable as possible, without the flaws the previous version had. Btw, I agree, alternatives should stay at the bottom, but should be expanded. And yes, i did mean that healthy endoscopy image should be next to the diseased one so that someone who is not a professional can also understand what changes take place. A dehaustration image right underneath that would illustrate the point magnificently. --Dr.Gonzo 23:12, 8 March 2006 (UTC)


I must say, I agree with Dr. Gonzo here when it comes to terminology. I'm a freelance writer specializing in medical, diet, and natural health articles and I wade through this language on a daily basis in scientific journals and research papers. Granted, this is much clearer than a research paper on "The insulinotropic, antihyperglycaemic and glucagonostatic effects of stevioside in vivo", but only marginally so. Bonus points if you understand all of that at first read.

It's understandable that Samir wrote this at his own level because inherently we write in our own voice, and his is obviously a well educated and technical one. However, if the purpose of this article is to inform the average layman of his or her options, it's invariably going to fail or at the very least cause them to do extensive research on just the terminology to understand the core information displayed in the article.

Over the years of freelance writing I've jumped from Technical, to Business, to Medical and many other fields along the way. One thing I've learned is it's absolutely essential that you learn to write in the voice of your average reader, or market. Failing to do so just ends up frustrating your market and giving them a negative impression of you and the information you portray.

I'm willing to rework parts of the article at request, but I don't want to step on anyone's toes since I'm new here. I've been looking over a lot of the work many of the editor's on this talk page have done and have to say I'm impressed with the overall quality. Keep up the good work! -- Oncehour 09:42, 2 April 2006 (UTC)

[edit] Changes to therapy

Great job by User:Andrewr47 to stratify therapy by disease extent! -- Samir (the scope) 04:01, 11 April 2006 (UTC)

[edit] Pictures

The endoscopy picture is fine, but I object to the mouth ulcer picture. -- THEBlunderbuss 15:38, 4 May 2006 (UTC)

Hi, was wondering what the reason was for your concern? I realize it's your picture, but you released it under GFDL and it's a reasonable representation of a finding that you can see in UC -- Samir (the scope) धर्म 18:41, 4 May 2006 (UTC)

I didn't have ulcerative colitus. -- THEBlunderbuss 13:46, 8 May 2006 (UTC)

It's a great picture! People who have UC can get aphthous ulcers very similar to the one photographed. It fits well with the article -- Samir (the scope) धर्म 15:18, 8 May 2006 (UTC)

I concede. It's not like it specifically says that I got the canker sore that way. I just didn't want that picture to mislead anyone. "hey, that doesn't look like MY ulcerative colitis mouth sore." -- THEBlunderbuss 02:27, 10 May 2006 (UTC)

But for the record, it was originally Creative Commons, until wikipedia stopped that nifty template for it. -- THEBlunderbuss 22:01, 10 May 2006 (UTC)

I've UC, and the pictures are ok. Maybe I add some of mine. Frostbite Q. Kelvin 04:30, 10 October 2006 (UTC)

[edit] Folic Acid deficiency

Is there a source for the need for a folic acid supplement with sulfasalazine? M dorothy

[edit] HLA B-27

I'm not able to find any reference for the assertion that UC correlates with HLA B-27. I've moved it out of "causes" to "research".M dorothy 13:53, 10 June 2006 (UTC)

Definitely plenty of info about HLA-B27. It needs a sub-section it is so important. Check any pathology book. —Preceding unsigned comment added by 128.125.28.127 (talk) 01:40, 1 June 2008 (UTC)

[edit] References

Still a lot uncited, will work on it -- Samir धर्म 02:46, 9 June 2006 (UTC)

[edit] GA failed

For these reasons :

  • See WP:LEAD for a better lead section.
  • and blood on rectal exam., abbreviations aren't favored.
  • Sometimes the initial sign of the disease is unrelated to the bowel, such as painful knees. why?
  • Needs brilliant prose more than lists.
  • Needs more wikilinks. e.g. tenesmus, Proctosigmoiditis, rectosigmoid, cecum...
  • and low grade fever., was there ever a grading system or is it to the doctor's own diagnosis?
  • Missing inline citations. Lincher 05:35, 18 June 2006 (UTC)

Thanks for this input. As a technical writer, however, I disagree with the concept of "brilliant prose". The purpose here is to convey a lot of information in an organized way. If this were done with "brilliant prose", the article would be much too long. And, the important concepts would not be accessible to the person who wants to skim to what is important to him.M dorothy 14:59, 18 June 2006 (UTC)

