text:
Talk:Ciclosporin

Cyclosporine to Ciclosporin move
This is a good page, is there any objection to moving it to the INN ciclosporin and having cyclosporine redirect there?

Let "ciclosporin" redirect to cyclosporine which is the compounds real name. Cacycle 21:13, 21 Dec 2004 (UTC)

In accordance with WikiProject_Drugs naming policy, I propose we move this page to the INN ciclosporin. If you have any concern with this proposal, please discuss it on this page. Matt 23:46, 21 Dec 2004 (UTC)

OK, use the INN, but add a prominent note that "cyclosporine" is the name that has been used in most scientific studies. Cacycle 11:23, 22 Dec 2004 (UTC)

WikiProject drugs is badly out of sync with general MoS guidelines, which must take precedence. Cyclosporine is almost universally used both in the scientific literature and in the news/popular accounts. Naming the article anything else is perverse. Fawcett5 22:41, 7 May 2005 (UTC)

Move - many other drugs whose names have changed from UK BAN to INN (eg the cephalosporins) have had their pages moved. Whatever the past pharmaceutical research literature might have been, its current common usage is as a medicinal drug used to treate humans and the INN terminology should surely apply ? David Ruben Talk 01:20, 16 February 2006 (UTC)
 * As for previous point re using a compound's real name, no one is realistically going to move paracetamol across to 4-(Acetylamino)phenol (I trust)? David Ruben Talk 11:46, 21 March 2006 (UTC)

You miss the point. Researchers (and everyone else) ALMOST NEVER call it anything but Cyclosporine.... Cyclosporine is the name pretty much universally used for this compound even in the current scientific literature. Naming the article anything else is mistaken, and out of sync with MoS guidelines. DO NOT MOVE. Fawcett5 13:33, 21 March 2006 (UTC)

By the way, cyclosporines systematic name is: IUPAC:30-ethyl-33-[(E,1S,2R)-1-hydroxy-2-methyl-hex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-dipropan-2-yl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

Not very useful as an article title, is it? 13:36, 21 March 2006 (UTC)

The point is researchers & drug chemists are a tiny minority of those who universally use this substance. The number of research papers should not, I believe, be the deciding factor; and not at all with that IUPAC name :-). However many research papers there have been, wikipedia is not an indexing system for scientific research (P.S. PubMed hits cyclosporine 28,665 vs cyclosporin 27,604 so not that different). Cyclosporine exists not for the benefit of researchers, but for its medical use, and as such it is the WHO who determined its official International Nonproprietary Name.  I am certain there are more prescriptions issued for this drug under that name, than the sum total of all research papers. Similarly the number of researchers is far outnumbered by the number "everyone else" i.e. doctors, pharamacists and patients handling prescriptions and then containers of the drug each day with the name 'Ciclosporin'. Other examples of wikipedia following INN is paracetamol (pubMed/google hits 10,947/2,580,000 vs tylenol 9,561/5,660,000 or acetomorphine 4,108/506). Likewise a drug almost universally originally known in the UK as 'DF118', is now mpore commonly known by the INN Dihydrocodeine. David Ruben Talk 15:36, 21 March 2006 (UTC)

Move. See Drug-related articles: "Where a compound has a WHO International Nonproprietary Name (INN), this should be used as the article title.". This has been part of the Naming conventions (chemistry) Wikipedia Guideline since July 2005. Counting Google hits is a poor way of determining policy since US spelling/usage would then be universal. I'm very happy to let the WHO argue over the best name for international usage, rather than for us Wikipedia editors to fall out each time the issue is discussed. Colin°Talk 16:54, 21 March 2006 (UTC)

Comment. The Official Policy on Naming conventions is summarized "Names of Wikipedia articles should be optimized for readers over editors; and for a general audience over specialists". Colin°Talk 16:54, 21 March 2006 (UTC)

Comment. I side with Fawcett5 on this issue, favoring "cyclosporine" over "ciclosporin," but perhaps this reflects an American bias. Andrew73 00:34, 22 March 2006 (UTC)

Move My first thought was "what is ciclosporin?" If this is a European spelling thing and we have a policy to name based upon some international guidelines, it sounds like it should move. However, I've honestly never heard of ciclosporin! InvictaHOG 02:49, 22 March 2006 (UTC)

 * Comment - Not European but Worldwide (as in W HO). INNs generally got rid of 'ph' for 'f' (hence cefalexin vs older cephalexin) and 'y' became 'i' (hence amoxicillin vs amoxycillin, aciclovir vs acyclovir). So Ciclosporin vs Cyclosporin should be apparent. (don't worry we too had great fun in UK learning bendroflumethiazide for bendrofluazide and furosemide for frusemide, but have been spared, for now, ephidrine for adrenaline) David Ruben Talk 05:35, 22 March 2006 (UTC)

Move It would be good to standardise on INNs. And, possibly, it hadn't occurred to me until now that "cyclosporine" is the United States Adopted Name (USAN) – which probably explains its observed prevalence in (predominantly North American) journals as noted by Fawcett5 above. I'll also raise a counterpoint that "cyclosporine" is not used at all here in Australia, where "cyclosporin" is the Australian Approved Name and Neoral capsules are alternately labelled "cyclosporin" and "ciclosporin". -Techelf 03:51, 14 May 2006 (UTC)

 * Indeed, in line with most other articles on medicines, standardised to INN names and so moved. Separate section on "Naming" is redundant as clearly now describes USAN and former BAN. David Ruben Talk 00:29, 20 May 2006 (UTC)

Suggest deletion from mode of action
Suggest removal of "It has also an effect on mitochondria. Cyclosporine A prevents the mitochondrial PT pore from opening and inhibits thus cytochrome c release, a potent apoptotic stimulation factor. However, this is not the primary mode of action for clinical use but rather an important effect for research on apoptosis." from the "mode of action" section. Reason given in last line of quote. --Username132 (talk) 22:36, 19 May 2006 (UTC)

 * I disagree. I'm using this compound for research not directly related to what it is prescribed for as a drug. That paragraph was helpful. As it is, the article for cyclosporin, the chemical compound, is clearly wrapped up in this article for the drug. As such, this article should reflect more than just the mechanism of action of the drug as prescribed. 130.253.176.109 (talk) 20:04, 30 November 2010 (UTC)

Olive Oil as a solvent
During the initial investigation of it's possible use, one major issues facing its application was the lack of an effective solvent, that's until the accidental discovery by a Greek medical research student that it'd dissolve in olive oil. I find this most interesting but am uncertain of its encyclopaedic value. Should this be added to the article, and if so, where and how? Oosh (talk) 10:50, 20 January 2009 (UTC)

Restasis
The most popular drug for Ciclosporin in the United States is Restasis.Mdriver1981 (talk) 04:39, 25 June 2009 (UTC)

/ˌsaɪklɵˈspɔərɨn/
What the hell is /ɵ/? In which dialect of English is it a phoneme, used in this position? —Preceding unsigned comment added by 92.124.45.8 (talk) 11:57, 3 August 2009 (UTC)

IARC Group I Carcinogen
Somewhere in the main part of this article it should be noted that CYCLOSPORINE IS A KNOWN CARCINOGEN IN HUMANS.

98.246.50.76 (talk) 01:39, 26 August 2009 (UTC)

Moving it back to cyclosporine
This should be cyclosporine of course (46,000 hits in ISI citation index; 153,000 Google books hits). "Cyclosporin" is name of chemical compound. But drug makers misspell names of chemical compounds to name their drugs. Hence the "ciclosporin" (just like "neoral") (1,300 ISI hits; 20,000 Google books hits). It should be moved back. Biophys (talk) 02:15, 13 July 2011 (UTC)
 * May be moved back, not must. Since that 2006 move, Wikipedia has adopted a consensus-based naming guideline, part of the Manual of Style, according to which drug articles must be located at their INNs. According to WP:COMMON, this guideline outweighs the usual provision of "common names".
 * The INN—and, thus, the correct article title—is "ciclosporin". This has nothing to do with drug makers; INNs are meant for widespread adoption throughout the world and, therefore, usually do not contain letters not present in certain alphabets, such as "Y", "K", or the "PH" digraph. See the discussion above for other valid reasons why the article should remain at Ciclosporin. Fvasconcellos (t·c) 16:45, 13 July 2011 (UTC)
 * Can you please provide any links proving that it should be "ciclosporin" and not "cyclosporine" per INN? Google search shows it is actually "cyclosporine" per INN . If you look at links in drugbox, it is "cyclosporine" everywhere: PubChem, DrugBank, CAS number, ChEMBL, etc. Besides, this is actually a natural product, not anything invented by man. Hence WP:Common name should prevail.Biophys (talk) 21:30, 13 July 2011 (UTC)
 * P.S. I just checked again WP:Common name. It does not make any exceptions for naming of drugs. It tells: Wikipedia does not necessarily use the subject's "official" name as an article title; it instead uses the name that is most frequently used to refer to the subject in English-language reliable sources. Please note: in reliable sources. This is scientific literature. Please realize: INN is only one of such reliable sources. BTW, one could reasonably argue that DrugBank is just as good as INN, or even better as an easily and publicly available resource. Why do not we follow DrugBank nomenclature? I would not mind. Biophys (talk) 21:46, 13 July 2011 (UTC)
 * See Common_name. WP:MEDMOS is one such explicit convention, where using names other than the most common name for some article titles has been discussed and determined, by consensus, to be the most helpful method.
 * INNs are determined, published and maintained by the World Health Organization (which makes them inherently "better" than DrugBank) and are specifically meant to avoid ambiguity and make things simpler. As their name implies, they are an international standard for drug naming (as the ICD-10 is for naming diseases, for instance).
 * There is no "DrugBank nomenclature" per se; DrugBank simply uses the names of drugs as provided by their manufacturers (probably the United States Adopted Names, which are used by the FDA, in most cases), as the "About" section of the website states.
 * Proof that "ciclosporin" is the INN can be found in any major pharmacotherapy textbook or dictionary of chemical compounds, such as Martindale: The complete drug reference and the British National Formulary. (I have my copies beside me: page 1822 of Martindale, 36th edition, and page xiii of BNF 57.) If you want an online-accessible resource, see this document from the Medicines and Healthcare products Regulatory Agency:.
 * By the way, "ciclosporin" is now the British Approved Name as well as the INN.
 * —Fvasconcellos (t·c) 17:20, 14 July 2011 (UTC)
 * We do not name articles per any organizations, British or international. We name articles per the name that is most frequently used to refer to the subject in English-language reliable sources. This is official policy. This particular organization took the most common and scientifically correct name (cyclosporine A), distorted it by replacing a couple of letters, and we suppose to use their name? "Ciclosporin synthetase"? That's ridiculous. Such name is never used in scientific literature (zero ISI hits). Biophys (talk) 18:20, 15 July 2011 (UTC)

