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rainydaysmastiffs

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Reply with quote  #51 

And for people to follow through with the tests every time there's a clinic or to donate blood on dogs for further studies if they do come back postive.


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Reply with quote  #52 
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But at this time it is better then nothing.  All we can do is test, test, test and hope and pray they come up with a DNA marker soon.


I do very much agree with this.  I am curious how many at this time (and I'm sure many won't answer) will use this test as they do a hip or elbow test, when they might receive a C+ , change the diet and then receive a C-   Will they not breed or will they experiment to find out if it really was C+ or a dietary factor....

I do hope that this DNA comes soon so that the testing is more refined and the answers more concrete.

I remember when I first read these boards and there was much talk about PPM's.  I thought it was the plague in mastiffs and after study and reading perspectives I no longer feel that way.  Not faced with that issue in our breeding line I am currently unaffected by it but at one time there were discussions that paralleled the Cystinuria discussions. 

My mind is always open and I do believe in testing.... very important!

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Reply with quote  #53 
Hey guys, I really hate to be the one pointing this out, but blind faith should only be given to God.  LOL  UPENN has just admitted to someone that giving their dog 100 mg of cystine a day will definately cause a FALSE POSITIVE(assuming the dog is around 200 lbs, 10 mg of cystine per pill and one pill for every 20 pounds).  How much cystine is in and created by a whole chicken?  I know that most dogs live on a prepared food of some kind, but there are many people out there that feed their dogs several whole chickens a day. That is known to be very high in cystine and cystine producers.
     There seems to be a little confusion on whether any cystine should ever be present in urine or not.  The simple answer, to my understanding, is YES, not no as we are often lead to believe.  A dog is not metabolically lacking for having any cystine in his urine ever.  He only has a true/possibly inheritable condition when he cannot filter out a NORMAL amount of cystine.
     OK, now I am gonna have to let out a little true emotion here.  Although I certainly DO respect the people and work being done with cystinuria, we are beating our heads on the wall by continuing to test in the same manner for 10 years, and expecting different results.  Honest to goodness, that is one criteria used for judging sanity....  Repeating the same thing over and over, while expecting a different result is, by definition, insanity.  The testing method must be improved.  Forget how unreliable the test is at this point, the method itself is self deprecating.
     Cystinuria is not diagnosable simply by a dog having cystine in it's urine.  It is a naturally occuring event that happens any time the body produces(by ingesting too much causative material) or takes in more raw cystine than it can eliminate.  Saying otherwise is misleading of the researchers.  Especially when they are now admitting ways in which false positives can be created. 
     In order for ANY scientific study to hold any merit certain protocols MUST ALWAYS be adhered to.  We should NOT be testing for the mere presence of cystine, but the level a dog is able to process in a given time frame. 
     It is, or at least should be, very easy to determine a normal level.  If they would just use as few as 20 volunteers to eat the same diet with a high cystine level, measure the levels, take away food for 1 day and test them all again the same time frame later, we would be able to easilly see the rate at which the average mastiff filters out cystine.  We could then test all of our dogs in the same way and KNOW for certain whether they are normal or not. 
     Please do not get me wrong, I would certainly cringe at any dog testing positive, but given the right circumstances, like a dog living on a diet truly high in cystine and cystine producers, I feel(and evidently even UPENN now admits), that a false positive is not only likely, but predictable since there is a limit to how much cystine even a normal functioning dog can filter out. 
     When any mammal ingests too much of virtually anything, it is always excreted out in urine and sweat.  Maybe some of you guys that are still talking to them reguarly can ask them why they are not persuing this from another angle after 10 years.  Ask them point blank how much cystine a normal dog can filter out in a day.  If they answer with a definative answer, then ask them why they are not measuring that instead of arbitrary and random samples.  If they can't even give us an answer to how much a normal dog can filter out, then ask them why they have not done this control study yet.  How can they perform any kind of research without a true or at least valid and pertinent control group. 
     Sorry to ramble again.  They may have already done this and it is just not common knowledge or something I cannot forsee has prevented their ability to do this.  I hope that the former is true and could definately understand the latter happening.  If it is not either one of them however, it starts looking pretty bad.  Either it has not been thought of yet and a simple minded breeder from Kentucky has thought of a potentially better scientific method that they have not tried or the research has been stalled for other reasons....  I am not a conspiracy theorist, but I do know that following a money trail often leads to the right answers to some often not thought of questions.  We DESERVE the right to know the truth about how effective these people are being with their research when they are accepting our money too.
  I truly do understand that UPENN is the best we have at this time.  If they have not taken the time to do the basics though, we are nowhere.  For heaven's sake, we could probably get a dozen people here to participate in our own study by putting them on the urine spot supplement for one day, eliminate the food for 24 hours, monitor/notate their water consumption and send samples from their next 5 urinations, with the time elapsed from initial ingestation.  Any clinical chemistry lab can test cystine levels in urine.  Any of them.  Why do we not have those values?  Again, just my thoughts. 