I have to disagree with you there, this article should not be like an excerpt from a technical manual, it needs to be accesible to laymen. And in that sense, it does need more prose. It's very informative as is, but also very boring and overly technical. --Dr.Gonzo 15:51, 18 June 2006 (UTC)
  • see WP:GI for my comments. I say we make this the next GI collaboration of the week -- Samir धर्म 04:05, 20 June 2006 (UTC)
I'm an experienced RN and a UC patient. I was surgically cured in 1997; my disease started late (age 29) and progressed rapidly (from the distal 7cm of colon to the hepatic flexure 11 months later, to pancolitis 15 months after that). Imuran (azathioprine) was the only medication that was able to give me a formed stool after I first showed symptoms, but it sent my LFTs through the roof. Fortunately, they returned to baseline once the Imuran was d/c'd. (I was mad, too, because Imuran allowed me to get off prednisone completely – but the cost was a liver biopsy and an ERCP. Liver biopsies hurt. A lot. I digress, though.)
I have to agree with Dr. Gonzo and Lincher about the style of this entry – it absolutely needs more prose. If I was a patient coming here for information, this entry would look to me like a long list (make that several long lists nested in more long lists) of doctorspeak (no offense, docs!). It's very difficult to read and digest (no pun intended), and if the point is to educate a layman or a patient about the condition – as I think it is – more paragraphs, more sentences, and fewer bullet points are necessary. The content is top-notch, but I don't think anything can be 'skimmed' here because the thing is just too long. It's very intimidating and someone in search of information – and reassurance, if s/he has UC or thinks s/he does – will and should look elsewhere until some changes are made. Collaboration of the week is a good idea.
I'll try to find one of my own endoscopy photos to scan in – the photo I have in mind clearly shows the demarcation between my ulcerated bowel and my normal bowel, and it would be helpful to show the striking difference between normal and ulcerated bowel. I hope I can find the photo. - KrakatoaKatie 04:35, 20 June 2006 (UTC)

[edit] Photo

It's been pointed out to me that the photo on the top of the article has ulcers that look serpiginous (which is more Crohn's like). The purulent stuff is definitely UC like, but this probably isn't the most representative UC photo. Better photo would be appreciated! -- Samir धर्म 06:09, 24 June 2006 (UTC)

I would like to point out that I don't get mouth sores any more (that was the only one like that, which I ever got). There is a possibility that I DO have ulcerative colitis, or at least IBS. Nothing a steady intake of prune juice and avoidance of all fried foods couldn't fix. -- THEBlunderbuss (talk) 09:59, 11 December 2007 (UTC)

I was diagnosed with UC about 18 months ago, would anyone like to view the photo from the sigmoidoscopy in order to determine if it would be an improvement? (Yes, nowadays after a colonoscopy, you're given a shiny color photograph of your lower bowel. In case you ever wondered what it looked like.) Also, it would probably be too graphic, but does anyone think that this article would be improved by an image of the...crap, how does one properly refer to mucoprulient discharge? Anyway, I think that you get the drift. I'm in the middle of a flare-up, and any necessary photos should be obtained before I can get it under control, probably a week or two.LeeRamsey (talk) 00:45, 27 January 2008 (UTC)

[edit] Hydrogen peroxide and ulcerative colitis

I don't know if this should be included. It's not a mainstream view as far as a cause. I'll grant that there are case reports of hydrogen peroxide causing colitis, but I don't think there is consensus at all of it being a specific cause of UC now -- Samir धर्म 07:42, 18 July 2006 (UTC)

  • Let me elaborate a bit: It is agreed that peroxide is a cause of chemical colitis. No question. It is also agreed that antioxidants have been hypothesized in pathogenesis of ulcerative colitis. However, with respect to peroxide being a specific cause of ulcerative colitis per se, there are only two references in the literature:
    • Sheehan JF, Brynjolfsson G. Ulcerative colitis following hydrogen peroxide enema: case report and experimental production with transient emphysema of colonic wall and gas embolism. Lab Invest. 1960 Jan-Feb;9:150-68. PMID 14445720
      • I think "ulcerative" colitis referred to in the title is literally colitis that ulcerates (i.e. chemical colitis with ulcers). I've asked for the abstract to be sent to my office and will clarify further when I can peruse it, but I don't think this paper cites peroxide as a cause of UC in any way.
    • Pravda J. Radical induction theory of ulcerative colitis. World J Gastroenterol. 2005 Apr 28;11(16):2371-84. PMID 15832404
      • This is really the only publication that espouses a putative causative relation between hydrogen peroxide and UC
  • There are many chemicals that cause shallow confluent ulcers in the colon similar to ulcerative colitis that are unrelated to causality in UC. I don't think there's enough evidence that hydrogen peroxide is related enough to causality to merit a mention. -- Samir धर्म 08:11, 18 July 2006 (UTC)
  • These unusual caues are important for two reasons. First, you should probably ask about these things when somebody presents with what appears to be UC. If the person has done something like this, one could hope this is the cause, and that the condition will clear up and not recur, so long as the person doesn't do it again. Second, a person who has a history of UC should be cautioned against doing things that might trigger the disease. It's fairly likely that somebody with UC would try a massive dose of vitamins without realizing that it could be a risk factor for an episode. And, there is probably somebody out there recommending peroxide enemas for whatever ails you.M dorothy 15:18, 18 July 2006 (UTC)
    • I agree with you that when someone presents with what appears to be UC, chemical colitis, including hydrogen peroxide must be considered. No question. And yes, people with UC should avoid peroxide enemas. Definitely. But the same hold true for so many other things: NSAIDS cause colitis; people with UC should avoid NSAIDS. Same with soap enemas. Same with some antibiotics. -- Samir धर्म 01:17, 20 July 2006 (UTC)
      • Here's the question to me: is this article is about colitis or ulcerative colitis? If we're discussing colitis as an umbrella term, it's only logical that H2O2 would cause chemical colitis if administered in an enema, because the stuff is so hard on sensitive tissues. (Hydrogen peroxide doesn't kill any bacteria - it is useful to bring dirt to the surface of a deep wound, but I think it does more harm than good especially now that less irritating agents are available.) If we're writing about UC, however, I think H2O2 causation is a pretty obscure theory, probably not notable enough to be included unless there are more relevant studies of which we're unaware. KrakatoaKatie 22:59, 20 July 2006 (UTC)
        • We don't (yet) have an article on chemical colitis. Perhaps we should create one, and merely note the possibility at this point. Also, perhaps we should distinguish a "cause" from a "trigger": there is a possibility (or liklihood) that a chemical insult could trigger an episode in somebody that has the disease, or has a predisposition to it. M dorothy 05:25, 21 July 2006 (UTC)

