Re: Re: PSC - The arteriosclerosis of the bile duct (LONG reply to Nina)

[Guest guest]

If CFTR was the cause for most PSC, don't you think that we wouldnt have a 20% chance of PSC reoccuring after transplant? I mean, transplanting a organ with a genetic problem should fix the underlying genetic problem in that organ. That's why I don't understand why there is so much talk about CFTR in PSC. Please shed some light on this for me if anyone could. wrote: Dear Nina;Sorry to hear that Sam's ALP is not improving with the fish oils. As an aside

I'd like to mention that I found this patent from Dr. D. Freedman relating to PPARalpha, fibrates, PSC and CFTR. In a nutshell, it looks like he's "patented" the use of fibrates, EPA and DHA (i.e. fish oils) in the treatment of PSC! And he's claiming that the cystic fibrosis gene is a "cause of PSC".__________________________Applicaton #: 20060160867 07/20/06Methods for modulating ppar biological activity for the treatment of diseases caused by mutations in the cftr geneSome of the relevant sections of the patent are reproduced below:[0004] Approximately one in 2000 Caucasians have cystic fibrosis (CF), a genetic disorder caused by inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR protein, a member of the ABC transporter family, forms a chloride channel localized to the plasma membrane. The protein consists of five

domains: two membrane-spanning domains that form the chloride ion channel, two nucleotide-binding domains that hydrolyze ATP, and a regulatory domain. Expression of the CFTR gene is highest in cells that line passageways of the lungs, pancreas, colon, ileum, and genitourinary tract. [0005] In addition to CF, defects in the CFTR gene are associated with diseases including, for example, pancreatitis, chronic obstructive pulmonary disease (COPD), asthma, chronic sinusitis, primary sclerosing cholangitis, and congenital bilateral absence of the vas deferens (CBAVD). .....[0007] The invention features a method for treating a disease in a human patient that has a mutation in the CFTR gene by administering to the patient a therapeutically effective amount of a peroxisome proliferator-activated receptor (PPAR) inducer, a PPAR agonist, an AP-1 inhibitor, a STAT inhibitor, an NFkB inhibitor, or an LXR

agonist. PPARs generally include PPAR.alpha., PPAR.delta., and PPAR.gamma.. Diseases caused by mutations in a CFTR gene include, for example, cystic fibrosis, pancreatitis, chronic obstructive pulmonary disease (COPD), asthma, chronic sinusitis, primary sclerosing cholangitis, liver disease, bile duct injury, and congenital bilateral absence of the vas deferens. The diseases that are treatable by the therapeutic methods of the invention include any disease caused by any of the 1,300 or more mutations in the CFTR protein. See for example, J. Zielenski, Canadian CF registry database; Cutting et al., Nature 346:366-369, 1990; Dean et al., Cell 61:863-870, 1990; Kerem et al., Science 245:1073-1080, 1989; Kerem et al., Proc. Natl. Acad. Sci. USA 87:8447-8451, 1990; and Welsh et al., "Cystic Fibrosis," Metabolic and Molecular Basis of Inherited Disease (8.sup.th Ed. 2001), pp. 5121-88. Particularly amenable to treatment are

diseases caused by a deletion of the phenylalanine normally present at amino acid residue 508 of the CFTR protein (.DELTA.F508). The patients being treated according to the methods of this invention may be heterozygous or homozygous for a CFTR mutation. [0008] Useful PPAR inducers and agonists affect any PPAR, but particularly PPAR.gamma., (e.g., PPAR.gamma.1 and PPAR.gamma.2), PPAR.alpha., and PPAR.delta.. Examples include eicosapentaenoic acid; any of the thiazolidinediones, but particularly pioglitazone (ACtos.TM., Takeda Pharmaceuticals), rosiglitazone (Avandia.TM., GlaxoKline), thioglitazone and analogs thereof; L-tyrosine derivatives such as fluoromethyloxycarbonyl; non-steroidal anti-inflammatory drugs such as indomethacin, ibuprofen, naprosyn, and fenoprofen; and anti-oxidants such as vitamin E, vitamin C, S-adenosyl methionine, selenium, idebenone, cysteine,

dithioerythritol, dithionite, dithiothreitol, and pyrosulfate. Additional examples of PPAR.alpha. agonists and inducers include DHA, WY14643, and any of the fibrates, particularly, fenofibrate, bezafibrate, gemfibrozil, and analogs thereof. __________________________Best regards,Dave (father of (21); PSC 07/03; UC 08/03)

Don't be flakey. Get Yahoo! Mail for Mobile and always stay connected to friends.

[Guest guest]

I just

love your golf analogy Dave. Thank you so much for putting this very

scientific data in terms a suburban housewife would understand. You are

GREAT!!!

Joanne (mom of Todd, 20, psc 01, crohns 02,

tx twice 03, recurrent psc 05, type 1 diabetes 06, living life to the fullest

07)

I'd like to make an

analogy that PSC is

like being struck by lightining. Imagine that a risk factor for being

struck by lightning would be wearing a metal helmet (carrying a

mutant CFTR allele). This might not be too bad if you stayed indoors!

But if you went out to a golf course in the middle of a thunder

storm, watch out!! So imagine a second risk factor, such as belonging

to a golf club, and actively playing golf (IBD). Those with a golf

cart (Crohn's) might be able to wear a metal helmet (mutant CFTR)

without getting stuck by lightning because they spend more time off

the ground. Having a golf cart (Crohns') would appear to be

protective. Those without a golf cart (UC) and wearing a metal helmet

(mutant CFTR) would have a much higher probability of being struck by

lighting because they spend more time in contact with the ground. Men

play golf more often than women, and so the incidence of being struck

by lightning on a golf course is twice as high in men as in women.