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rainydaysmastiffs

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Reply with quote  #54 
Chris,
You have brought us some very valid points and we were reticent on bringing out these findings while they did some more research on what this means to the Mastiff community, but now it's been 4 months and we have not heard of any changes in the process of how they are handling the collection of information (or urine for that matter).

Keep in mind, though, that it is not just the 100 mg of cystine that may be the problem.  It may very well be the methionine that pushes the dog over the top.

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Reply with quote  #55 
Chris,
You have brought out some very good points.  As I understand it UPENN has now switched their research to try and find out how diet effects cystinuria.  I know 10 yrs is a long time to wait for answers but we have blindly been following OFA's recommendations for 40 yrs.  While all the time exposing our dogs to radiation, which by the way can cause mutation of gene's.  Then we wonder why cancer is on the rise in our dogs.  Again, it is all we have at the time.  The DNA marker for PRA was found by a private research lab, is this the way to go?  I don't know!

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Reply with quote  #56 

I would definately recommend a private lab if they will follow proper protocols.  Wow, a one line response.  That is odd for me....  LOL 


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Reply with quote  #57 

Anita, I agree.  From my understanding, what you say is correct.  


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Reply with quote  #58 
What exactly is the test for cystinuria? It should be quantitative - but it must not be? The Merck Vet Manual says that 97% of cystine is reabsorbed.. so 3% goes in the urine. It would seem like you could get a false positive depending on diet. To take out the food aspect, why not have the dogs fasted before collecting the urine?
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Reply with quote  #59 

Because that would be too easy???.... LOL 

Find the norm level and all dogs could be easilly tested.  I would think...

Granted, eliminating cystine entirely would give everyone false negatives, but we could test that way if they were given the same diet.


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Reply with quote  #60 

Simply testing for a certain amount of cystine cannot work.  A basic testing of the level can and will show the same result in two dogs with different intake levels of cystine if their ability to process is inversely proportionate.  One can be positive and the other negative, but the test results would show the same for both.


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Reply with quote  #61 

Simply testing for a certain amount of cysteine cannot work

HI :>)
Oh Lord :>)  OK Here i go again .I feel Anna May said it all :>)
And very scientifically,as she always does :>)

I'm not that good at explaining  things :>)  So here goes ,the world according to Marge ,on Cystinuria :>)

I think UPENN does know how much Cysteine ,should be in the urine of a dog .

And ITHINK ,that's how they measure, If the Dog has Cystinuria .

If it has more than it should have , the dog is not getting it out of His system ,fast enough ,

Now I know the test is a weak one by far ,but that's all we got folks

And i myself ,if i had a Mastiff come back Positive ,he would no longer be used as a stud ,If he was one of the most , wanted studs out there ,He would be frozen ,and id wait for a DNA test ,to come .

I would not breed to any Mastiff, if i knew it was in ,His line And he was clear.

If I had a Bitch that threw ,positive off springs ,she would be fixed .
And i would push to have all off springs fixed and never bred .

If i had a Bitch that came from a Bitch that threw a positive ,she would never be bred .

I know its a hardship and a heart break ,for those that have out standing Mastiffs ,and have had this in their lines to start over .

But that's what i would do ,id start with a new Bitch ,and go from there .

If you have a litter and its in the lines , then sell on a limited regertration

Until we find out something more positive .Other wise we will not have any Mastiffs too breed to ???

Its up to us on how and what we breed ,and what will be passed on to the future of the breed . Hell they already have enough problems ,but none that are as costly as this

Untill its all been settled ,on how and when they get it .I guess we will have to go with what we have . And play by those rules ??

I know some one said to me ,that it was not a death sentence ?

Well if i had to pay 600.00 a month too keep a Dog going ,and if he needed the surgery ,that would probly be 1500.00 or more ,and still need the meds .

It would be a death sentence for my Dog . I could not afford that .

I feed the top food ,i go to the best Vets ,But i could not afford 600,00 month  for my Mastiff .