[edit] Radical Induction Theory

Although peroxide damage is central to the radical induction theory, I don't want to confuse people in the main article. The point under the unusual causes heading is that peroxide could be a cause of an episode, and you really shouldn't do this, or introduce any other harsh chemicals.

Although the free radical theory is not "mainstream", it is, so far as I can determine, the only theory explaining ulcerative colitis. This game is played by certain rules, and ignoring a reasonable hypothesis is not one of the options. Unless somebody comes forward with an objection to this theory in a peer-reviewed journal, or publishes an experimental result that disproves the theory, it will become, by default, the "mainstream theory".

The free radical theory does not call for much change in the treatment of the disease. The theory however suggests that the epithelial membrane is fragile in some people, and that this fragility is central to the disease. M dorothy 05:58, 21 July 2006 (UTC)

There are many theories for the cause of UC: Th1 v. Th2 responses (PMID 16831396, PMID 16548766, PMID 16378007, PMID 16083712, PMID 16048556, PMID 15146247, PMID 12876555, many more), hygiene hypothesis (PMID 16696783, PMID 15288007, PMID 11693209), autoimmune theories (PMID 16620017, PMID 16584867, PMID 16498309, PMID 15559364, PMID 12672398 and many more) and the radical induction theory.
Agreed that the radical induction theory is a different hypothesis, and should be mentioned in the article. Mention of B6, iron and peroxide as putative causes of ulcerative colitis under this hypothesis is fair also. But I don't think it's fair that it should be expanded more than that -- Samir धर्म 09:39, 23 July 2006 (UTC)

I do not wish to further introduce the radical induction theory into the main article at this time. I became aware if the peroxide association through this source, but that is not the reason peroxide needs to be here.

Thanks for providing me with these citations. I will try to read them. Do these theories provide a comprehensive explanation of the disease? Is there evidence that disproves these theories? Are the theories subsumed into the radical induction theory?

Can the autoimmune theory explain the observation that removal of the colon seems to cure the disease? With Crohn's, the disease returns following surgery, as though something outside the intestine continues to malfunction. With UC, whatever was malfunctioning is gone after surgery, as though the intestine itself were the cause. M dorothy 05:15, 24 July 2006 (UTC)

I agree with you that peroxide does play a role in motility in UC. No question that the literature is supporting that. But, it doesn't have a known role in pathogenesis yet (so it could be put down as a putative cause at best). It just comes down to the weight of the evidence: In the past 5 years, there are over 500 clinical and basic science citations on PubMed for immune mechanisms of ulcerative colitis and just one as H202 as a cause. We're not here to judge, we're here to report, and it's only fair to report according to what consensus in the IBD community is. There are also no case reports of peroxide causing a flare of UC either -- Samir धर्म 05:46, 24 July 2006 (UTC)

I do not seem to be able to gain full access to these citations on-line.M dorothy 05:56, 27 July 2006 (UTC)

[edit] Th2 response citations

Th1 v. Th2 responses (PMID 16831396, PMID 16548766, PMID 16378007, PMID 16083712, PMID 16048556, PMID 15146247, PMID 12876555, many more) Based on the abstracts, none of these citations is offering a theory of the disease; they are merely discussing interesting associations. It would be fair to say that all of these see damage to the epithelial membrane as a cause of immune response, although none are are endorsing peroxide damage. PMID 16831396 and PMID 16378007 seem to be looking at pre-existing membrane damage as a cause of immune response. On the other hand, PMID 16083712 seems to be suggesting that IL13 damages the membrane, suggesting causation from immune response.M dorothy 05:56, 27 July 2006 (UTC)

