gray matter affected in earliest stages of MS

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Postby OddDuck » Sun Nov 21, 2004 10:44 am

But, you have to admit, without quantum physics, we probably wouldn't even have the MRI right now, would we?

Deb

EDIT: Robin..........perhaps now, though, you'll understand why I tend to shy away from "causal relationships" as absolutes, huh? :wink:
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Postby raven » Sun Nov 21, 2004 11:18 am

I agree that cognition and intellect can be separated by definitions. I was rather referring to their separation in the context of cognitive dysfunction and MS. It would be my contention that they are both affected.

I totally agree with separating causal relationships and absolutes, however in postulating a theory it is necessary to assume certain relationships as fact without proof. Einstein would have had a very difficult job 'proving' relativity. We do however need to make sure that any such assumptions are highlighted.

Please sir, can I go now? my brain's full... :wink:

Robin
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Postby OddDuck » Sun Nov 21, 2004 11:48 am

I totally agree with separating causal relationships and absolutes, however in postulating a theory it is necessary to assume certain relationships as fact without proof.


:lol: Be careful about saying THAT too loudly or in mixed company! Take it from me! :wink:

Please sir, can I go now? my brain's full...


Correction.......it's "madam". hehehe......... Yes, you're dismissed.

Thanks for the fun (and laugh) this morning, Robin!

(And besides, you'll get no argument from ME. I'm still on your same page.)

Have a great day!

Deb
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Postby BioDocFL » Sun Nov 21, 2004 12:20 pm

I think it would be difficult to measure intelligence changes with enough accuracy to use it as a timely diagnostic method. There are changes with age even without MS so how can you tell what to attribute the changes to.
I have been having trouble trying to figure out in which cell types the problems could originate. Most likely there are several different types and different patterns. At first I was thinking that the chromosome fragmentation that I believe leads to loss of epigenetic control would happen in oligodendrocytes, since I was thinking myelin formation was the main problem, due to a change in the polyamine levels. Still a possibility. Then I started thinking about neurons having problems with glutamate uptake due to polyamines affecting the glutamate transporters and receptors. Still a possibility. In that case demyelination is not necessarily the prime or only problem. The cells I have mentioned so far though, oligodendrocytes and neurons, are differentiated, ie. matured. Recently Raven brought up the microglia. Then I heard about glia as being sort of cells in waiting, or immature cells that can grow into gray or white matter and help in repair of brain connections. These glia then are something interesting I want to study more. These could have the accumulated DNA damage I was talking about, perhaps having occurred over time from exposure to excess levels of heavy metals. When these cells are stimulated to mature, due to some stressful event (bacterial or viral infection or hormone changes), the hidden damage and chromosome fragmentation could then be exposed. This could then lead to loss of epigenetic control and the consequences I went into previously with regards to polyamines.
So I am thinking of an example scenario: A young person growing up in a northern region where there is alot of iron and other heavy metals around. A water supply in the area where the youngster lives gets occasional high levels of heavy metals. The heavy metals get in the cells and generate free radicals that damage the DNA but most of the damage is repaired on a routine basis. However, some damage that is not repaired due to less accessibility accumulates in quiescent cells (like glia). Later in life the glia with the damage are stimulated to grow due to a need to replace other brain cells lost to an infection or age. Something that MSers and nonMSers would have to do occasionally. But now the stimulated glia cells can not control the expression of polyamine enzymes (and/or other genes like metalloproteases?). This could then lead to the damage that grows into lesions when there is a local loss of control of metalloproteases and/or polyamine enzymes. Perhaps other genes can be involved too. I'll try to see if I can find out which chromosomes the metalloproteases come from. There could be hidden damage in any of the chromosomes but I still like to consider the X and the inactive X since that can help explain the female ratio. Hormones could certainly play a role in that ratio though. I know that the ornithine decarboxylase gene, an initial enzyme in polyamine synthesis and a heat shock protein, can be stimulated by estrogen.
Seems to me that we have to leave a lot of room in any hypothesis for possible variations. But perhaps we are making headway against one dogma: that an autoimmune reaction is the initial event. That demyelination is necessarily an initial event may be another dogma we need to deal with.
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Postby OddDuck » Sun Nov 21, 2004 12:26 pm

I was rather referring to their separation in the context of cognitive dysfunction and MS. It would be my contention that they are both affected.