And thats the plain truth ,You start out buying a  show pup . Your dreams are  to have the top stud dog out there .
Costs a lot of money too just do that :>)  You do all the testing .
Again a lot of money , then you find out, He has Cystinuria !

And he is a stone former , Some one calulate  ,all the money that has been spent ,on said Dog ? And there is no amount of money that you can cover in Heart Ache

We test so we can breed ,and sell healthy Pups . So why breed C+ Im sure then its for the money ????

I know some say ,not all will be stone formers ,but they will carry the gene .

I know im as long winded as Chris Im sorry
Marge

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Reply with quote  #62 

Hi Marge.  I agree with how you feel cystinuria should be handled at this stage.  My aggrevation with the testing method is where I have issues.  At this time, dogs tested positive for cystinuria in the U.S. should not be bred(unless it is done with the intent to help the research in some way).  I am not advocating anything else.  Please do not confuse my aggrevation and concerns with the current method/testing for an excuse to breed C+ dogs.  The sad part is however, that with the current systems in place, there will probably be some very nice mastiffs passed up on, which only hurts the breed, because the testing is so easilly fallable at this time.  It is safer to avoid a dog when red flags come up than to use it.  I just hate to know that some very nice and therefor valuable, breeding stock will inevitably be lost from the gene pool because of the current protocols in use.  Once again, PLEASE do not confuse my doubts about the methods in place as an advocation of treating it any differently.  That is really why it ticks me off so much.  We still HAVE to treat it in that manner and eliminate some good stock from our choices because the test and methods are so poor.  Good thoughts and points made Marge. 


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Reply with quote  #63 
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The sad part is however, that with the current systems in place, there will probably be some very nice mastiffs passed up on, which only hurts the breed, because the testing is so easilly fallable at this time.  It is safer to avoid a dog when red flags come up than to use it.  I just hate to know that some very nice and therefor valuable, breeding stock will inevitably be lost from the gene pool because of the current protocols in use.


Its not just that the test is fallible Chris..its that there is so much wrong information being stated by various people and confusing 'communications' from UPenn themselves about cystinuria, which might not even be 'true' cystinuria in mastiffs.
The reality is;
-After 10 yrs UPenn know nothing, or rather, only know what its not. They
 know its not the same metabolic disorder as other breeds, they know its not
 the same gene responsible, they know it dosn't follow simple mode
 of inheritance patterns.
-of the thousands of tests done over 10 yrs about 100 dogs have gone on to
 form stones (according to Gieger at UPenn). 
-if collected properly the test only screens for cystine in the urine and I
 am not sure if that includes the 'allowable 3%",  which then only identifies
 a risk of developing uroliths..it does not confirm a diagnosis of cystinuria.
-until they actually know more...for those of us in other countries getting 
 the urine spun down routinely by a local vet is probably a good option (I've
 done this already with teddy since he was a pup)    
-many dogs may have tested pos simply because of their diet
-even if a breeder tests, they can't say their dogs are 'clear' and any
 line where there has been a pos reading anywhere puts up a red flag, fingers
 are pointed etc..paranoia ensues..
maybe they have other information I don't or something.

For now I think the sensible thing to do is to take Marguerite Perrenouds mothers' and Dr Newmans advice anyway and keep all chicken out of my dogs diets, just in case, and do a bit of research on which foods are high in methionine.  

Chris..your idea to find out what normal cystine levels are for a mastiff is a good one..any thoughts about getting that going somehow?

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Reply with quote  #64 
Ahh man.  I was afraid I was gonna get stuck with that when I was posting.  LOL  I have so much going on in other areas right now that I really did not want to go there at this particular point in time.  I guess we can work on that though.  It may be a bit above my pay grade to do, but we can do it I am sure. 

     How many of you reading this post have adult males that are willing to contribute to a study like this?  It will be more complicated than my much abbreviated scenarios earlier, but we should be able to find the upper limit norm for the amount that can be filtered out with specific diets with a LOT of urine tests.  Some time and a fair amount of money for the tests will be required as well.  Individuals would have to send out and pay for their own tests to make this affordable.  We would probably be using local labs instead of labs at UPENN to save time/money.  If anyone would like to email me privately with your willingness to participate, feel free.  Before we make any kind of model for the survey or get down to it, because it is more complicated than it may seem, I would have to see enough interested people willing to go through this before we went forward with anything. 