IL-13 is a Th2 cytokine that the authors of that citation suggest affects the permeability at tight junctions. It doesn't really make sense to say that the Th2 hypothesis is not offering a theory of causation for UC; it is, but there are just a lot of unknown variables. The hypothesis is that Th2 cytokines are invoked by some initiating stimulus leading to mucosal inflammation. It is an accepted hypothesis in the UC literature. The whole rigmarole around the ACT 2 trial was how infliximab was a useful therapy for UC given that TNF was a Th1 cytokine. It would be WP:OR to suggest that alternative hypotheses are more accepted than the ones I quoted -- Samir धर्म 07:25, 27 July 2006 (UTC)
Pravda's paper appears to be carefully crafted to meet the criteria of the Scientific method. I do not see anything comparable in the TH2 abstracts. There may, however, be a valid objection in that Pravda's paper does not, as I recall, specifically address the TH2 correlation or subsume this theory, such as it is.M dorothy 02:55, 28 July 2006 (UTC)
Well, it is an interesting citation and a hypothesis that's different from what's been in the literature. I'll show it to my residents next week at rounds. -- Samir धर्म 04:58, 28 July 2006 (UTC)

[edit] Hygiene hypothesis

(PMID 16696783, PMID 15288007, PMID 11693209). These citations do not really include a comprehensive theory of the disease. I believe, however, that there is a better cite out there that I have read. I agree that the radical induction theory needs to explain this observation or subsume this theory.M dorothy 05:57, 28 July 2006 (UTC)

[edit] Citation

We need to cite some of the treatment information -- Samir धर्म 03:25, 28 July 2006 (UTC)

One objection to both the UC and Crohn's articles is length. Althoough these have great detail, I believe we should shorten both articles by factoring the drugs and treatment into separate articles. I could write short summaries for the main articles, based on the American College of Gastro... practice guidelines.M dorothy 06:14, 28 July 2006 (UTC)

That is an excellent idea, we should definitely spin off therapy sections -- Samir धर्म 06:15, 28 July 2006 (UTC)

[edit] Autoimmune Disease

The List of Autoimmune Diseases shows UC as uncertain. Also, the practice guidelines for the American College of Gastro... make no mention as to whether the disease is regarded as autoimmune. This is in contrast to Crohn's, where a clear consensus appears.M dorothy 05:39, 28 July 2006 (UTC)

But the statement that I removed is factually incorrect. UC is not usually treated as if it were an autoimmune disease. Cytoreductive therapy works for most autoimmune diseases. Doesn't work for UC. 5-ASA isn't used to treat any autoimmune disease. Steroids are used to treat many conditions that are autoimmune and aren't autoimmune. I've removed it again. -- Samir धर्म 06:06, 28 July 2006 (UTC)

5-ASA, or at least sulfasalazine, is used to treat rheumatoid arthritis, which is widely regarded as an autoimmune disease. Nonetheless, I think we are more or less in agreement here. I will try to think of a way to word this so as to meet your objection.M dorothy 06:23, 28 July 2006 (UTC)

[edit] References

I've reworked the references. Please adhere closely to cite.php. One article was cited seperately on four different occasions. Some other points:

  • Citing a study about sepsis to explain "benefits" of nicotine in UC is outrageous, especially when this is a SciAm article and not a peer-reviewed reference.
  • What childhood infections are associated with UC? We're not talking rubella, are we?
  • Why are we lending such enormous credence to the theories of Dr Pravda?

Something is not quite right. JFW | T@lk 23:43, 2 August 2006 (UTC)

Thank you for your assistance with the refs. The article is taking no position as to the validity of the radical induction theory. It is clearly presented as a theory. However, in taking an alternative look at the disease, Dr. Pravda mentions a lot of facts that other sources don't mention. These are relevant to the subject, regardless of relevance to the theoryM dorothy 05:20, 3 August 2006 (UTC)

    • Yes, but honestly it's only mentioned in one fringe paper in a third-tier journal. I'm removing the reference to Pravda save for a single line. The theory has its own article, and that's forking it enough. It's clearly not recognized as a theory for pathogenesis of ulcerative colitis in the GI community. I've put in an RfC, see below -- Samir धर्म 07:04, 28 August 2006 (UTC)

[edit] Pseudopolyps

Great pic! -- Samir धर्म 05:21, 4 August 2006 (UTC)

I got it from here -- which also has a (very) lame/incomplete English version.
If you're looking for some intestinal polyp pics... there are a few the German version. Most of the images are in the Wikicommons and annotated in English. Aside from the polyps, there are also some tasteful (yet juicy-looking) colonic adenocarcinoma pics. I briefly thought about adding one to Wikipedia... but thought they might be a bit much for people not desensitized to seeing body parts, blood et cetera... and just freshly diagnosed with a goomba of that variety. Nephron  T|C 06:37, 4 August 2006 (UTC)
I added a few more pictures from the German Wikipedia's UC article. To the best of my knowledge they do represent UC... but I've only seen about 3-4 pictures of UC and don't have the benefit of having done dozens of endoscopic procedures. Any case, the licencing of the pictures is messed, 'cause I couldn't choose public domain-- the choice wasn't in the drop-down menu. Perhaps you can sort throught that one. The German Wikipedia states they are public domain.[1][2] They originate from a gastroenterologist in Hamburg:
Mein Name in Dr. Joachim Guntau.
Ich bin leitender Oberarzt der Gastroenterologie im Albertinen-Krankenhaus Hamburg und habe mit meinen Kollegen 2 Internet-Atlanten veröffentlicht: Einen Endoskopieatlas und einen Sonographieatlas. Beim Recherchieren bin ich auf einige Ungereimtheiten auf medizinischen Seiten gestoßen, die ich versuche ein wenig zu verbessern.
Translation:
My name is Dr Joachim Guntau. I am a senior attending physician at the Albertinen Hospital in Hamburg in the department of gastroenterology. Together with two of my collegues we have published Internet-atlases: one endoscopic atlas and one sonography atlas. During the research, I came across a few inconsistencies on the medicine pages, which I have tried to correct. Nephron  T|C 07:51, 4 August 2006 (UTC)