Actually, from having suffered for a period of about three years from cognitive, but not intellectual dysfunction myself; AND borrowing from what little has been ascertained from testing, measurements, and patients' descriptions of cognitive dysfunction as it specifically relates in MS, I would personally have to differ from your opinion on that. Based on the foregoing "facts" as they are known to me, it appears that cognition and intellect/intelligence both are NOT affected simultaneously in MS.

I guess I'd just have to ask you to trust me on that one, though. Forgive me, but I sort of don't want to take the time to present ALL of my substantive material, or go into a whole LOT of epic detail about my own personal experiences with cognitive but NOT intellectual decline and dysfunction. I can tell you, though, that HAS to be one of the WEIRDEST experiences and feelings I have ever gone through. Talk about "split"!

You can think just fine and process just fine. You have no interruption in knowledge. But you are unable to "remember" things well or "find words" that you know you know..........things like that. Sometimes you can literally intrinsically observe your cognitive function and even perception moving in slow motion. I can't even describe the weirdness of it.

(Which personal dysfunction, I might add, has been totally reversed - Thank God - in my situation.)

So........to get back on track. And applying the principle of using certain relationships as fact without proof (i.e. what little is currently known and postulated by researchers regarding gray matter AND cognitive dysfunction in MS), I would have to stand by my original thought that if the gray matter were affected FIRST in MS, there should be some initial presentations of "intelligence" dysfunction (again applying the traditional, fairly universally, used definition).

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Postby raven » Sun Nov 21, 2004 12:42 pm

Of course I trust you Deb. :)

In that case I'll pose a question. Is intelligence more amenable to repair through plasticity than cognition? Particularly with respect to memory. Memory implies storage within a region. Processing can be distributed across many non-specific regions.

I'll sign off with a thought for Bromley.

Is there anything worse than not knowing?

Knowing that things are bad is awful, but only as awful as the bad thing itself. Believing that things are bad, but not being sure, not knowing is simply unbearable because then you are dealing with all of the worst case
scenarios all at once, without any sort of closure or steadiness. In some situations the worst possible outcome is not as bad as simply not knowing the outcome.

I want to be able see it coming.

My imagination is far too overactive to be able to deal with some sorts of ambiguity. I play things out too many times, too many ways.

At times I cannot be trusted with my own thoughts.

Robin

EDIT: Wesley, yes I agree. Particularly if we assume that susceptibilty to MS is controlled by epigenetic markers. Exposure to heavy metals or bacterial / viral toxins could cause these markers to be expressed and MS to appear.
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Postby OddDuck » Sun Nov 21, 2004 1:23 pm

Is intelligence more amenable to repair through plasticity than cognition? Particularly with respect to memory. Memory implies storage within a region. Processing can be distributed across many non-specific regions.


Ok...number one. Do you consider "memory" as part of "intelligence"? Someone can have a terrific memory, but be unfortunately very dysfunctional in actual intelligence at the same time. Personally, my thought is the two are separate.

Your posture for this exercise is that memory "implies" storage within a region. Are we certain of that? Remember my post a little bit ago regarding the analogy of memory storage in the brain with memory storage on a computer hard drive?

Gut answer on whether intelligence might be more amenable to repair through plasticity (operative word there) than cognition? My answer would be no. Not through "plasticity", biological plasticity, that is. Cognition probably would be, though. (This is via applying a purely scientific approach, though - what little that we - collectively speaking - as a medical society can claim we know.)