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Reply with quote  #65 
place, there will probably be some very nice mastiffs passed up on, which only hurts the breed, because the testing is so easily fallable at this time.  It is safer to avoid a dog when red flags come up than to use it.  I just hate to know that some very nice and therefor valuable, breeding stock will inevitably be lost from the gene pool because of the current protocols in use.  Once again, PLEASE do not confuse my doubts about the methods in place as an advocation of treating it any differently.  That is really why it ticks me off so much.  We still HAVE to treat it in that manner and eliminate some good stock from our choices because the test and methods are so poor.  Good thoughts and points made Marge. 

HI Chris ,i agree with you :>)
I never meant to  imply that you wanted to breed a C+ dog :>)
Hope you know me better than that :>)


It is dissipointing  that we have no true test to use .

As i said in my former long winded post :>) If a Dog comes back positive ,and you feel he is a must ,for a breeding program .

Then freeze his sperm ,till something like a better test comes along ??

What else is there to do? They say Positive means positive , You can take a positive ,and retest ,and at that time ,he could be a negative ??

But the word is there is no false positives , Many breeders have tested every breeding they have ever done .

Pups were tested before they went to new homes . Well now we find we need to do them at least at 18 months ,and then every year there after .

I heard that some males are negative , and then around 7 yrs they come up positive ??

All we have is the tests we have now I don't breed ,and when i did it was not often ,I don't expect to breed Dyce ,hes 4 but i did have Him tested anyway :>)

All there is to say is test ?? As for your test breeding's ,i agree ,but i don't think ,they want to do that ,since it will take such a long time ,to find out if a male is positive ,from a test breeding

That's all we have Folks

Marge

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Reply with quote  #66 
Unfortunately I'm not usually able to spend very much time on message boards and once in a while look to see what's going on, but I guess I must miss a lot of interesting discussions around here.  I am so happy that so many of you have obviously been thinking seriously about all of this and I wish I could visit the message boards more often to hear what you have to say...

Michelle, I am so happy to hear that your C+ (previous stone former boy) is doing so well and has been stone free for so long with just a change in his diet and neutering.  That is exactly the type of information that UPenn needs to know as it may help them to understand the molecular puzzle of the disease.  "Maybe" neutering him caused a decrease in his hormones along with the decrease in protein in his diet and the increase of the fluid it all helped him to stop forming the stones...  I have heard of another C+ dog that after being neutered has been testing C-.  We need info like this to pass on to the researchers to help them figure out the puzzle.

Also, the input from others has led to UPenn doing a diet study with Mastiffs and other breeds, so that is very exciting!

I was in contact with Angie and Dr. Giger and they prepared a memo and protocol to determine the effects of our regularly used diets and supplements. Apparently some people are feeding their Mastiffs very high protein diets and supplements.

The last I heard, PennVet still thinks the C+ dogs can't appropriately reabsorb the cystine through their kidneys and if given larger amounts it's not getting reabsorbed and thus dumped into the urine.  I thought they were focusing on protein supplements, but it was never clarified what supplements they were focusing on...  Some of the C+ Barf fed dogs are doing the same thing.  When you put them on a standard, commercial kibble, they go on to test normal.  The theory is that a truly C- dog can handle the extra protein and cystine and reabsorb it by the kidneys.  A C+ dog has a defect in its kidneys and therefore cannot handle the extra cystine load which results in dumping of cystine and other amino acids (COLAs) into the urine. 

The way I understood Dr. Giger, he does not think these dogs are false positives, but the extra supplements are identifying C+ dogs that may have gone undetected if they had not been fed the extra protein &/or amino acids.  Based upon his experience with other breeds he thinks that truly C- dogs will not show excess cystine in the urine when fed the same diet &/or supplements.  Also, if I understood Dr. Giger correctly they are hoping their study of the diet/supplement effects may help in more sensitively detecting Mastiffs at risk of cystinuria and other breeds as well as potentially lead to effective therapy.

Thanks again and let us hope these new efforts will allow us further to detect and prevent cystinuria in Mastiffs!!

Anna

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Reply with quote  #67 

THANKS ANNA!!


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Reply with quote  #68 

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The last I heard, PennVet still thinks the C+ dogs can't appropriately reabsorb the cystine through their kidneys and if given larger amounts it's not getting reabsorbed and thus dumped into the urine.  I thought they were focusing on protein supplements, but it was never clarified what supplements they were focusing on...  Some of the C+ Barf fed dogs are doing the same thing.  When you put them on a standard, commercial kibble, they go on to test normal.  The theory is that a truly C- dog can handle the extra protein and cystine and reabsorb it by the kidneys.  A C+ dog has a defect in its kidneys and therefore cannot handle the extra cystine load which results in dumping of cystine and other amino acids (COLAs) into the urine. 