[edit] RfC

The pathogenesis of ulcerative colitis is unknown, but basic and clinical researchers in gastroenterology have identified that it may be related to cytokine release from some stimulus (traditionally favouring the Th2 pathway), autoimmune causes, or the so-called "hygiene hypothesis", where environmental causes are considered as a primary factor in pathogenesis. There are more than a hundred PubMed citations on basic and clinical evidence to support this in the adult and pediatric populations. These theories are discussed at every major gastroenterology meeting by experts. I've listed representative citations at Talk:Ulcerative colitis#Radical Induction Theory

In April 2005, Jay Pravda published a paper entitled "Radical induction theory of ulcerative colitis" PMID 15832404 describing a putative pathogenic mechanism for ulcerative colitis. The paper was published in "World Journal of Gastroenterology", which has an unrecognized impact factor because it was dropped from the listings for excessive self-citation [3]. It has not been cited by a single other publication, and has not been presented at any major international gastroenterology conferences.

However, our article on ulcerative colitis cites Pravda's paper 4 times and contains 12 lines (in my browser) to the theory and its corollaries. This is entirely too much for a fringe theory, and, in my mind, is a violation of WP:SOAP.

I've reverted the reference to a single line, and request comment on the same. The pre- and post-diffs are here [4] -- Samir धर्म 07:20, 28 August 2006 (UTC)

I support your version and also feel that the fork article should be sent for AFD. Wikipedia is not in the business of promoting one little-known theory on a major disease. JFW | T@lk 15:59, 28 August 2006 (UTC)
I've nominated the fork for AFD: Wikipedia:Articles for deletion/Radical Induction Theory of Ulcerative Colitis. JFW | T@lk 16:29, 28 August 2006 (UTC)
I think that you've done a fair job of handling the theory and, until more information is gathered to support it, the article should remain as you have left it. InvictaHOG 17:05, 28 August 2006 (UTC)

[edit] MMSC

  • Moved from top

Help: It has been too long since I have edited here. My formating skills have lapsed. Can somone fix up the references I've just added for Vitamin U and the studies on the impact it has been shown to have on reducing, avoiding or healing lesions/ulcers? Knoma_Tsujmai

I've removed them. Not UC references, sorry, not related to pathogenesis of the disease -- Samir धर्म 23:17, 17 October 2006 (UTC)
I disagree Samir. Can you look a bit into these links? MMSC (vitamin U) has been shown to be effective in the treatment of UC:
Studies show that Vitamin U helps to prevents and can revert ulcer damage in gastric tissues.
The cause of UC may be debated (is it autoimmune, etc); but the symptoms can be significantly lessened by MMSC.
Take another look at these links if you would:
Quoted: "Role of sulphydryl-containing agents in the management of recurrent attacks of ulcerative colitis. A new approach."
Quote: "This double-blind randomised study investigated the role of sulphydryl-containing agents in the management of recurrent attacks of ulcerative colitis. ... These results demonstrate that sulphydryl-containing agents play a key role in the treatment of and protection against ulcerative colitis."
Role of sulphydryl-containing agents in the management of recurrent attacks of ulcerative colitis. A new approach: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1362613&query_hl=10&itool=pubmed_docsum
Knoma_Tsujmai
  • Hi Knoma, I agree that there is basic science evidence on the cytoprotective effects of sulphydryl derivatives in ulcerating disease. However, the one clinical trial (PMID 1362613) evaluating MMSC in UC has certain limitations (primarily because it was done in 1992, and we've learned much on UC since then). First, it was a trial on left sided UC, that we know from the literature is best managed with rectal 5-ASA (PMID 10925961, PMID 7654892, PMID 15951542) or combination therapy. Secondly, there are questions about the endpoints in the trial cited. I just don't think there's enough evidence for it to be included in the article. Thanks -- Samir धर्म 17:13, 18 October 2006 (UTC)
  • I again have to disagree. MMSC is a substance that is obtainable over the counter, does not require enemas and either alone or in combination has been show to help people recover from gastric ulcers. It has to be at least as effective (if not more effective) than the Kampo herbal medicine that is already in the article (and people have let stand). Why remove this? If even one person is able to help speed or augment their recovery then this information is worth leaving in. I'll admit I'd love to see more US studies on it, but as MMSC is something that cannot be 'patented' or packaged up at hundreds of dollars a dose I do not expect to see that happen. I think that is sad, but it is the reality. Please reconsider letting this stand as is. User:Knoma_Tsujmai

[edit] Why the removal of references to TCM/Kampo in the alternative treatment section.

Clearly the eastern hemisphere of this small planet also is coping with this disease using herbal medicines.