I agree that we should stick with the INN nomenclature per Fv. Doc James (talk · contribs · email) 22:56, 20 July 2011 (UTC)
 * I also agree that we should stick with the INN nomenclature. The INN for this medicament is ciclosporin (see for example  or ).  Furthermore since ciclosporin is approved and prescribed as a drug in a large number of countries around the world, the INN per WP:MEDMOS takes precedence over how the compound is named in the scientific literature. In contrast,  is an enzyme that is rarely mentioned outside of scientific circles, therefore if we had an article about cyclosporin synthetase, it would be appropriate per WP:NAMINGCRITERIA to name the article as it is used in the scientific literature. Boghog (talk) 04:10, 21 July 2011 (UTC)
 * Agree that we should use ciclosporin. I live in Europe, and from my viewpoint this is definitely the WP:COMMONNAME. I only know the spelling with y from American sources on the internet. And these cross-continental differences are precisely the reason why WP:PHARM agreed on the International Nonproprietary Name. --ἀνυπόδητος (talk) 06:33, 21 July 2011 (UTC)

We stick with the INN for the same reasons I gave in the last discussion (above), five years ago (gosh!) Colin°Talk 08:00, 21 July 2011 (UTC)
 * I disagree with all of you (WP:COMMONNAME is not about England or US; it is about all English-language RS), but consensus is clear. However, this particular name depends on the context (there is no such thing as "ciclosporin synthetase" in biological literature). Amazingly, DrugBank authors have no problem with selecting the most common name for every drug, but wikipedia has a problem. Biophys (talk) 19:33, 29 July 2011 (UTC)

 * DrugBank says that they post the "Standard name of drug as provided by drug manufacturer", not the most common name. Since DrugBank is a Canadian outfit, the manufacturer will very likely provide the Canadian database with whatever name is accepted by the Canadian Therapeutic Products Directorate.  In this case, a brief search shows that TPD chose the USAN name over the rINN.  WhatamIdoing (talk) 05:08, 4 August 2011 (UTC)
 * Yes, that is what they claim. But I am not sure if they do it. In all cases I checked they are using the most common name, for example cyclosporine . DS Wishart is actually an NMR person, so he is probably on the same side as me. Biophys (talk) 15:23, 4 August 2011 (UTC)

Poor quality
I was about to translate this article into Chinese, but later I found out that it's written terribly...lol. Azathioprine, being also immunosuppressant, consisting of more than half "side effects", yet I only saw a few lines here (without even mentioning it's a IARC Group I Carcinogen). However, in fact cyclosporine has not much less adverse reactions than Azathioprine. Moreover, I don't think cyclosporine is THAT important on treating heart disease. It's only used experimentally so far, isn't it?--Jsjsjs1111 (talk) 12:51, 16 January 2012 (UTC)

More information located at this link on cyclosporin A
Hey everyone,

There's a lot of information about Cyclosporin A located here, if anyone is interested - http://ntp.niehs.nih.gov/ntp/roc/twelfth/roc12.pdf - I don't have much time so I only included the bit about prevention and rejection of bone marrow, liver etc... But if anyone wants to add more info, there's a lot here. -- Activism  1234  22:32, 10 July 2012 (UTC)

History
I have a correction and a reference for one of the needed citations in the beginning of the article but I am not firm with Wikipedia editing, so I will post it here:
 * "The cyclosporins were originally discovered in 1970 by workers at Sandoz Ltd. in Switzerland who were attempting to identify new antifungal agents."

''Borel, J.F. 1982. The history of cyclosporin A and its significance. In Cyclosporin A: Proceedings of an International Conference on Cyclosporin A, ed. D.J.G. White, p. 5. New York: Elsevier Biomedical '' — Preceding unsigned comment added by 88.69.179.107 (talk) 08:19, 17 July 2012 (UTC)

Use With Hashimoto's Thyroiditis
I want to know why this hasn't considered for use with Hashimoto's Thyroiditis where one's own immune system gradually destroys one's thyroid making one dependent upon hormone replacement. Any replies to this question would be greatly appreciated.Godofredo29 (talk) 01:02, 4 November 2013 (UTC)
 * I would suggest asking at Reference desk/Science.--Jsjsjs1111 (talk) 17:46, 5 November 2013 (UTC)

Interactions? For example, Pycnogenol?
Anyone can find how much Pycnogenol is probably safe (mg)?

All I know pycnogenol does not do much Acutely. Build-up effect is needed for best benefits. http://examine.com/supplements/Pycnogenol/ http://examine.com/discussion/Pycnogenol/

http://www.webmd.com/vitamins-supplements/ingredientmono-1019-pycnogenol.aspx?activeingredientid=1019&activeingredientname=pycnogenol Copy paste: Medications that decrease the immune system (Immunosuppressants) interacts with PYCNOGENOL

Pycnogenol seems to increase the immune system. By increasing the immune system pycnogenol might decrease the effectiveness of medications that decrease the immune system.

Some medications that decrease the immune system include azathioprine (Imuran), basiliximab (Simulect), cyclosporine (Neoral, Sandimmune), daclizumab (Zenapax), muromonab-CD3 (OKT3, Orthoclone OKT3), mycophenolate (CellCept), tacrolimus (FK506, Prograf), sirolimus (Rapamune), prednisone (Deltasone, Orasone), corticosteroids (glucocorticoids), and others.

ee1518 (talk) 11:07, 18 February 2015 (UTC)

Only two of our references use the spelling 'ciclosporin' ? ? ?
Of our 43 references, only two use the spelling 'ciclosporin.' And one of these is a multi-source reference which include three other references with the spelling cyclosporin.

In fact, our entire reference list is filled with spellings of both cyclosporin and Cyclosporine, and it's not always entirely consistent on the matter of capitalization. Do a control F for find and type in cyclo- and see what ends up highlighted.

I know we had this discussion before -- like ten years ago! -- but it sure seems like it's an affectation and we're trying to make some purist political point. FriendlyRiverOtter (talk) 20:25, 7 December 2016 (UTC)
 * Yep this has been discussed pretty much to death. If you want to start a new move discussion please do so but please don't add further editorializing comments in the article.   Reviewing the discussions above, I don't think there is much likelihood that a move discussion will succeed.   I suggest you review the discussions as well.  Thanks. Jytdog (talk) 20:43, 7 December 2016 (UTC)
 * Yup we go with INN. Similar to how just because the USA uses miles and has the largest publishing houses in the world does not mean the rest of the world cannot agree to go with metric. We are global and therefore use global standards. Doc James  (talk · contribs · email) 05:12, 8 December 2016 (UTC)
 * And of course, if we had an article about cyclosporin synthetase, per WP:COMMONAME, we would use the spelling cyclosporin and not ciclosporine. Boghog (talk) 05:43, 8 December 2016 (UTC)
 * If ciclo- is the global standard, I'm all in favor of having it be the title of our article. I can only say that what was common in our references and what was not, really jumped out at me.  And everyone, thank you and you're very welcome.  Thank you for the nice compliments.  Yes, I did make a good contribution by adding the alternate spelling cyclospirin.  Again, I did this simply by paying attention to our references.  And I'm glad we're all in favor of using common names.  I just hope we're not making it analogous to the Royal Spanish Academy where we might pay lip service to common usage, but then at the end of the day elevate some kind of purist ideal standards.  FriendlyRiverOtter (talk) 19:19, 8 December 2016 (UTC)

"cyclosporin" versus "ciclosporin"
Ciclosporin is the official spelling. Thus while mention that it is also spelled "cyclosporin" in the lead sentence, after that IMO we should be using "ciclosporin". User:Boghog. Doc James (talk · contribs · email) 19:09, 20 December 2016 (UTC)
 * When discussing the natural product, it should be spelled cyclosporin. Boghog (talk) 19:12, 20 December 2016 (UTC)
 * What reference do you have for this? The ref uses "ciclosporin" for the natural product. Doc James  (talk · contribs · email) 19:13, 20 December 2016 (UTC)
 * Try the first reference provided in Ciclosporin. I can provide tons more. Boghog (talk) 19:25, 20 December 2016 (UTC)
 * Sure. But the four spellings are all used interchangeably (ciclosporin, cyclosporine, cyclosporin, and ciclosporine). There is nothing special about one over the over. It is not like you spell it one way and you mean the medication and you spell it another and you mean the natural product. Doc James  (talk · contribs · email) 19:33, 20 December 2016 (UTC)
 * Common usage says otherwise. Boghog (talk) 19:38, 20 December 2016 (UTC)
 * Do you have a reference that says "ciclosporin" does not also mean the natural product? I have provided one above using it in the sense that it does. Doc James  (talk · contribs · email) 19:44, 20 December 2016 (UTC)
 * The reference you cited above is a medical reference. Can you find a single example where "cyclosporin synthetase" is spelled "ciclosporin synthetase"? Cyclosporin synthetase is what produces the natural product. Boghog (talk) 21:14, 20 December 2016 (UTC)
 * That is a name of something else. Doc James  (talk · contribs · email) 03:48, 21 December 2016 (UTC)
 * That enzyme was named after the natural product. It is the same thing. Boghog (talk) 04:13, 21 December 2016 (UTC)