Well based on that 'theory', breeders could just feed their pups a standard kibble all their lives..never give them abnormal amounts of protein and they will not test positive..no excess cystine in the urine, no cystinuria...no problem.

So all these dogs are expected to be removed from the gene pool because they can metabolise normal levels of protein but cannot handle abnormal amounts of protein?

geez..I'm over it...


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Reply with quote  #69 

  Don't really know that this emoticon is relavent, but when I went looking for one that was and saw this one, relavent went out the window.  LOL  That is hillarious!  LOL 


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Reply with quote  #70 
Hi everyone, I'm coming out of "lurk" mode for a monster sized post - sorry in advance for the size.

First off, I feel that this has been a great discussion on a subject that not only affects breeders and owners of C+ dogs, but affects anyone who will possibly use a stud dog or buy a puppy in the future.  Therefore it affects almost ALL of us. 

The following is basically an amalgamation of notes I've taken off the net (mostly wikipedia), in my attempt to fully understand what is going on in both a normal Cystine/cysteine synthesis process, and what's going on when it's abnormal. (with the end result being C+ urine).  A scientific and completely objective approach must be taken.
 
In order to understand a disease, it’s important to know how the normal Cystine processing system works. It’s best to think of the whole process as a constant recycling of building materials.

So what exactly is Cystine? It is an important amino acid dimer, a pair of cysteine amino acids joined together by a disulfide bond.

Imagine each single cysteine amino acid as a building block with a big hand reaching out. This hand is composed of one Sulfur atom and one Hydrogen atom (-SH), this group referred to as a thiol group (or mercapton).

When the thiol groups of two cysteines get close to each other, the cysteines “hold hands” and combine their thiol groups together in in oxidation reaction, where the Hydrogen atom is given off and the Sulfur atoms form a bond (hence the term di-sulfide bond). This forms Cystine, a colorless solid.

This bonding action is what makes Cystine very important in biological functions. It is important in determining the tertiary (3D) structure of proteins. Imagine a bunch of these hand-holding cysteine amino acids (Cystines) coming together in folds and layers - the building blocks of proteins and tissues. Human hair is 5% Cystine. Kinks in curly hair are the result of many Cystine formations.

Side note - if you ever permed or relaxed your hair, you have taken advantage of the Cystine in your hair. Perm solutions use chemical oxidants to take out the extra Hydrogen atoms from loose cysteines, creating Cystines with disulfide bridges, and therefore more kinks in the hair. Chemical hair straighteners are reductant chemicals, adding an H atom and cutting those disulfide bridges in half, reducing the Cystine to cysteine and straightening the kinks in the hair.

Cystine isn’t produced in the body, it must be ingested, and this is the start of the recycling process. Cystine rich proteins such as those found in chicken, soy, whey protein from milk, eggs, etc enter the intestines where they are broken down. The Cystine is then transported through the intestinal wall through transporter proteins (think of them as gates in cell membranes) into the blood stream and sent to various cells of the body, where it is broken down into two cysteines, which can be used to build more Cystine. Think of it like a chop shop, in which protein arrives and it’s not exactly what you (the biological system) needs, so it’s taken apart (Cystine broken into cysteine), then the parts are reassembled elsewhere into a new form (new Cystines and new protein structures).

The "chop shop" inside the cells is referred to as the “SAM-e cycle”. SAM-e refers to the coenzyme S-adenosyl methionine, a derivative of the amino acid Methionine. In addition to recycling ingested Cystine into cysteine, the SAM-e cycle can biosynthesize Cystine into other useful materials such as more SAM-e and glutathione (which is actually used as a “preventive” to cysteine forming into Cystine when not needed.) The SAM-e process is a pretty complicated process that requires Methionine (another enzyme that must be ingested from protein sources) and adequate levels of Vitamin B (B9 (folic acid) B6 (pyridoxine) or B12 in order to work correctly. (Side note, SAM-e, S-adenosyl methionine is marketed as a supplement against depression, liver disease, and osteoarthritis.)

Methionine is ingested from protein sources such as fish, meat, sesame seeds, and brazil nuts. It is sometimes added as an ingredient to pet food.

Once the SAM-e cycle is done in the cells, any extra cysteine that wasn’t used is filtered through the blood system and into the kidneys, where a transporter protein (picture a gate in the kidney cell walls) takes the cysteine and puts it back into bloodstream, where it will be available again for any cells to use in their SAM-e cycles. This is the recycling process, the cysteine should always stay in this “closed loop“ system.