Mental processing, it has been shown, can often be "relearned" or "re-imprinted", maybe "re-activated" is a better term, in areas of the brain that originally didn't do that particular processing prior to damage to another part of the brain that did. (i.e. stroke victims regaining lost intellectual functions through various rehabilitation techniques.) Although not "proven", there is indication that is the case. Take certain improvement in autism as a result of application of certain repetitive methodologies, for example, also. (I won't go into detail, of course, for this discussion.)

Besides, I'm not talking about totally losing finite memory imprint in MS. The memories are still residing within the brain, but the pathway to retrieve those memories are what is affected in MS. It's like you start to go there (electro-physiologically), but never arrive to the destination. Now, certain traumatic brain injuries that completely obliterate certain portions of the brain usually does result in the actual memory imprint residing in that portion of the brain being lost forever, also. (Such as what happens in some stroke victims.)

Unfortunately, though, not NEAR enough is even known about the brain and how it works to even form too many opinions on anything.

As far as the rest of your statements, including your "edit" to Wesley, Robin..........man, I could almost swear that you read my mind at times.

Deb
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Postby OddDuck » Sun Nov 21, 2004 1:34 pm

Darn, it looks as if I didn't click on the "submit" button when responding to Wesley, so I'll post my response now.
********************************

Hi, Wesley!

Yes, I totally agree that "measurement" of intellectual dysfunction would be qualitatively a remote prospect. It would mainly have to be ascertained based on patients' descriptions, I would think. So, yes.......trying to "prove" any of the gray matter theories right now might prove itself to be quite the undertaking! It IS quite the mind exercise, though, thinking about this. (Which, rumor has it, mind exercise of this type appears to provide actual biological beneficial effects in and of itself.) :wink:

Regarding the "auto-immune" theory. Yes, we've come full circle again, haven't we? Hence why I end up shying away from causal relationships, ESPECIALLY as it pertains to MS! Combine my thoughts on metaphysics with causal relationships in ANYTHING, and I get frustrated (in my head, that is). I can follow it all with no problem and really enjoy doing so and interjecting, and do have my own opinions, etc., but as far as ever "settling" on any one particular causal relationship for MS.........well, that may prove to be quite the undertaking for me personally. :? :) I'm not saying impossible.........just might be difficult for me. I am still of the belief that there may be so many complex combinations as to make it almost impossible to define.

I do see, though, where you are observing and appreciating the many different aspects of "MS the disease". That's great to have minds like yours involved! BRAVO! I certainly won't or can't say that any of your thoughts or hypotheses are off base....that's for sure!

Logic appears to still dictate in your posts, so I'd have to say you are definitely on to something in my opinion! (For whatever THAT is worth, of course!)

Keep on keeping on!!

Deb

EDIT: And the paradox as it pertains to some of my statements above is the fact that I have no problem with "cause and effect" for practical applications, as long as the cause and effect principle can be reliably duplicated to a fairly high degree of consistency.
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Postby lurker1 » Mon Nov 22, 2004 3:22 am

Wow. Let me speak for any other lurkers out there and say that this thread is totally fascinating. While it sometimes floats above my comprehension I am impressed by what you three are trying to do and i have a lot of faith that you are doing it well.

I do have a little bit of experience with the more theoretical/philosophical side of the cognition/intellect debate, and for the most part i'd just suggest that you're opening up a huge can of worms there, and agree with wesley that it might be a less productive direction to take this discussion. Before we finish reading all the empiricist philosophy we need to get our definitions straight, magnetic resonance technology will have improved enough for us to see what's physically going on. (I hope.)

I have a question for Wesley about his latest "black box" model. (Man, there should be a permanent forum on this site, where anyone can start a thread by posting a theory and challenging anyone to find flaws in it.)

What is the "accumulated DNA damage" of which you speak? Does this primarily relate to pre-programmed cell death-- i.e., in the damaged microglia the DNA tells them to die faster? This is a frightening idea because it seems pretty tough to design a therapy for this kind of problem. But it also seems a little off to me, because I'd think that something as clunky as a magnetic charge could upset all sorts of things in microglial DNA, and that it would be strange to see a uniform "disease" born out of that sort of mutation.