Okay so this was spelled "cyclosporin". The enzyme is then named after the old spelling. The spelling for the substance is then officially changed to "ciclosporin" to fit with global nomenclature and no one bothers renaming the enzyme. Our policy is still to use the INN. Doc James (talk · contribs · email) 05:05, 21 December 2016 (UTC)
 * There are ~some~ refs that "ciclosprin synthetase" - here. Many fewer than with the "y".  It makes sense that biologists would have generally stuck with the original spelling in the the name for the protein; they never had to deal with INN/USAN etc.  Interestingly the MESH term (for both natural product and drug) is "Cyclosporin" per .   I don't know people in the field are super anal about it.  Heck people sometimes still call the drug "cyclosporine A" like .  Not worth anybody getting tangled  too fierce about either way i think.  it is not like they are different things - then it would be. Jytdog (talk) 05:12, 21 December 2016 (UTC)

That is a guideline, not a policy and that guideline only applies to drugs, not natural products. The enzyme is named after the current spelling of the natural product. The natural product was originally spelled cyclosporin by German speaking scientists to denote that it contains a cyclic structure. This spelling is still used today. Boghog (talk) 05:16, 21 December 2016 (UTC) The official spelling only applies to the drug, not the substance. Why should biochemists be bound by the INN? Boghog (talk) 05:41, 21 December 2016 (UTC)

 * yah they are both used today. i grant you that ~generally~  people talking about the drug use the "i" and generally people talking about what-came-from-fungus with "y" but it isn't a high wall and again what is the point?  I will grant you there is a big point if you are talking about the family  - the cyclosporines.   but if we are talking about cyclosporine A/ciclosporin i don't see why it matters, and you have given no reason why.... so please say -- why does it matter? Jytdog (talk) 05:20, 21 December 2016 (UTC)
 * I was objecting to the removal of mentioning that cyclosporine is a natural product from the lead. There are really two issues.  The more important whether it should be mentioned that it is a natural product (obviously it should).  The second issue is how it is spelled.  Boghog (talk) 05:35, 21 December 2016 (UTC)
 * Drugs.com uses Cyclosporine but they are Americans and as we all know America still uses Miles.
 * The US gov and publishes however are prolific and such is why we see USAN often more popular than INNs. Doc James (talk · contribs · email) 05:43, 21 December 2016 (UTC)

 * Wikipedia does not necessarily use the subject's "official" name as an article title; it generally prefers to use the name that is most frequently used to refer to the subject in English-language reliable sources. Ciclosporine is confusing to our English language readers because they are far more likely to see cyclosporine in other English languages sources. The analogy to the metric system is flawed. Many English speaking countries use the metric system, but the letter "y" has not been dropped from the English alphabet. Boghog (talk) 05:47, 21 December 2016 (UTC)
 * I do not care if we have "Cyclosporin, also known as ciclosporin" and then use cyclosporin for the rest. As long as we are not implying that the two spellings mean different things.
 * We do use "paracetamol" even though "acetaminophen" is more common. This is a British / American spelling thing. As long as we are consistent. Doc James  (talk · contribs · email) 05:24, 22 December 2016 (UTC)
 * As the lead sentence, synonym section of the infobox, and the Ciclosporin section make clear, there is little chance that readers will think that the two different spellings mean different things. Boghog (talk) 11:28, 22 December 2016 (UTC)
 * As it stands currently I agree. Doc James  (talk · contribs · email) 02:09, 23 December 2016 (UTC)

This entire discussion is depressing, and the same one took place on the French page. Ciclosporin is a spelling mistake that appeared in 1980, and got somehow propagated since. The name comes from the cyclic structure. We do not use bicicles as far as I know? The people deciding the "official" name did not know how to spell in English, and picked this form, which is really an absolute nonsense. However, despite the fact that one spelling is 1) correct, 2) the original one, 3) largely more used, WP decides to use another one. Not worse a fight, but a few tears of frustration perhaps. Nicolas Gambardella (talk) 14:32, 15 May 2020 (UTC)

References in 'History' are skimpy
We currently end our 'History' section:

 * "Ciclosporin was subsequently approved for use as a drug in 1983."

That is, with no references at all. I'm planning to include a Los Angeles Times article and an in-house source from Columbia University. This is not ideal. Admittedly, this is not a peer-reviewed source, but it's better than nothing. Work remains to be done. Although actually, I like having a range of different types of references.FriendlyRiverOtter (talk) 20:51, 28 February 2017 (UTC)

Milestones in Cardiac Care, Los Angeles Times, Jill Gottesman, March 20, 1988.

 * ' .  .  1979: Experimental use of cyclosporine begins in the United States. It dramatically increases a recipient's ability to overcome rejection. (In 1983, it is accepted for use by the FDA.)  .  .  '

Columbia University Medical Center, Dept. of Surgery, Cardiac Transplant Program, June 9, 1984 First Successful Pediatric Heart Transplant.

 * ' .  .  .  Columbia was one of only a few centers in the United States to begin trials of cyclosporine, the revolutionary immunosuppressant drug that was the first to successfully tamp down a body’s immune response to prevent organ rejection. It gained FDA approval at the end of 1983,  .  .  .  '

Completed, and another member has added a third source. FriendlyRiverOtter (talk) 21:56, 28 February 2017 (UTC)

--

Drugs@FDA: FDA Approved Drug Products [Click on "Approval Date(s) and History . . . "], Drug Name(s): Sandimmune (Cyclosporine), Company: Novartis, Action Date: 11/14/1983, Action Type: Approval, Submission Classification: Type 1 - New Molecular Entity, Review Priority: Priority.

Notice the conflict in dates.

Corollary: There's no perfect source!

There's more work to be done, and we welcome your help. FriendlyRiverOtter (talk) 23:06, 28 February 2017 (UTC)
 * If you can get your hands on it, the book The Billion Dollar Molecule by Barry Werth has a really great history of cicloporin in it. I have it and will try to dig that up.   But if you never read it, it is a great read. Jytdog (talk) 00:14, 1 March 2017 (UTC)
 * I like good stories well-told! And I'm assuming this book has a ton of endnotes, which is a good thing.  FriendlyRiverOtter (talk) 17:47, 1 March 2017 (UTC)

---

http://onlinelibrary.wiley.com/doi/10.1002/j.1875-9114.1991.tb02654.x/epdf?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=www.google.com&purchase_site_license=LICENSE_DENIED_NO_CUSTOMER

 * this source from Wiley is saying Nov. '83. FriendlyRiverOtter (talk) 18:03, 1 March 2017 (UTC)

 * There may be a slight delay between announcement and official implementation of the approval. We are talking a difference of one month of an event that happened 34 years ago. Boghog (talk) 18:17, 1 March 2017 (UTC)

 * I actually think the disagreement among references is a good thing. In a roundabout kind of way of course!  It reminds us that we have to really work the references and strive to include a variety of references.

 * We Wikipedians probably spent too much time worrying about typesetting and the formality of the writing. I know I can fall into this.  We probably spend two-thirds of our overall time on this part.  And it probably should be reversed, two-thirds of the time on the references, and only one-third on the writing itself. FriendlyRiverOtter (talk) 21:42, 1 March 2017 (UTC)

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Patent Attack and protection through Indian reservation.
"''Restasis’s patents are under attack on two fronts, and moving the rights may shield them on one side. Last year, the drug -- which treats chronic dry eye -- brought in $1.49 billion in sales.

“I would expect it creates a playbook for other cases down the road both for us and for others,” Bob Bailey, Allergan’s chief legal officer, said of the agreement with the tribe.''"

https://www.bloomberg.com/news/articles/2017-09-09/casinos-aren-t-enough-as-native-tribe-makes-deal-on-drug-patents

--Wikipietime (talk) 15:47, 9 September 2017 (UTC)

Merger proposal: from Optimmune
I propose that Optimmune be merged into Ciclosporin. There is not much information in the Optimmune, and it would be better explained in the context of the ciclosporin article in the "history" and other "veterinary use" sections. DferDaisy (talk) 20:30, 21 November 2018 (UTC)
 * Yes and done. Doc James  (talk · contribs · email) 21:34, 21 November 2018 (UTC)

Veterinary use of ciclosporin
Also used for dogs with immune modulated hemolytic anemia 2600:1700:4E34:29A0:FD0E:5FE1:7982:98C8 (talk) 16:26, 5 March 2024 (UTC)

title: Talk:Ciclosporin


text:
First Avenue (nightclub)

First Avenue and 7th St Entry are two historic music venues housed in the same landmark building in downtown Minneapolis. The nightclub sits on the corner of First Avenue North and 7th Street North, from which the venues get their names. The two are colloquially distinguished by locals as The Mainroom and The Entry.