I once added such information to the article with Pubmed references. References were deleted since they showed only clinical trials on mice and not men. Let me remind you that Inflixmab/Remicade was "developed from a mouse:human chimerized antibody". One cannot categorically say that clinical trials of specific medicines on mice are without correlation to the effect on humans. If nothing else the clinical effect on mice tells us the effect of these medicines are not placebo effects. Thus 2000 years use of such herbal medicines on humans in China and Japan with empirical results are partly confirmed.

But now the TCM/Kampo references have been completely deleted.

Why?

I wish doctors in general were an ounce more open minded, humble and willing to absorb knowledge outside their "western medicine box" - at least when the true cause of UC is NOT known.

I for one disagree with labeling removal of colon as a "cure". Especially since I have found information that UC was re-established in a transplanted colon - hinting at a more complex cause-and-effect. BUT whatever I think, I still think it is better to have a multitude of viewpoints, since it will stimulate research and breakthrough ideas.

Keeping the "Alternatives" section overly sanitized does not promote creative solution thinking or completeness of the subject.

Cheers, Rune

Cite evidence and it will be included. Don't cite evidence and it won't. -- Samir धर्म 00:31, 2 November 2006 (UTC)

→ Well, the evidence references were originally included but deleted. (Catch 22) Anyway goto PMID 10528991 Perhaps also of interest - one of the identified flavonoids of this traditional medicine - baicalein - PMID 11914968. 11:45 UTC, 2 November 2006, Tellus, Sol system, MW galaxy, The outskirts. /Rune

→ Add also to the evidence PMID 10945829 - Berberine chloride is another known compound of the Kampo/TCM medicines used for UC. See also some photos on this external page of clinical trials on rat colons. /Rune

[edit] Adacolumn

I moved this section from "alternative treatments" for discussion:

A total of 10 000 patients have been treated with selective cleaning of the blood in Japan and Europe. This method may offer an option to patients that do not respond to the tradidional medicines or have medicine intolerances. It is a proven method that shows a 50-70 percent remission rate. For more information see: http://www.otsukapharma.info/medical_professionals/patients.htm

Since this is approved in the EU and Japan but not the US, I have no way of knowing its efficacy or much else about it. Should Adacolumn be included in the section on alternative treatments? KrakatoaKatie 06:53, 29 May 2007 (UTC)


Why not include it? It is a fact that patients will sometimes cross borders to try specific medical treatments. There is information relating to the USA and Canada on http://www.adacolumn.com/index.htm and http://clinicaltrials.gov/ct/show/NCT00162942 => currently in the "recruiting patients" phase.

At the very least it should be included in the "Ongoing research" section.

Also be aware that not only readers from the US is using the us/english version of Wikipedia for reference - so don't be so arrogant. As long as the geographic area where the treatment is available, I see no problem with this.

You "have no way of knowing its efficacy" ?? - so please explain to me how europeans and japanese differ signifcantly from the US population ? Or is it just that you don't trust the corresponding authorities in the EU that matches the FDA in the US? The clinical trials and documentation demands are every bit as strict if not more.

I know there is currently a significant segregation of European and US drug testing and approval. But keep in mind that this division has been made primarily for economic and political reasons. Not for medical reasons.

Please include it again.

83.109.128.30 21:34, 29 May 2007 (UTC)NN

Please refrain from personal attacks – calling me "arrogant" does not help your credibility. I simply asked for discussion on the process and how effective it is in treating UC, because I'm not familiar with it. - KrakatoaKatie 02:03, 3 June 2007 (UTC)

Well, sorry if that came across too harsh. Although I think some latitude should be allowed. The information was verifiable by doing a 2 minute Google search - that was the basis of my irritation. It may be quick for you to delete something, but it costs me time and effort to put it back. Anyway I see Samir has now removed the information I added for Adacolumn under "Ongoging research" under the pretext of it being "written like an advertisment" ??

I must confess I have found some of Samir's editings (read: removals) "interesting" - to the point where I wonder if he receives funding in some form or shape from a "big-pharma" company? It is well known that these are interested in (if the EU is anything to judge that by) limiting any competing new medicines or treatments that could otherwise erode their established economic foundation.

83.109.151.173 22:25, 7 June 2007 (UTC)NN

Well now, some of us have found your "edits" quite interesting: All of your edits are about Adacolumn and you accuse me of receiving funding from a big-pharma company? You added: "Adacolumn blood cleansing. A total of 10 000 patients have been treated with selective cleaning of the blood in Japan and Europe. This method may offer an option to patients that do not respond to the tradidional medicines or have medicine intolerances. It is a proven method that shows a 50-70 percent remission rate. For more information see: http://www.otsukapharma.info/medical_professionals/patients.htm" with a link to a commercial site. This is akin to advertising, hate to break it to you. There is literature on Adacolumn and UC, cite it in your edits and it constitutes a reliable source. Cite a commercial source and it gets removed as advertising. Throw on personal attacks and no one here will take you seriously -- Samir 22:34, 7 June 2007 (UTC)
For example, here's a Sandborn review from 2005: PMID 16378006. Other relevant articles: PMID 17532273, 17531555. There's literature, and it's a novel idea. We should add it to the article. But not in a spammy way that cites the Otsuka page. -- Samir 22:56, 8 June 2007 (UTC)