However, in both humans and dogs with genetic Cystinuria, there is a defect in the gene that codes for the transporter protein in the kidneys. The mutation is in genes SLC3A1 and SLC7A9. These “gates” aren’t built correctly, thus they don’t open correctly, and the cysteine is not absorbed back into the blood stream, it is lost into the bladder and out through the urine.

Cysteine still has that thiol group (SH) reaching out like a big hand. This is bad news, because it creates a tendency for the cysteines to group together as Cystines in the bladder and the urinary tract, thereby forming Cystine Stones. Drugs such as Thiola affect the thiol groups and keeps the cysteines from forming into disulfide bonded Cystine, and Penicillamine which actually bonds with the cysteines to form a mixed disulfide that is more soluble than Cystine.

Unbonded cysteine travels freely through the urinary tract and come out in the urine.

When Sodium Nitroprusside is added to urine containing cysteine, it reacts with the thiol groups and causes a color change, identifying the presence of cysteine.

C+, Cystinuria, which basically means “cysteine in the urine.”

This is where it gets interesting.

In the middle of that whole “recycling process” there is something produced during the SAM-e cycle called “homocysteine”. It is a homologue of cysteine, which means that it has the same functions and properties as cysteine, but also has a slight increase in mass due to an additional methyl group attached. It still has the functional thiol group SH (the big hand reaching out), so I believe a Sodium Nitroprusside test would be positive regardless of whether it’s cysteine or homocysteine in the urine. This would have to be verified with UPENN.

I haven’t been able to find out with internet research, but I believe that even a normal transporter protein system in the kidney would not accept homocysteine back into the bloodstream, and any homocysteine entering the kidney would always be filtered out as a waste? Again, UPENN might be able to verify that.

Think of homocysteine as the Mr. Hyde to cysteine’s Dr. Jekyl. Homocysteine is bad news. It’s only real function is that it is produced as a “step” in the SAM-e cycle, and it should never get out in the bloodstream in a normal system.

However, sometimes homocysteine does get out into the system, where it causes all kinds of trouble. It permanently degrades normal cysteine molecules by interfering with the cross linking of the disulfide bridges and gradually changing protein structures. It affects collagen fibers and the tissues they reinforce - fascia, cartilage, ligaments, tendons, bones, skin, cornea and lenses of the eyes. High blood serum levels of homocysteine are associated with hardening and narrowing of the arteries, high cholesterol, liver damage, possible alzheimers, increased risk of stroke and heart attack. In fact, before the age of 30, almost ¼ of homocystinuric patients die of heart attack.

So what exactly causes the homocystiene to “escape” the SAM-e process and enter the bloodstream? (also high levels of excretion in URINE) In humans, two things have been noted:

1. HOMOCYSTINURIA - A recessive genetic disorder caused by mutations of the genes CBS, MTHFR, MTR, and MTRR. This is a defect in the ability to properly metabolize methione in the SAM-e cycle.

Therefore instead of being a brief step in normal biosynthesis, homocysteine is a product that is released into the system. Physical abnormalities of humans born with genetic homocystinuria include:

Tall, thin build

Long limbs

Knock knees (aka VALGUS or bow legs)

90% have ectopia lentis (subluxated or luxated lenses in the eye, causes cataract formation)

(side note - ectopia lentis is a recessive disorder in Tibetan terriers and sChinese sharpeis, also seen in various other breeds)

People with genetic homocystinuria are advised to have a diet low in protein and methionine.

High doses of Vitamin B6 (pyridoxine) is recommended to balance sodium and potassium and decrease formation of homocysteine.

Some need treatment with TMG (trimethylglycine) which functions closely with folic acid, B12, and SAM-e. TMG can serve as the methyl donor (instead of methionine) and once it gives up a methyl group it becomes DMG (diethylglycine), which inhibits the formation of homocysteine.

Side note : Betaine HCL is the chloride salt of TMG and used as a dietary aid. TMG paired with lysine is used by the ton in livestock farming to increase muscle mass and carcass weight.

2. INDADEQUETE DIETARY LEVELS OF THE B VITAMINS - when there aren’t enough folates/B vitamins in the SAM-e cycle, the whole process is disrupted and homocysteines are produced.

 

So yes, homocystinuria can be a genetic disease, OR it can be caused by a dietary inefficiency of B Vitamins.

http://en.wikipedia.org/wiki/Homocysteine

Therefore, I think it’s important to find out from Upenn whether the Nitro Prusside test can differentiate between cysteine and homocysteine in the urine.