The building was constructed in 1937 as the Minneapolis depot of the Greyhound Lines bus system and operated for 31 years. Allan Fingerhut purchased the facility in 1970 and converted it into a nightclub. During the 1980s, First Avenue flourished and became a landmark in the music and entertainment industry, playing a seminal role in establishing the '80s funk rock sub genre via the Minneapolis sound, and being the primary local venue for hometown star Prince. Since its rise to fame in the 1980s, First Avenue has hosted many notable local and national music acts. The building is marked by more than 400 large stars on its exterior commemorating these performers, along with other figures notable to the city.

The venue's history and cultural significance has resulted in local and national recognition. Journalist David Carr wrote in The New York Times that First Avenue's cultural weight and history is matched by only a few clubs in the United States: CBGB, Maxwell's, Metro Chicago and the 9:30 Club. It was also one of the first clubs to book Black performers in Minneapolis's once largely segregated music scene.

The nightclub was featured in Prince's commercially successful 1984 film, Purple Rain.

Greyhound Lines Facility, opening
The building opened as a bus depot in 1937, decades after Greyhound Lines was founded in Hibbing, Minnesota. It was noted for its Art Deco style and amenities of air conditioning, shower rooms, and public telephones. The interior floor was checkered terrazzo, while the exterior was shiny blue bricks with white trim. The bus station moved to its present location on 10th Street in 1968.

The transformation from a bus depot into a concert venue has a disputed history. Clearly, Allan Fingerhut, heir to the Fingerhut mail-order merchandise company, had capital and invested $150,000, and Danny Stevens of the band Danny's Reasons had a hard-to-get liquor license. Both men agree promoter Skip Goucher had the original idea for a nightclub in the bus depot.

They opened The Depot on April 3, 1970, with Joe Cocker and Mad Dogs & Englishmen and a stage crowded with 27 musicians and singers who turned in two magnificent sets. Among Cocker's Mad Dogs & Englishmen that night were Leon Russell, Rita Coolidge, Claudia Lennear, Jim Keltner, Jim Price and Bobby Keys.

Disco era
Following two years of steady business, The Depot was faced with a new reality: the public music scene was changing. Psychedelic rock was out and disco was in. In order to stay on top of this new trend, the club needed to change its image. After a short remodel, The Depot in July 1972, evolved into Uncle Sam's, a national franchise of the American Avents Corporation of Cincinnati. A red, white, and blue patriotic-themed club with recorded dance music, a drummer, a DJ, and a light-up plexiglass dance floor became what doorman Richard Luka described as, "Studio 54 for the discriminating Kmart shopper." In about late 1973, Steve McClellan (who'd become the club's talent buyer and eventually general manager) started working at Uncle Sam's as a bartender. He would enter American Avents' management training in 1975.

After American Avents left in 1979, general manager McClellan hired his former high school classmate Jack Meyers to help him manage money. Dan Lessard managed the bar staff. The club's name was shortened to Sam's in early 1980. The club got its third name change on New Year's Eve 1981 when it became First Avenue.

7th St Entry
The 7th St Entry is a smaller stage (capacity 250) attached to the historic First Avenue (capacity 1500). This space was once a restaurant (the "Greyhound Cafe") and later a coatroom, before staffer Danny Flies and McClellan spent $1,500 to turn it into a barebones music venue as part of Sam's. Meyers donated his own Bose speakers for stage monitors. Like Jay's Longhorn Bar and Duffy's, the Entry catered to local bands, often too new to play the Mainroom.

The Entry opened its doors on March 21, 1980, with Cathy Mason fronting Wilma & the Wilburs, who were first to play, as warmup for headliner Curtiss A.

Danceteria
Chrissie Dunlap began to work days in the office in 1979, about the time McClellan booked the Ramones and Pat Benatar in back-to-back, sell out concerts. Disc jockeys Kevin Cole and Roy Freedom developed weekend dance nights dubbed Danceteria inspired by the New York club of that name, often creating enough business to pay the club's bills. The club has, through much of its existence, survived on the success of its dance nights. As EDM and rave culture grew in the 1990s, Cole mentored younger local DJs such as Woody McBride, DJ Apollo (Dory Kahalé) and E-Tones at Danceteria and other DJ nights such as House Nation Under a Groove and Depth Probe, helping to create a thriving and distinctive techno-music scene in the upper Midwest.

The Prince explosion
Discrimination had created a race barrier in the Minneapolis music scene. Encouraged by Dunlap to write their own material, Jimmy Jam and the 11-piece Mind & Matter were able to break through with bookings by McClellan in the mid-1970s. First booking Black acts in the one-hit wonder Lipps, Inc., with lead singer Cynthia Johnson, McClellan decided to book Prince in 1981, for $2,500 plus part of the gate. Before he died in 2016, Prince was to play nine full First Avenue concerts. Over time, many of his fans thought he owned the club.

Recorded live in 1983 by a Record Plant truck parked outside at an August 1983 show, "Purple Rain" became the title of the film Purple Rain. Prince's management team offered First Avenue $100,000 to use the mainroom for filming in late November into December 1983, with the clause that the Entry would remain open. Most of the club's employees were extras in the film. The production gave the club its patch panel and dimmer packs. McClellan feared the audience had changed from genuine music lovers to a lot of tourists; still, he and Meyers were grateful for the boost in revenue.

Changes in ownership
The club was briefly closed by Fingerhut in late fall 2004 for financial reasons, causing a wave of protest from music fans. The issues were quickly resolved (the judge presiding in the bankruptcy case noted, "I gather there is some urgency about this"), and the club was reopened by new partners Meyers, McClellan, and former business manager Byron Frank, with shows resuming after one week's closure. An experienced crowd surfer, Minneapolis mayor R.T. Rybak reneged on his promise to stage dive at the first show after reopening.

McClellan ended his 32-year stint at First Avenue in 2005, and began to focus on local music non-profit, the Diverse Emerging Music Organization (or DEMO). After McClellan's departure as general manager, Jack Meyers was appointed to the position and continued until 2009, when Nathan Kranz took over. Dayna Frank took over for her father the same year.

Notable events
The nightclub has been the starting point for many acts that have come out of the Twin Cities, including Prince, The Replacements, Hüsker Dü, Soul Asylum, Semisonic, and Lizzo, among others. Bands and artists have performed at the nightclub and influenced the Minneapolis music scene from 1970 onward, as exemplified by the silver stars that adorn the black building's exterior (every star has the name of an artist who has played at First Avenue or 7th St Entry). First Avenue also appeared in Prince's 1984 film Purple Rain, and many of the film's music performances take place at the venue.

U2 wrote part of October at First Avenue, during sound check.

Grammy Award-winning alternative-country star Lucinda Williams was married on stage following a performance at First Avenue in 2009.

Gwar guitarist Cory Smoot played his last performance at the venue on November 3, 2011—he died just hours afterward.

The club was named in Playboy Magazine's Guide to Best Nightclubs in the World at #15 out of 20 in the November 2013 issue.

During the Theory of a Deadman concert on August 12, 2015, part of the ceiling collapsed, pulling down part of the sprinkler pipes. Three people were slightly injured, two of whom were taken to the hospital.

The non-profit Developing Music and Arts Foundation (DMAF) was founded by the club in 1999. It was rechristened The Diverse Emerging Music Organization (DEMO) in 2004 as an independent entity.

Productions
In 1970, The Depot recorded the first live album from the venue, titled Gathering at The Depot, featuring artists such as Danny’s Reasons and The Litter.

Daniel Corrigan is a First Avenue photographer since 1981 whose work fills the book Heyday. Later after the advent of ubiquitous digital photography, he became an employee in the facilities department, and made a series of under-two minute videos for the Minnesota Historical Society describing his photos. ,, , , , , ,

Local Minnesota band Trampled by Turtles released their album Live at First Avenue in November 2014.

First Avenue & 7th St Entry published a promotional book in 2000, First Avenue & 7th Street Entry: Your Downtown 'Danceteria' Since 1970. The book was written, edited and designed by Rebecca Noran; and contains information on the history of the club. Furthermore, the club published a magazine entitled First Avenue In House for a brief time from September 1998 to August 2000.

In November 2005, First Avenue released its first compilation CD celebrating 35 years of history. The 16 track CD, Bootlegs Volume 1, is a collection of songs recorded in either the mainroom or the 7th St Entry. Most of the songs on the CD were bootlegged, thus forming the title of the CD. Bootlegs was produced by Karrie Vrabel, with the liner notes written by Steve McClellan. All the proceeds of the CD go to McClellan's non-profit organization, DEMO. The goals of his organization are "to support musicians while promoting gender equity; diversity of music style and genre; diversity of musicians from local communities; careers in all stages of establishment; and the staging of performances with high production values." First Avenue is also home to F1RST Wrestling, a local professional wrestling company currently owned by professional wrestler Arik Cannon. It showcases Minnesota's top wrestling talent and brings in bigger names, including Sean Waltman, Jerry Lynn, Tyler Black, Colt Cabana and others. F1RST Wrestling currently holds its WRESTLEPALOOZA events at First Avenue which feature a combination of pro wrestling, live music and burlesque.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: First Avenue (nightclub)


text:
Talk:Altered Images

Untitled
after which McElhone formed Texas, a group which would have intermittent UK success but is largely unknown in the U.S.