Hmm, this is where logic fails. You say it should be added but you remove it ?! This does not add up... My intention was to add this information so that patients are aware it exists - I personally did not know it existed until a couple of weeks ago - and it may indeed be of interest to my son who has UC where the docs are now talking about surgery after Remicade gave him serious pneumonia. In what shape, form or linguistically customized way it is added to pass your camel-through-a-needle-eye phrasing is not really of interest in the big picture here. The information on Adacolumns pages seem factually correct and your own findings in Pubmed confirm this - indeed there would be legal penalties if it was false information - so why in the world do you choose to remove rather than edit the information according to your preferences ??? I can assure you that my interest for "advertising" (aka make something known to the public) is fueled by something much stronger than "big pharma" - namely the well-being of my young son and not wishing anyone have to remove their large intestine by surgery unnecessarily. Surgery in my opinion (also based on what I read in discussion forums on the topic) is not such a final solution as the doctors promote it as. Complications and repeat surgery and a (especially for kids) lower quality of life are factors that are hard to avoid.


217.204.142.41 23:39, 10 June 2007 (UTC)NN

I just did a search on the [6] there is no research there showing any type of clinical research being done for colitis. I did find [7] which shows it is being clinically trialed for Crohn's disease. ----CrohnieGalTalk/Contribs 12:42, 11 June 2007 (UTC)


Well, here is some actual usage at the National Hospital, Rikshospitalet, Norway. http://www.rikshospitalet.no/view/readavdi.asp?nPubID=3075 Section:

Hvem får behandlingen?

Adacolumn kan anvendes til pasienter med revmatoid artritt og ulcerøs colitt, eventuelt også ved andre lignende sykdommer, hvor annen behandling ikke har gitt tilfredsstillende effekt.

Translation :

Who can get this treatment?

Adacolumn can be used for patients with rheumatoid arthritis and ulcerative colitis, potentially also for other similar diseases, where other treatment has not given satisfactory effect.

Personally I find it interesting that several diseases with unknown root cause respond to the same medication or treatment. This hints at one or more common causes which the current simulations and knowledge is not yet able to grasp. Particularly Crohns and UC have a significant overlap in terms of the same medicines being used.

83.109.151.173 16:03, 15 June 2007 (UTC)NN


Some information from another Scandinavian country, Sweden: http://crohns.se/fragor/20847_Skillnader_mellan_Remicade_och_Adacolumn

Briefly a patient asks for the difference between Remicade (Inflixmab) and Adacolumn.

Gastro Enterologist Dag Risberg answers (translated to the best of my abilities):

Remicade and Adacolumn are two completely different treatments: Remicade is a medicinal drug with potent anti-inflammatory effects, which is administered directly into the bloodstream. Indications so far has been Rheumatoid Arthritis and severe Crohns disease that do not respond satisfactory on usual medicines as e.g. cortisone.

Adacolumn first of all is not a medicine, but rather a "medical-technical aid", comparable to kidney dialysis. The treatment consists of inserting one cannula in one elbow and pump the blood through a filter, back via another cannula in the other elbow. In this filter a number of white bloodcells and other harmful elements which are considered to contribute to inflammation in for example Crohns will be trapped. According to my own experience 30-60% of patients responds to Adacolumn, depending on the type of disease etc. An advantage is of course that one generally sees no side effects, of disadvantages can be mentioned the high price and extremely limited access to this treatment in Sweden, and further that a lack of objective studies that confirm the treatment effectiveness of Adacolumn.


Dag Risberg 27 dec 2005

83.109.151.173 17:43, 15 June 2007 (UTC)NN


See this page http://www.otsuka.com/oapi/OAPIPipeline.asp According to this the Phase I, II, and III testing as well as Filing for Ulcerative Colitis and Crohns are finished and it is now at the approval phase.

Further if you look at the press release archives http://www.otsuka.com/oapi/OAPIArchives.asp you see Ulcerative Colitis mentioned in April 2004.

  • So, are we in agreement of adding this info to the main page?
  • Any protests?
    • Reasons for protesting?
  • Under what section should it be posted?
    • Ongoing Research or Alternative?
      • Note that adacolumn is approved in EU and Japen. So I guess it depends if Wikipedia's english version should be reserved for the US point of view (Ongoing Research) or a world point of view (Alternative Treatment)


NN

[edit] I added some links to the external and organization

The one [8] title just mentions Crohn's disease but if you check the link you will see it is a resourse for inflammatory bowel diseases. --CrohnieGalTalk 18:12, 19 June 2007 (UTC)

[edit] Ulcerative Colitis - Too long for a main page

The treatment section has main pages. IMO these subsection should be linked to in an outline and the Treatment section should be shorted to a summary table with embedded links. Maybe only be one linkout for treatment (KISS - common sense directive) and further subpages should be linked to from the treatment page.

Taking treatment out of view, as I understand Samir put a lot of work into renovating the page, know how difficult that is, having renovated some of my own disasters. But structurally the page is too complex and actually, backwards.