Being a male golfer without a golf cart and wearing a metal helmet,

and then going out to play golf in a thunderstorm results in a high

risk of being struck by lightning.

Dave

(father of (21); PSC 07/03; UC 08/03)

[Guest guest]

So – they key appears to be to not

go outdoors to play gold in a thunderstorm. I am not sure though how to

translate that part of the analogy into real life!

BTW – Suzanne came home on Saturday

and we are fumbling through the six elimination diet in complete compliance

with the doctor’s suggestions. So, I am not sure if we are playing

golf in a thunderstorm while eating food or not! I am not a golfer so I don’t

even know what kind of food golf clubs have!

LINDA

(Mom of Suzanne,

17; IBD 1/04; PSC 3/04)

From: [mailto: ] On Behalf Of Joanne

Grieme

Sent: Wednesday, January 31, 2007

8:12 PM

To:

Subject: RE: Re: PSC

- The arteriosclerosis of the bile duct (LONG reply to Nina)

I just love your golf analogy Dave. Thank you so much for

putting this very scientific data in terms a suburban housewife would

understand. You are GREAT!!!

Joanne (mom of Todd, 20, psc 01, crohns 02, tx twice 03, recurrent

psc 05, type 1 diabetes 06, living life to the fullest 07)

Dave

(father of (21); PSC 07/03; UC 08/03)

[Guest guest]

Dave,I have been reading these post and then reading them again. I have to take it slow and I am not sure I get it in total.So thank you very much for the analogy !! It really helps.LeeI realize this is a very heavy scientific discussion. For the benefit of non-scientific audience, I'd like to make an analogy that PSC is like being struck by lightining. Imagine that a risk factor for being struck by lightning would be wearing a metal helmet (carrying a mutant CFTR allele). This might not be too bad if you stayed indoors! But if you went out to a golf course in the middle of a thunder storm, watch out!! So imagine a second risk factor, such as belonging to a golf club, and actively playing golf (IBD). Those with a golf cart (Crohn's) might be able to wear a metal helmet (mutant CFTR) without getting stuck by lightning because they spend more time off the ground. Having a golf cart (Crohns') would appear to be protective. Those without a golf cart (UC) and wearing a metal helmet (mutant CFTR) would have a much higher probability of being struck by lighting because they spend more time in contact with the ground. Men play golf more often than women, and so the incidence of being struck by lightning on a golf course is twice as high in men as in women. Being a male golfer without a golf cart and wearing a metal helmet, and then going out to play golf in a thunderstorm results in a high risk of being struck by lightning.Best regards,Dave (father of (21); PSC 07/03; UC 08/03)

[Guest guest]

Dave,I have been reading these post and then reading them again. I have to take it slow and I am not sure I get it in total.So thank you very much for the analogy !! It really helps.LeeI realize this is a very heavy scientific discussion. For the benefit of non-scientific audience, I'd like to make an analogy that PSC is like being struck by lightining. Imagine that a risk factor for being struck by lightning would be wearing a metal helmet (carrying a mutant CFTR allele). This might not be too bad if you stayed indoors! But if you went out to a golf course in the middle of a thunder storm, watch out!! So imagine a second risk factor, such as belonging to a golf club, and actively playing golf (IBD). Those with a golf cart (Crohn's) might be able to wear a metal helmet (mutant CFTR) without getting stuck by lightning because they spend more time off the ground. Having a golf cart (Crohns') would appear to be protective. Those without a golf cart (UC) and wearing a metal helmet (mutant CFTR) would have a much higher probability of being struck by lighting because they spend more time in contact with the ground. Men play golf more often than women, and so the incidence of being struck by lightning on a golf course is twice as high in men as in women. Being a male golfer without a golf cart and wearing a metal helmet, and then going out to play golf in a thunderstorm results in a high risk of being struck by lightning.Best regards,Dave (father of (21); PSC 07/03; UC 08/03)

[Guest guest]

Dave,I have been reading these post and then reading them again. I have to take it slow and I am not sure I get it in total.So thank you very much for the analogy !! It really helps.LeeI realize this is a very heavy scientific discussion. For the benefit of non-scientific audience, I'd like to make an analogy that PSC is like being struck by lightining. Imagine that a risk factor for being struck by lightning would be wearing a metal helmet (carrying a mutant CFTR allele). This might not be too bad if you stayed indoors! But if you went out to a golf course in the middle of a thunder storm, watch out!! So imagine a second risk factor, such as belonging to a golf club, and actively playing golf (IBD). Those with a golf cart (Crohn's) might be able to wear a metal helmet (mutant CFTR) without getting stuck by lightning because they spend more time off the ground. Having a golf cart (Crohns') would appear to be protective. Those without a golf cart (UC) and wearing a metal helmet (mutant CFTR) would have a much higher probability of being struck by lighting because they spend more time in contact with the ground. Men play golf more often than women, and so the incidence of being struck by lightning on a golf course is twice as high in men as in women. Being a male golfer without a golf cart and wearing a metal helmet, and then going out to play golf in a thunderstorm results in a high risk of being struck by lightning.Best regards,Dave (father of (21); PSC 07/03; UC 08/03)