That's a bit US-centric, isn't it? Would it be more accurate to say 'intermittent UK success bit is largely unknown outside Britain'? sheridan 20:59, 2004 Dec 21 (UTC)
 * You realise the band is called Texas? 80.4.202.8 (talk) 02:05, 8 August 2009 (UTC)

Texas are Scottish and named after the film Paris, Texas. 92.0.42.40 (talk) 15:19, 20 February 2010 (UTC)

YouTube links
This article is one of thousands on Wikipedia that have a link to YouTube in it. Based on the External links policy, most of these should probably be removed. I'm putting this message here, on this talk page, to request the regular editors take a look at the link and make sure it doesn't violate policy. In short: 1. 99% of the time YouTube should not be used as a source. 2. We must not link to material that violates someones copyright. If you are not sure if the link on this article should be removed, feel free to ask me on my talk page and I'll review it personally. Thanks. ---J.S (t|c) 04:29, 8 November 2006 (UTC)

Yes On Merging
I think my article and the main "Altered Images" article being merged, which already appears to have happened, is a good idea. A deletion of my existing article would be fine with me. It works better as a part of the "Altered Images" article, as the article on just the song is too short. --Putnam269 (talk) 00:49, 19 October 2008 (UTC)

Merge please. —Preceding unsigned comment added by 61.7.186.232 (talk) 14:32, 2 February 2009 (UTC)

 * agreed, someone please merge! Feudonym (talk) 12:09, 27 May 2009 (UTC)

 * Oppose if someone were to expand the song properly, which was a fairly successfully charted single, both the song and the band articles would be big enough to survive on their own. My 80s pop knowledge is sadly not backed up by Reliable Sources on my bookshelf though. Casliber (talk · contribs) 21:11, 20 August 2009 (UTC)
 * Yes please merge. the song article is not only short, it's so small as to practically not exist. What's the reason to think that there are sources out there that make it notable enough for its own article? MartinPoulter (talk) 16:51, 26 August 2009 (UTC)

External links modified
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Dead Pop Stars
I am going to edit the sentence which includes "but badly timed in its release the day of John Lennon's death" which claims 'Dead Pop Stars' was released on the day Lennon died but he in fact died in December 1980 and the song, according to Discogs, was actually released on 27 Feb 1981. With reference to the Guinness Book of Hit Singles, the song first charted in the UK on 28 Mar 1981 which ties in with the Discogs release date. If anyone can find a more concrete reference proving it was initially released on the day Lennon died then please revert this edit. Solatha (talk) 15:54, 27 November 2020 (UTC)
 * Straight away Discogs is not a reliable source. Clare Grogan suggests that "[it got pulled on the day it was released because that was the day John Lennon died]"; possibly 27 February was when it was rereleased, but you'll want a better source.-- Laun chba ller 16:12, 27 November 2020 (UTC)

title: Talk:Altered Images


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Sidekicks (1992 film)

Sidekicks is a 1992 American adventure action comedy-drama film directed by Aaron Norris and starring Jonathan Brandis and Chuck Norris.

Plot
Barry Gabrewski is a troubled and bullied asthmatic boy who lives with his widowed father, Jerry (Beau Bridges), in Houston, Texas. A loner, Barry has vivid daydreams about being Chuck Norris' sidekick, and about battling against Norris' movie enemies. Said foes are often personified by Barry's everyday nemeses, such as class bully Randy Cellini (John Buchanan); Coach Horn (Richard Moll), their loudmouthed and demanding PE instructor; and apathetic Principal Mapes (Gerrit Graham). Noreen Chan (Julia Nickson-Soul), Barry's favorite teacher, often plays the damsel-in-distress in these daydreams, most of which parody assorted Chuck Norris films (notably Missing in Action, The Delta Force, and The Hitman).

Barry wants to learn martial arts; yet he is rejected by arrogant dojo-master Kelly Stone (Joe Piscopo) -- who also happens to be Randy's sensei—for being too weak. Instead, he is taken on as a student by an old Chinese man called Mr. Lee (Mako), Noreen's sly uncle and the owner of a local Chinese restaurant, "Frying Dragon". Mr. Lee finds creative ways of teaching Barry to defend himself from bullies; he devises training methods that increase Barry's endurance, thus helping the boy's asthma. Lee also deduces Barry's hero-worship of Norris, from Barry's daydreams; he creatively incorporates this into Barry's training, devising scenarios that seem more dangerous than they are...so that Barry will feel heroic for succeeding at them.

Lee enters himself, Barry, and Chan into a local team Karate tournament but is a bit stymied to learn that a team must have four members. Norris is attending the tournament as a guest and, at Lee's urging, Chan convinces Norris to join the team. Norris is both willing to help an ardent fan and has his own motivation for participating: he has encountered Stone on several occasions and wants to teach him "a lesson in humility". Barry is stunned to find himself working together with his hero.

The tournament involves four events: Breaking, Men's Weapons, Female Kata, and Freestyle fighting. Stone's team narrowly defeats Chan in the Female Kata, but Lee defeats Cellini, one of Stone's students, in Breaking. True to his word, Norris defeats Stone in Freestyle fighting, and Barry—aided by a vivid daydream—scores a victory in Men's Weapons. The result is a tie between Stone's team and Lee's team. In the tie-breaker, Lee is allowed to choose the participants, and chooses Barry and Cellini, saying Barry is the member of the team with "something to prove". Stone chooses the event, Breaking. Barry is dismayed to be confronting Cellini in the latter's best event, but Lee tilts the odds in Barry's favor by using a small amount of lighter fluid to set Barry's bricks on fire. Faced with a much more heroic-seeming task, Barry wins.

After the tournament, Barry is seen talking to Norris, thanking him for his help. Norris vanishes, and it is implied that Barry has found the strength to live his life without the need for his daydreams. A young boy in a wheelchair finds Barry's Chuck Norris magazine and reacts with an excited "Wow!"

Cast

 * Jonathan Brandis as Barry Gabrewski
 * Chuck Norris as Himself
 * Beau Bridges as Jerry Gabrewski
 * Mako as Mr. Lee
 * Joe Piscopo as Kelly Stone
 * Danica McKellar as Lauren
 * John Buchanan as Randy Cellini
 * Richard Moll as Mr. Horn
 * Julia Nickson-Soul as Ms. Noreen Chan
 * Gerrit Graham as Mr. Mapes
 * Eric Norris as Biker Punk
 * George Franklin Sturgis V as Himself
 * James McIngvale as Lauren's Brother

NOTE: Nickson-Soul's character-name is an inside reference to Chuck Norris's movie An Eye for an Eye, in which Mako portrayed James Chan (the father of a murdered journalist, who teams up with Norris' character to hunt down her killers).

Filming

 * 810 Zola Rd., Houston, Texas. (Barry's home)
 * Lamar High School (Houston, Texas)
 * Tranquility Park
 * Wortham Theater Center
 * Williams Waterwall
 * Allen's Landing
 * Texas Southern University
 * Westchester Junior High, Spring Branch (Demolished, 1994?) (Houston, Texas)

Sidekicks was filmed primarily in Houston, TX. It was the pet project of well-known Houston furniture outlet owner Jim "Mattress Mac" McIngvale, who (in partnership with Chuck Norris and his "Kick Drugs out of Schools" campaign) invested 8 million dollars in producing this movie. Chuck Norris, who had appeared in many local television commercials for McIngvale, suggested the idea of creating this film, and "Mac" agreed to finance and produce it. In McIngvale's book, Always Think Big, he states going into film and producing was "extremely hard work".

Box office
The film debuted at No. 2 at the box office. It grossed $17,180,393 during its domestic release.

Critical response
The film received largely negative reviews from critics. Based on 19 reviews gathered, the film has a 26% from Rotten Tomatoes, with an average score of 4/10.

title: Sidekicks (1992 film)


text:
Anandavardhana

Ānandavardhana (c. 820 – 890 CE) was a Kashmiri court poet and literary critic, honored with the title of Rajanak during King Avantivarman's reign. Anandavardhana authored the Dhvanyāloka, or A Light on Suggestion (dhvani), a work articulating the philosophy of "aesthetic suggestion" (dhvani, vyañjanā).

Ānandavardhana is credited with creating the dhvani theory. He wrote that dhvani (meaning sound, or resonance) is the "soul" or "essence" (ātman) of poetry (kavya)." "When the poet writes," said Ānandavardhana, "he creates a resonant field of emotions." To understand the poetry, the reader or hearer must be on the same "wavelength." The method requires sensitivity on the parts of the writer and the reader. The complete Dhvanyāloka together with Abhinavagupta's commentary on it has been translated into English by the Sanskritist Daniel H.H. Ingalls and his collaborators.

Ānandavardhana is mentioned in Kalhana's Rajatarangini. He was noted to not have cited or commented on Daṇḍin's work, instead preferring Bhamaha or Udbhata.

Dhvanyāloka
Anandavardhana classifies three categories of poetry:

 * 1) Dhvani kavya (prominence of suggestion)
 * 2) Gunibhuta vyangakavya (secondary place of suggestion)
 * 3) Chitra kavya (portrait like - absence of suggestion)

He categorizes Dhvani kavya as the best form of poetry, Gunibhuta vangiya kavya as the second class and the third or lowest class is said to be Chitra kavya.

The philosopher Abhinavagupta (c. 950 – 1016 CE) wrote an important commentary on Dhvanyāloka titled the Locana, or The Eye.

Assessment by Modern Sanskritists
Modern Sanskritists have a very high opinion of Ānandavardhana. Commenting on Ānandavardhana's Dhvanyāloka, P.V. Kane writes that "the Dhvanyāloka is an epoch-making work in the history of Alaṅkāra literature. It occupies the same position in poetics as Pāṇini's Aṣtādhyāyī in grammar and Śaṅkarācarya's commentary on Vedānta". Daniel H.H. Ingalls calls Ānandavardhana "the most brilliant of all Sanskrit critics".