If not, the mastiff community and scientists need to work together to look at all possible causes of cysteine or homocysteine in the urine.

Here are some questions and scenarios that we may want to investigate:

1. Have any mastiffs ever tested positive at a very young age and continued to test positive throughout their lives? This would make me think that these individuals have true cystinuria (like Newfs), a genetic disorder of the kidney transporter genes, whether it be SLC3A1 and SLC7A9, or a gene that hasn’t been found yet.

2. Is there any possible way that a complete overload of cystine in the diet would overload a genetically normal kidney and cause excess cysteine to spill into the urine? This is one of the questions that I’ve heard people asking often, has it ever been directly answered by UPENN?

3. For the dogs that test positive later in life and sometimes test negative, is there a way to find out if it is cysteine or homocysteine being excreted into the urine? Is it possible to run blood tests to detect the presence of homocysteine in the blood? This can be done in humans.

4. If homocysteine is indeed found in the blood and/or urine of dogs, is the any research currently being done to see if there are genetic defects in methionine synthesis on the cellular level, such as what happens in humans with recessive homocystinuria?

5. Is anyone (including UPENN) actually open to the idea that homocystinuria (if this is indeed what we are dealing with) can be brought on by inadequate levels of the B Vitamins? Is there a way to measure levels of Vit B in dogs that test postive? Or even in dogs that are testing negative and do a comparison?

6. Is it possible that you could increase Cystine and/or Methionine containing protein in the diet of an otherwise normal dog, and without an additional increase in B Vitamins, it would cause Homocysteine to be produced?

7. If a lack of B Vitamins can cause excess homocysteine, would it be possible that a lack of methionine in a normal system could mess up the SAM-e cycle as well?

8. Is there any possible way that an intestinal absorption disorder could prevent the proper absorption of methionine and/or B Vitamins, thereby messing up the SAM-e cycle and creating a homocystinuric condition in a dog that seemingly gets the correct amount of nutrients, and has neither genetic cystinuria or homocystinuria?

NOTE - intestinal absorption disorders are real disorders that have been identified in many breeds of dogs. For example, Lymphangiectasia is a chronic form of protein-losing enteropathy in which reduced lymph leads to malabsorbtion of fat and fat soluble vitamins in the small intestine. Symptoms include low blood protein levels and high levels of protein in the stools, decreased blood lymphocytes, decreased cholesterol. Hypocalcemia, rickets, growth issues dues to poor absorption of Vitamin D and Calcium. Pleural effusion, edema in limbs, and chylothorax due to ruptured lymphatics.

9. Have any C+ dogs had any of the above symptoms? Growth issues? Low blood protein? High Stool Protein? Chylothorax?

Dogs with lymphangiectasia or other similar intestinal absorption conditions are helped by a diet low in fat but HIGH in quality protein. Supplements of fat soluble vitamins, vitamin B12 injections, corticosteroid treatments and antibiotics for occasional bacterial overgrowth in the intestines.

They say that almost all Norwegian Lundehunds have this type of gastrointestinal disorder, although some are asymptomatic.

They are tested by measuring Vitamin B12 and folate in serum, and alphal-proteinase inhibitor in fecal samples (which is a marker for gastrointestinal protein loss).

Is it a possibility to run these tests on C+ mastiffs and/or mastiffs having symptoms of malabsorbtion, and see if there is a link?

10. Since it’s all males that are testing C+ in mastiffs, is it possible that another (x-linked) genetic disorder other than genetic cystinuria or genetic homocystinuria could cause elevated levels of cysteine or homocysteine?

Could there be an X-linked intestinal protein malabsorption disorder in mastiffs that eventually leads to elevated homocysteine levels in the blood and urine?

In humans there is an x-linked malabsorption condition called “X-Linked Familial Hypophosatamia, aka Vitamin D Resistant Familial Rickets).

http://www.cigna.com/healthinfo/nord417.html

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=307800

11. If the circumstances above are indeed a possibility, can Upenn do research on other possible diseases that might elevate cysteine or homocysteine levels, or does the Cystinuria grant limit the research to genetic Cystinuria only?

So, thank you to everyone who actually got through this whole giant post, I hope I put it together clearly.

Does anyone have any thoughts or other theories based on this info? I'd love to hear some ideas, and I think if we all put our heads together, we can beat this.