1. Symptoms

2. Diagnosis and pathology (or simply pathology) If a whole section on clinical presentation is needed then -> subpage. Clinial presentation of ulcerative colitis.

3. Epidemiology

4. Genetics

5. Treatment

After reading the page I asked myself the question, what is ulcerative colitis? I read articles on pubmed and they give different descriptions. The literature makes heavy mention of anti-nuclear antibodies, which is mentioned with several other genetically (HLA) linked diseases that are mentioned on the page. Anti-nuclear antibodies are for other organ disease correlate with severe disease. There is no particular evidence of anti-food antibodies with the disease. Viruses, are, however implicated in the increase of anti-nuclear antibodies in other diseaeses. Multiple autoimmune conditions may involve ulcerative colitis, and multiple HLA are invovled in these conditions, DR3-DQ2.5 is suppressive. Less genetics does not need more mention, what it needs is less of a genetics section. Epidemiology, unless it pertains to ethnic or geographic differences, is superfluous. Diseases associated with UC can be placed on its own page. I have created one such page for celiac disease. The problem with autoimmune disease, as one gets away from the core pathology, elevated but low frequency associations can be found with many other diseases. Ergo it is not possible to cover all associated disease in a concise main page.

Example: Ulcerative colitis is associated with other diseases main page: ulcerative colitis associated conditions

Also, there are many factual tidbits that lack references on this page. Maybe if one looked for peer-reviewed material for these references one might be able to clean a few out that were without reference?

This page is not that far away from being a really good page, short of a clean up.Pdeitiker 02:30, 7 September 2007 (UTC)

[edit] epidemiology

Though the statement saying UC is more common in women is cited, I can't pull up the article myself. I've read conflicting information, including that it's more common in men and, separately, that there's no difference between genders. The latter is cited in this article... UpToDate is reputable, but I have to question it, too, since it ignores bimodal distribution... But when it comes down to it, do we really know? Anyone who can speak to the epidemiology of UC (and CR), please weigh in.

http://patients.uptodate.com/topic.asp?file=digestiv/10728

rhetoric 05:19, 21 October 2007 (UTC)

[edit] Phosphatidylcholine

Rather impressive results in a small trial in steroid-refractory UC. JFW | T@lk 22:25, 1 November 2007 (UTC)

[edit] Diagnosis

Diagnosis often does not occur until after 2-3 years of significant symptoms, often assumed to be hemmoroids or Irritable Bowel Syndrome, significant facts that I didn't see mentioned in the aticle. Something else pertinent, although I'm not sure if this could be worked into the article, is that many Gastroentrologists don't accept pediatric patients because of insurnce reasons. Which makes a certain amount of sense, but was fairly ridiculous when I was a 16 and a 5'10", 140lb. pediatric patient who metabolized drugs as an adult would, and could understand procedures/explain symptoms more adequately than many adults are capable of.LeeRamsey (talk) 01:00, 27 January 2008 (UTC)

[edit] Smoking and UC

Smoking and UC is mentioned in this article but not the evidence that quitting can cause UC and resuming can stop it. See: http://members.iinet.net.au/~ray/2consequences.htmlRayJohnstone (talk) 17:23, 5 April 2008 (UTC)

[edit] Bacterial infections

Is there no data to support possible role of bacterial infections? To my knowledge there are several strains that may or (to be fair) may not play a role in UC. Any thoughts on why is this an area that is continually ignored or discounted? I'm struck by the heavy leaning towards targeting/treating symptoms and the focus on the immune system. As a user of Wikipedia I'm looking for more than just the "party line" - that UC is genetic - so that pharma companies can sell their molecules. To do this article (and more importantly patients) justice, requires a critical look at the role bacteria in UC. How can we ignore it when we've just begun to scratch the surface of what makes up our intestinal flora? —Preceding unsigned comment added by 70.71.203.66 (talk) 03:07, 28 April 2008 (UTC)

[edit] Why should accutane info not be included?

Why should accutane info not be included? 75.169.53.136 (talk) —Preceding comment was added at 23:13, 18 May 2008 (UTC)

Properly sourced it probably should. The reference you've provided however, is too promotional and you've spammed it. --Ronz (talk) 02:48, 19 May 2008 (UTC)

Its a source, just because its a commercial source doesn't mean its spam. Find a better source or leave the info unsourced. 75.169.53.136 (talk) 02:55, 19 May 2008 (UTC)

The information has been spammed to multiple articles at the same time without discussion. The reference used failed WP:SPAM and WP:RS. The new source is better, but I think it needs better sourcing per WP:NPOV. --Ronz (talk) 03:35, 19 May 2008 (UTC)
I agree with Ronz, the information does not pass multiple policies as stated in the reverts. Thanks, --CrohnieGalTalk 12:10, 19 May 2008 (UTC)
You can actually read English, right? 75.169.49.214 (talk) 19:14, 25 May 2008 (UTC)

The link is Washington Post. If you continue to delete valid information. I will report you. I changed the source. Perhaps you should actually READ before making edits. 75.169.49.214 (talk) 19:13, 25 May 2008 (UTC)