Sushil Kumar De, along with Kane, considered there to be no work similar to the Dhvanyaloka in the corpus of Sanskrit literature. Franklin Edgerton and Louis Renou also considered the work to ge exceptional in its treatment of poetic theory and aesthetics.

Lawrence McCrea considers the Dhvanyaloka to be influenced by Mīmāṃsā, particularly by how it approached an exegesis of the Vedas.

title: Anandavardhana


text:
Grandmontines

Grandmontines were the monks of the Order of Grandmont, a religious order founded by Saint Stephen of Thiers, towards the end of the 11th century. The order was named after its motherhouse, Grandmont Abbey in the eponymous village, now part of the commune of Saint-Sylvestre, in the department of Haute-Vienne, in Limousin, France. They were also known as the Boni Homines or Bonshommes.

Founding
The exact date of the foundation of the order is very uncertain. The traditional story involves serious chronological difficulties, and is based on a bull of Gregory VII, now known to be a forgery. The founder, St. Stephen of Muret (Étienne in French; also called 'of Thiers') was so impressed by the lives of the hermits whom he saw in Calabria that he desired to introduce the same manner of life into his native country.

Stephen, being ordained, in 1073 obtained the Pope's permission to establish an order. He is said to have settled in Muret near Limoges in 1076, where he made himself a hut of branches of trees and lived there for some time in complete solitude. A few disciples gathered round him, and a community was formed. The Order of Grandmont has been claimed by both Benedictines and Canons Regular as a branch of their respective institutes, although the Grandmontines always maintained that they were hermits.

They tended to seek out woodlands and uplands to situate their monasteries. The architecture of the order of Grandmont is notable for its simplicity. A single barrel vaulted nave with a slightly wider apse. Three windows at the east and one at the west. The entry to the church, in most surviving cases, is in the northwest side.

The Rule
The so-called "Rule of St. Stephen" was compiled at the request of the fourth prior, Étienne de Liciac, by Hugh of Lacerta, and embodies the customs of Grandmont some twenty or thirty years after St. Stephen's death in 1124. The founder himself left no authentic writings. His maxim was "There is no rule save the Gospel of Christ"; as this was the basis of all rules, to practise its morality was to fulfil all the duties of a good religious. The life was eremitical and very severe in regard to silence, diet and bodily austerities; it was modelled after the rule of the Camaldolese, but various regulations were adopted from the Augustinian canons. The superior was called the Corrector. The early Grandmontines were noted for their extreme austerity. Poverty was most strictly observed; the rule forbade the possession of lands, cattle, revenue, or impropriate churches. So concerned were the Grandmontines regarding simoniacal entry that in the customary composed about 1170, it was forbidden to ask a candidate seeking to join, about bringing money, or buying clothes, or equipment for a horse. Begging was only permitted when there was no food in the house, and even then the local bishop was first to be informed of their state. Although discipline was severe, the rule of silence was relatively lenient.

They developed a reputation for simplicity of life and generosity to the poor, along with an emphasis on hospitality. They acquired the nickname the Bonshommes.

Zenith
After the founder's death in 1124, sometime around 1150, having been compelled to leave Muret due to disputed ownership, the hermits settled in the neighboring desert of Grandmont, whence the order derived its name. The influence of the Grandmontines reached its height in the twelfth century. Under Étienne de Liciac the order spread rapidly, and in 1170 numbered sixty monasteries, mostly in Aquitaine, Anjou and Normandy. Under his successor, Bernard de Boschiac, eighty new foundations were made, and the "bons hommes" were to be found in nearly every diocese of France.

Their holy austerity roused the admiration of all beholders, and the kings of England and France vied with one another in bestowing favours upon them. Henry II of England had the monastery rebuilt, and King St. Louis IX of France erected a Grandmontine house at Vincennes near Paris. There were three Grandmontine monasteries in England: Alberbury in Shropshire, Craswall in Herefordshire, and Grosmont Priory in North Yorkshire.

The system of lay brothers was introduced on a large scale, and the management of the temporals was in great measure left in their hands; the arrangement did not work well.

Decline
The golden age of Grandmont however lasted only sixty years after the founder's death. After then, the history of the order is an almost uninterrupted series of disputes, as quarrels between two categories of monks were a constant source of dissension. Even in the twelfth century, the ill-defined position of the lay brothers caused troubles. They were far more numerous than the choir-monks, and were given entire control of all temporalities so the latter might be free to carry on spiritual duties. Gradual relaxation of the rules of poverty led to great possessions, and thus increased the importance of the lay brothers, who now claimed equality with the choir-monks. This led to scandalous scenes. The political situation embittered these dissensions, the order being divided into two parties, French and English. Successive popes tried to restore peace, but in vain. In 1219 the prior of Grandmont and forty monks were again expelled by the rebellious lay brothers. In 1244 the papal delegates advised a union of the order with the Cistercians as a means of ending the disputes. This threat and the expulsion of a large number of monks produced a certain degree of peace. Numbers, however, declined; about 1150, the order had over 1200 members, but towards the beginning of the fourteenth century only 800. Moreover, a relaxation of the rule (1224) led finally to the cessation of all observance.

In 1317 Pope John XXII, sometimes said to have been a Grandmontine monk, issued the papal bull Exigente debito to save the order from complete destruction. Its organization was altered and certain mitigations were approved. The number of houses was reduced from 149 to 39. The prior of Grandmont was made an abbot, and the superiors of the dependent houses, who had hitherto been known as "Correctors", were for the future to bear the title of Prior. The Abbot of Grandmont was to be elected by his own community, and not, as before, by the deputies of the whole order. A general chapter, to be attended by the prior and one monk from each dependent house, was to be held annually.

These vigorous measures brought about a slight recovery, but in spite of the vigilance of the Holy See and the good administration of the first abbots, the improvement was of short duration. The order suffered severely during the Hundred Years' War. From 1471 until 1579 Grandmont was held by commendatory abbots; shortly after the latter date there were only eight monks in the monastery. On one occasion, the abbey was seized by the Huguenots, but in 1604 these were expelled by Abbot Rigaud de Lavaur.

The Strict Observance
In 1643 Abbot Georges Barny (1635–1654) held a general chapter, the first for 134 years, at which Charles Frémon was authorised to found the Strict Observance of the Order of Grandmont. This new branch, which remained under the jurisdiction of the abbot, was conspicuous for the primitive austerity of its observance, but never numbered more than eight houses.

By the beginning of the eighteenth century the two Observances together numbered only about 150 members, but the quarrels were as frequent and as bitter as ever. Grandmont was one of the first victims of the Commission des Réguliers. The monks of the Strict Observance were dispersed in 1780, but the struggle for existence was prolonged until 1787, when the last abbot died. The monastery was finally destroyed at the beginning of the nineteenth century, and nothing but a few fragments of wall now remains.

Legacy
Apart from a number of lives of St. Stephen, the most important work issuing from Grandmont was Gérard Ithier's treatise "De institutione novitiorum"—a favourite spiritual work in the Middle Ages, usually but erroneously attributed to Hugh of St. Victor.

The original habit of Grandmont was a coarse tunic with scapular and hood, brown in the early days but changed later to black. The monks gradually laid aside the humble scapular and hood in favour of rochet and biretta. The original habit was resumed by the Strict Observance. The founder had expressly forbidden the reception into the order of houses of religious women, nevertheless four small monasteries of women in the Diocese of Limoges were admitted.

Outside France the order only possessed five houses: two in Navarre (Spain) and three cells in England up to the middle of the 15th century. These latter were Alberbury, Craswall and Grosmont Priories, and as usual in Grandmontine monasteries, were occupied by a very small number of monks.

Later centuries witnessed mitigations and reforms in the life, and at last the order was suppressed just before the French Revolution. In 1979 the former Grandmontine priory of Sainte-Trinité de Grandmont of Villiers was to become the home of a small group intent on restoring the Grandmontine life style; with the permission of the local bishop they began to attempt the restoration of the principles of S. Stephen's monastic life, in the modern world.(Hutchison, Carole A.)

The Grandmontines featured in an episode of the popular BBC TV drama Bonekickers entitled Army of God.

title: Grandmontines


text: User talk:138.88.150.236

title: User talk:138.88.150.236


text:
Thymidine kinase

Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:
 * Thd + ATP → TMP + ADP

where Thd is (deoxy)thymidine, ATP is adenosine triphosphate, TMP is (deoxy)thymidine monophosphate and ADP is adenosine diphosphate. Thymidine kinases have a key function in the synthesis of DNA and therefore in cell division, as they are part of the unique reaction chain to introduce thymidine into the DNA. Thymidine is present in the body fluids as a result of degradation of DNA from food and from dead cells. Thymidine kinase is required for the action of many antiviral drugs. It is used to select hybridoma cell lines in production of monoclonal antibodies. In clinical chemistry it is used as a proliferation marker in the diagnosis, control of treatment and follow-up of malignant disease, mainly of hematological malignancies.

History
The incorporation of thymidine in DNA was demonstrated around 1950. Somewhat later, it was shown that this incorporation was preceded by phosphorylation, and, around 1960, the enzyme responsible was purified and characterized.

Classification
Two different classes of thymidine kinases have been identified and are included in this super family: one family groups together thymidine kinase from herpesvirus as well as cellular thymidylate kinases, the second family groups TK from various sources that include, vertebrates, bacteria, the bacteriophage T4, poxviruses, African swine fever virus (ASFV) and Fish lymphocystis disease virus (FLDV). The major capsid protein of insect iridescent viruses also belongs to this family. The Prosite pattern recognizes only the cellular type of thymidine kinases.