-Kay Stivason

 

 

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margelutz

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Reply with quote  #71 


Does anyone have any thoughts or other theories based on this info? I'd love to hear some ideas, and I think if we all put our heads together, we can beat this.

-Kay Stivason



HI Kay :>)
Great post ,probably made more sense than we have ever seen :>)
I know they say to take B12 pills to ward off High  levels of Homocystenie .

Too ward off a heart attack , and that's how they can tell if you are a candidate for a Heart Attack ,if you have high blood levels in your blood .


So do you think if we gave out Mastiffs ,that are positive put them on B12 pills or Gave them B12 shots , would help ?


As in taking  a C+ Mastiff giving B12 shots ,then take Him back in to have Him tested and see what the out come could be????

I also know of some breeders, that give their Mastiffs, Sammie to calm them down ,do you think that would also be a NO NO ??

Great post ,
Thanks
Marg e

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margelutz

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Reply with quote  #72 
Hi Again :>)
I hope Anna May has seen  this post ,and can ask UPENN all these questions :>)

And come back with some answers :>)

Marge

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Teresa

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Reply with quote  #73 

Excellent post! Most of the questions I cannot answer, but I do know that one of the upcoming test is to feed a "test diet" that SHOULD cause a C+ dog to test positive and maybe even force a female into excreting cysteine thus testing positive (which contrary to popular lore has NOT happened yet). I do not have the details yet, but when I hear, I'll be glad to share it.


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annagmay

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Reply with quote  #74 
Kay, thank you for doing your homework and looking into this further.  I do not know in what depth UPenn has looked at all of the other diseases and disorders that cause the body to not digest proteins and amino acids correctly and cause the excess cystine and other amino acids to dump into the bladder, but I do know they have done that. 

There are various similar disorders that cause different phenotype besides excess cystine and other amino acids in the urinary tract such as excess cystine in the blood, the intestines, and even cystine crystals in the eye... As you obviously know, it is extremely time consuming studying all of this stuff because it can be very interesting if you're interested in such things and everything you look up leads to something else to look up...

UPenn has looked at the various gene mutations that causes cystinuria in different nationalities of humans and they've looked at their gene mutations...  We have shared our experience with Dr. Acland at Cornell in finding the gene that causes PRA in Mastiffs...  You probably already know this, but once we proved PRA was dominant in Mastiffs, he looked at eye diseases in humans that could cause retinal defects that were inherited in a dominant fashion and he looked closely at the gene that caused retinal pigmentosa in humans and looked at that gene in the Mastiffs and bingo he found the mutation.  Luckily for us, PRA was a simple Mendelian dominant inheritance, but unfortunately for us and our Mastiffs, Cystinuria is apparently much more complicated....

 So yes, UPenn has looked at other diseases and the mutations, but there focus now is specifically on Cystinuria. 

If owners want to do further diagnostic tests on their dogs, UPenn can run a lot of them in house, but some have to be sent out to other labs...

Anna



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LazarusMastiffs

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Reply with quote  #75 
11. If the circumstances above are indeed a possibility, can Upenn do research on other possible diseases that might elevate cysteine or homocysteine levels, or does the Cystinuria grant limit the research to genetic Cystinuria only?

Before they ever diagnoses cystinuria as a true disease in mastiffs, all other options SHOULD have been exhausted first, to keep us from chasing a disease that is really just an issue with diet, absorptions, etc.  It is also the first thing learned by diagnosticians.  Of course, researchers are human and will often jump to conclusions or look for answers that validate their own beliefs instead of being truly objective.  We are all that way.  I am not saying they are chasing ghosts, or even the wrong ghosts, just that from the info we have, it may be more of a shot in the dark than a probability.  Lots of different possibilities for conditions that can cause stones or high levels.  Some are genetic and some not.  One thing that they all have in common is that they are NOT cystinuria, yet some might test positive for it with some testing methods currently in place.  cough cough... 

BTW, saying that the body does not produce cystine is a bit of a misnomer and true at the same time.  During the process of digestion, which occurs in our body obviously, chemical reactions occur all the time.  Disulfide bonds can and do happen there, which will create cystine in the stomach and then move on to the body.  So cystine itself is not the only thing to watch, but known cystine producers as well.  I wonder if anyone at UPENN has checked into the affects of sulfa based antibiotics being given prior to testing?  Lots more questions than answers at this stage.  The only thing we know for sure is that we will have received a lot more wrong information than right information before we have a definitive answer.  It usually happens that way with research.  Many facilities do not like to give out opinions until they have definative answers for just such a reason...



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