Isozymes
Mammals have two isoenzymes, that are chemically very different, TK1 and TK2. The former was first found in fetal tissue, the second was found to be more abundant in adult tissue, and initially they were termed fetal and adult thymidine kinase. Soon it was shown that TK1 is present in the cytoplasm only in anticipation of cell division (cell cycle-dependent), whereas TK2 is located in mitochondria and is cell cycle-independent. The two isoenzymes have different reaction kinetics and are inhibited by different inhibitors.

The viral thymidine kinases differ completely from the mammalian enzymes both structurally and biochemically and are inhibited by inhibitors that do not inhibit the mammalian enzymes. The genes of the two human isoenzymes were localized in the mid-1970s. The gene for TK1 was cloned and sequenced. The corresponding protein has a molecular weight of about 25 kD. Normally, it occurs in tissue as a dimer with a molecular weight of around 50 kD. It can be activated by ATP. After activation, is a tetramer with a molecular weight around 100 kD. However, the form of enzyme present in the circulation does not correspond to the protein as encoded by the gene: the main fraction of the active enzyme in the circulation has a molecular weight of 730 kD and is probably bound in a complex to other proteins. This complex is more stable and has a higher specific activity than any of the lower molecular weight forms.

Recombinant TK1 cannot be activated and converted to a tetramer in this way, showing that the enzyme occurring in cells has been modified after synthesis.

TK1 is synthesized by the cell during the S phase of cell division. After cell division is completed, TK1 is degraded intracellularly and does not pass to body fluids after normal cell division. There is a feed-back regulation of the action of thymidine kinase in the cell: thymidine triphosphate (TTP), the product of the further phosphorylation of thymidine, acts as an inhibitor to thymidine kinase. This serves to maintain a balanced amount of TTP available for nucleic acid synthesis, not oversaturating the system. 5'-Aminothymidine, a non-toxic analogue of thymidine, interferes with this regulatory mechanism and thereby increases the cytotoxicity of thymidine analogues used as antineoplastic drugs. The reaction kinetics of thymidine and thymidine analogues phosphorylation is complicated and only partly known. The overall phosphorylation of thymidine to thymidine triphosphate does not follow Michaelis-Menten kinetics, and the various phosphates of thymidine and uridine interfere with the phosphorylation of each other. The kinetics of TK from different species differ from each other's and also the different forms from a given species (monomer, dimer, tetramer and serum form) have different kinetic characteristics.

Genes for virus specific thymidine kinases have been identified in Herpes simplex virus, Varicella zoster virus and Epstein-Barr virus.

+ ATP → + ADP

Thymidine reacts with ATP to give thymidine monophosphate and ADP.

Function
Thymidine monophosphate, the product of the reaction catalyzed by thymidine kinase, is in turn phosphorylated to thymidine diphosphate by the enzyme thymidylate kinase and further to thymidine triphosphate by the enzyme nucleoside diphosphate kinase. The triphosphate is included in a DNA molecule, a reaction catalyzed by a DNA polymerase and a complementary DNA molecule (or an RNA molecule in the case of reverse transcriptase, an enzyme present in retrovirus).

Thymidine monophosphate is also produced by the cell in a different reaction by methylation of deoxyuridine monophosphate, a product of other metabolic pathways unrelated to thymidine, by the enzyme thymidylate synthase. The second route is sufficient to supply thymidine monophosphate for DNA repair. When a cell prepares to divide, a complete new set-up of DNA is required, and the requirement for building blocks, including thymidine triphosphate, increases. Cells prepare for cell division by making some of the enzymes required during the division. They are not normally present in the cells and are downregulated and degraded afterwards. Such enzymes are called salvage enzymes. Thymidine kinase 1 is such a salvage enzyme, whereas thymidine kinase 2 and thymidylate synthase are not cell cycle-dependent.

Deficiency
Thymidine kinase 2 is used by the cells for synthesis of mitochondrial DNA. Mutations in the gene for TK2 lead to a myopathic form of mitochondrial DNA depletion syndrome. Another reason for TK 2 deficiency may be oxidative stress induced S-glutathionylation and proteolytic degradation of mitochondrial thymidine kinase 2. No syndrome caused by TK1 deficiency is known, probably as a defective TK1 gene would lead to fetal death.

Thymidine kinase during development
The formation of tetramer after modification of thymidine kinase 1 after synthesis enhances the enzyme activity. It has been suggested that this is a mechanism for regulation of the enzyme activity. The formation of tetramers is observed after the Dictyostelium development stage. Its use for fine regulation of DNA synthesis is suggested to have been established in warm blooded animals after they branched out from the vertebrates. Also the development of thymidine kinase like enzymes in the development has been studied.

Species distribution
Thymidine kinase is present in animals,      plants,  some bacteria, archeans   and virus. The thymidine kinases from pox viruses, African swine fever virus, Herpes simplex virus,        Varicella zoster virus and   Epstein- Barr virus have been identified and to a varying degree characterized. The enzyme form in virus is different from that in other organisms. Thymidine kinase is not present in fungi.

Identification of dividing cells
The first indirect use of thymidine kinase in biochemical research was the identification of dividing cells by incorporation of radiolabeled thymidine and subsequent measurement of the radioactivity or autoradiography to identify the dividing cells. For this purpose tritiated thymidine is included in the growth medium. In spite of errors in the technique, it is still used to determine the growth rate of malignant cells and to study the activation of lymphocytes in immunology.

PET scan of active tumors
Fluorothymidine is a thymidine analog. Its uptake is regulated by thymidine kinase 1, and it is therefore taken up preferentially by rapidly proliferating tumor tissue. The fluorine isotope 18 is a positron emitter that is used in positron emission tomography (PET). The fluorine-18 radiolabeled fluorothymidine F-18 is therefore useful for PET imaging of active tumor proliferation, and compares favorably with the more commonly used marker fludeoxyglucose (18F). A standardized protocol that will help comparison of clinical studies has been suggested.

Selection of hybridomas
Hybridomas are cells obtained by fusing tumor cells (which can divide infinitely) and immunoglobulin-producing lymphocytes (plasma cells). Hybridomas can be expanded to produce large quantities of immunoglobulins with a given unique specificity (monoclonal antibodies). One problem is to single out the hybridomas from the large excess of unfused cells after the cell fusion. One common way to solve this is to use thymidine kinase negative (TK−) tumor cell lines for the fusion. The thymidine kinase negative cells are obtained by growing the tumor cell line in the presence of thymidine analogs, that kill the thymidine kinase positive (TK+) cells. The negative cells can then be expanded and used for the fusion with TK+ plasma cells. After fusion, the cells are grown in a medium with methotrexate or aminopterin that inhibit the enzyme dihydrofolate reductase thus blocking the de novo synthesis of thymidine monophosphate. One such medium that is commonly used is HAT medium, which contains hypoxanthine, aminopterin and thymidine. The unfused cells from the thymidine kinase-deficient cell line die because they have no source of thymidine monophosphate. The lymphocytes eventually die because they are not "immortal." Only the hybridomas that have "immortality" from their cell line ancestor and thymidine kinase from the plasma cell survive. Those that produce the desired antibody are then selected and cultured to produce the monoclonal antibody. Hybridoma cells can also be isolated using the same principle as described with respect to another gene the HGPRT, which synthesizes IMP necessary for GMP nucleotide synthesis in the salvage pathway.

Study of chromosome structure
Molecular combing of DNA fibers can be used to monitor the structure of chromosomes in the budding yeast Saccharomyces cerevisiae. This provides DNA replication profiles of individual molecules. This requires that the yeast strains express thymidine kinase, which wild type yeasts do not, being fungi (see occurrence). Therefore, a gene for thymidine kinase must be incorporated in the genome.

Clinical chemistry
Thymidine kinase is a salvage enzyme that is only present in anticipation of cell division. The enzyme is not set free from cells undergoing normal division where the cells have a special mechanism to degrade the proteins no longer needed after the cell division. In normal subjects, the amount of thymidine kinase in serum or plasma is therefore very low. Tumor cells release enzyme to the circulation, probably in connection with the disruption of dead or dying tumor cells. The thymidine kinase level in serum therefore serves as a measure of malignant proliferation, indirectly as a measure of the aggressivity of the tumor.

Therapeutic applications
Some drugs are specifically directed against dividing cells. They can be used against tumors and viral diseases (both against retrovirus and against other virus), as the diseased cells replicate much more frequently than normal cells and also against some non-malignant diseases related to excessively rapid cell replication (for instance psoriasis). It has been suggested that the antiviral and anti-cancer activity of thymidine analogues is, at least partly, achieved by down-regulation of mitochondrial thymidine kinase.

Cytostatics
There are different classes of drugs directed against thymidine metabolism and thereby involving thymidine kinase that are used to control cancer associated cell division. Chain terminators are thymidine analogues that are included in the growing DNA chain, but modified so that the chain cannot be further elongated. As analogs of thymidine, this type of drugs are readily phosphorylated to 5'-monophosphates. The monophosphate is further phosphorylated to the corresponding triphosphate and incorporated in the growing DNA chain. The analog has been modified so that it does not have the hydroxyl group in the 3'-position that is required for continued chain growth. In zidovudine (AZT; ATC:J05AF01) the 3'-hydroxyl group has been replaced by an azido group, in stavudine (ATC: J05AF04) it has been removed without replacement. AZT is used as substrate in one of the methods for determination of thymidine kinase in serum. This implies that AZT interferes with this method and may be a limitation: AZT is a standard component of HAART therapy in HIV infection. One common consequence of AIDS is lymphoma and the most important diagnostic application of thymidine kinase determination is for monitoring of lymphoma.

Other thymidine analogues, for instance Idoxuridine (ATC: J05AB02) act by blocking base pairing during subsequent replication cycles, thereby making the resulting DNA chain defective. This may also be combined with radioactivity to achieve apoptosis of malignant cells.

Antivirals
Some antiviral drugs, such as acyclovir (ATC: J05AB01) and ganciclovir (ATC: J05AB06) as well as other nucleoside analogs make use of the substrate specificity of viral thymidine kinase, as opposed to human thymidine kinases. These drugs act as pro-drugs, which in themselves are not toxic, but are converted to toxic drugs by phosphorylation by viral thymidine kinase. Cells infected with the virus therefore produce highly toxic triphosphates that lead to cell death. Human thymidine kinase, in contrast, with its more narrow specificity, is unable to phosphorylate and activate the prodrug. In this way, only cells infected by the virus are susceptible to the drug. Such drugs are effective only against viruses from the herpes group with their specific thymidine kinase. In patients treated with this type of drugs, the development of antiviral drug resistance is frequently observed. Sequencing the thymidine kinase gene in Herpes simplex virus and Varicella zoster virus shows the rapid genetic variability and may facilitate the diagnosis of antiviral drug resistance.

After smallpox was declared eradicated by WHO in December 1979, vaccination programs were terminated. A re-emergence of the disease either by accident or as a result of biological warfare would meet an unprotected population and could result in an epidemic that could be difficult to control. Mass vaccination to combat a smallpox epidemic could be challenging because the only approved smallpox vaccine, Vaccinia Virus, can have severe side effects. Nevertheless, some governments stockpile Smallpox vaccine to insure against the possibility. However, the development of specific and effective antiviral drugs is prioritized. One possible approach would be to use the specificity of the thymidine kinase of poxvirus for the purpose, in a similar way that it is used for drugs against herpesvirus. One difficulty is that the poxvirus thymidine kinase belongs to the same family of thymidine kinases as the human thymidine kinases and thereby is more similar chemically. The structure of poxvirus thymidine kinases has therefore been determined to find potential antiviral drugs. The search has, however, not yet resulted in a usable antiviral drug against poxviruses.

As a "suicide gene" in gene therapy
The herpesvirus thymidine kinase gene has also been used as a "suicide gene" as a safety system in gene therapy experiments, allowing cells expressing the gene to be killed using ganciclovir. This is desirable in case the recombinant gene causes a mutation leading to uncontrolled cell growth (insertional mutagenesis). The cytotoxic products produced by these modified cells may diffuse to neighboring cells, rendering them similarly susceptible to ganciclovir, a phenomenon known as the "bystander effect." This approach has been used to treat cancer in animal models, and is advantageous in that the tumor may be killed with as few as 10% of malignant cells expressing the gene. A similar system has been tried using tomato thymidine kinase and AZT. In addition, thymidine kinase gene is used as a suicide gene to tackle dangerous graft-versus-host disease in hematopoietic stem cell transplant therapy named Zalmoxis that was conditionally approved in Europe in 2016

Tumor marker genes
A similar use of the thymidine kinase makes use of the presence in some tumor cells of substances not present in normal cells (tumor markers). Such tumor markers are, for instance, CEA (carcinoembryonic antigen) and AFP (alpha fetoprotein). The genes for these tumor markers may be used as promoter genes for thymidine kinase. Thymidine kinase can then be activated in cells expressing the tumor marker but not in normal cells, such that treatment with ganciclovir kills only the tumor cells. Such gene therapy-based approaches are still experimental, however, as problems associated with targeting the gene transfer to the tumor cells have not yet been completely solved.

Neutron capture therapy for tumors
Incorporation of a thymidine analogue with boron has been suggested and tried in animal models for boron neutron capture therapy of brain tumors. A very extensive number of thymidine derivatives containing boron have been described.

Antiparasitics
The protozoan parasite Giardia intestinalis lacks thymidylate synthase and compensates that by having a high-affinity thymidine kinase in order to efficiently use thymidine that it takes up from the surrounding environment. This makes the parasite sensitive to thymidine analogues such as zidovudine (AZT), which when phosphorylated by the enzyme effectively inhibits parasite proliferation in vitro and also looks promising as a antigiardial drug in infected rodents. The short treatment period needed (three days) reduces the risk of side effects as compared to the lengthy treatments when it was commonly used as an anti-HIV drug.

An alternative approach tested in Plasmodium falciparum (causing malaria) is the introduction of a TK gene in the parasite genome. This makes the parasite sensitive to BrdU treatment and also constitutes a sensitive indicator of replication of the parasite genome.

In serum and plasma
Thymidine kinase levels in serum or plasma have been mostly measured using enzyme activity assays. In commercial assays, this is done by incubation of a serum sample with a substrate analog and measurement of the amount of product formed. Direct determination of the thymidine kinase protein by immunoassay has also been used. The amounts of thymidine kinase found by this method does not correlate well with the enzyme activities. One reason for this is that a large amount of serum TK1 identified by immunoassay is not enzymatically active. This is particularly the case with solid tumors where immunoassays may be more sensitive.

In tissue
Thymidine kinase has been determined in tissue samples after extraction of the tissue. No standard method for the extraction or for the assay has been developed and TK determination in extracts from cells and tissues have not been validated in relation to any specific clinical question, see however Romain et al. and Arnér et al. A method has been developed for specific determination of TK2 in cell extracts using the substrate analog 5-Bromovinyl 2'-deoxyuridine. In the studies referred to below the methods used and the way the results are reported are so different that comparisons between different studies are not possible. The TK1 levels in fetal tissues during development are higher than those of the corresponding tissues later. Certain non-malignant diseases also give rise to dramatic elevation of TK values in cells and tissue: in peripheric lymphocytes during monocytosis and in bone marrow during pernicious anemia. As TK1 is present in cells during cell division, it is reasonable to assume that the TK activity in malignant tissue should be higher than in corresponding normal tissue. This is also confirmed in most studies.

Immunohistochemical staining
Antibodies against thymidine kinase are available for immunohistochemical detection. Staining for thymidine kinase was found to be a reliable technique for identification of patients with stage 2 breast carcinoma. The highest number of patients identified was obtained by combination of thymidine kinase and Ki-67 staining. The technique has also been validated for lung cancer, for colorectal carcinoma, for lung cancer and for renal cell carcinoma.

Fluorescent staining
2'-deoxy-2',2'-difluoro-5-ethynyluridine (dF-EdU) binds to Herpes simplex virus thymidine kinase but, because of sterical hindrance, not to human thymidine kinase. This reagent together with a fluorescent azide cause fluorescence of infected cells but not of uninfected cells. Therefore, this substrate analog makes it possible to specifically stain infected cells.

title: Thymidine kinase


text:
Sorachi

Sorachi may refer: to one of two places on
 * The Sorachi Subprefecture on the island of Hokkaidō, Japan
 * Sorachi District, Hokkaido on the island of Hokkaidō, Japan, which is divided between the Sorachi Subprefecture and the Kamikawa Subprefecture
 * Hideaki Sorachi, the author of the Gintama manga series
 * The 16594 Sorachi main-belt asteroid
 * Sorachi Ace hops for flavouring beer

title: Sorachi


text: User talk:128.193.171.229

title: User talk:128.193.171.229


text:
River Culm

The River Culm flows through the Devon Redlands in Devon, England and is the longest tributary of the River Exe. It rises in the Blackdown Hills at a spring near RAF Culmhead in Somerset, and flows west through Hemyock, then Culmstock (in the Culm Valley) to Uffculme. The river turns south, through Cullompton (and alongside the M5 motorway), skirting the northern boundary of Killerton Park to join the River Exe on the north-western outskirts of Exeter. The name of the river is thought to mean 'knot' or 'tie', in reference to the river's twists and loops.

Course of the river
The River Culm begins in a marshy field near Culmhead (picture 1). Four and a half miles from its source the river (OS ST17501455) is 1.5m wide (picture 2). At Gladhayes the river passes under a two-arched bridge (picture 3). About half a mile further the river is joined by the waters of Madford River. From here the river continues to Culmstock, a village straddling both sides of the river where the river is shallower. At Uffculme the river flows in a straight course and flows more slowly. The Spratford Steam, whose waters have flowed in a southerly direction, meets the Culm near Willand, and thereafter the river shares its valley with the present main railway line (former Great Western Railway) from Taunton to Exeter. The M5 motorway runs beside the railway, and all three continue past the market town of Cullompton. The river meanders a lot here and is prone to flooding. Shortly prior to reaching Hele - near Kensham House - the small River Weaver flows into the Culm from the east. It passes under a paper mill at Hele. North of Stoke Canon the river has many meanders. Shedding the motorway to the south of Hele, the river and the railway continue together into Exeter, although by then the Culm has joined the River Exe - just below Stoke Canon (picture 4).

The Culm in literature
The novel Perlycross by R.D. Blackmore is based on the Upper Culm Valley. Perlycombe is Hemyock, Perlycross is Culmstock and Perliton is Uffculme.

Perlycombe, Perlycross and Perliton, are but as three pearls on one string, all in a line, and contiguous. The string is the stream; which arising at the eastern extermity of Perlycombe parish, passes through the village, then westward through Perlycross, and westward still through the much larger village of Perliton. At Perlycombe it is a noisy little brook, at Perlycross, a genial trout stream; while Perliton, by the time it gets there, entitles it "the River Perle" and keeps two boats upon it, which are not always more aground than landsmen should desire.

title: River Culm