Or maybe i'm not understanding and "accumulated DNA damage" means something else. I can't really tell. If I still seem like i know what i'm talking about, rest assured that i don't, and i've picked up most of my bio/neurological language from casual surfing of sites like this one. But hopefully this question is useful to y'all. And if someone besides Wesley thinks they can answer it, go ahead.

Keep up the good work.
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Postby OddDuck » Mon Nov 22, 2004 5:52 am

Hi, lurker!

Thanks for the kind words!!

Yea, I think Robin and I realize we were getting a little "off" with our discussion. :wink: Oh, yes, we knew it couldn't go too far. We WOULD be here "forever" on that debate! Apologies there.

Not to speak for Wesley, of course, or anything, but a lot of his theory was posted under the thread called polyamines. I think right now, he is fine-tuning his thoughts. That's an excellent question, by the way! I believe I even initially threw out a very similar question. Also, though, you probably might need to remember "replication" when speaking about mutation.

As far as therapy goes, gene therapy isn't as far off as you might believe (desipramine helps prevent DNA fragmentation, and TZD is also a type of gene therapy - that interestingly enough, they are testing right now for progressive MS and are having some success). Not to mention stem cell research. But having said that, you have a very valid concern.

Here are my thoughts:

IF MS is a combination of DNA, and other combinations of "triggers" such as Wesley has mentioned, there still remains a full "cascade" of myriad dysfunctional events that are produced once MS has been "triggered". I prefer to refer to it as the timing of the body is all off. There are/can be several points along and/or during this cascade of events where treatment and/or therapy can be focused (at the very least). As far as a "cure", IF any of us are anywhere NEAR to being correct in some of our assumptions (which call this ego, but I think we're just as close as anybody else.... :wink:), it MAY be quite a while yet before MS can be considered completely preventable (either by vaccine or other methods of prevention). Not to sound negative, at all........but that is probably a realistic view of where our medical knowledge currently stands today. (Although, enormous strides are accomplished every day.)

But...........if we know what is triggering even SOME of the cascade events in MS (even if it is sort of like the chicken and egg teaser), then treatment should be able to be "taylored" to fit each individual to keep MS from exhibiting its presence fully. Right now, any therapies we have for MS just is not taylored specifically enough for MS. Not really. In MY opinion, so far, it has mainly been "let's throw THIS at it and see if it works". Maybe I'm a little wrong about that, but I'm an extremely detailed person, too, so it probably just appears that way from my perspective. Still, MS research has recently been finding ways to selectively target certain dysfunctions in MS, which is always exciting to me.

You know what is so coincidental? In touching upon MRI and quantum physics (maybe our conversation wasn't so useless after all......hehehe), the same type of pondering occurred to me. Knowing a little bit about how the MRI works, why isn't the MRI itself skewing or affecting DNA?

We all know what radiation does. I realize that the strength of MRI isn't that high, and all in all it is still a bit "crude", but you would think that MRI itself could be some form of treatment for SOMETHING. I might have to go look that one up. Of course, though, that truly gets us back into quantum. Phew!

I still believe the one thing the three of us still haven't factored back into our discussions is MHC. That's a biggie. There is enough research already that provides us with quite a bit of solid evidence for the huge role and involvement of MHC in MS. MHC traces right back to one or two specific chromosomes. Wesley is the expert at the front-end, though.

Here's an abstract that may help illustrate what I am referring to (remember, Wesley is involved in cancer research.)

Science. 1988 Oct 7;242(4875):69-71. Related Articles, Links


Distinct cloned class II MHC DNA binding proteins recognize the X box transcription element.

Liou HC, Boothby MR, Glimcher LH.

Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115.

The class II (Ia) major histocompatibility complex (MHC) antigens are a family of integral membrane proteins whose expression is limited to certain cell types. A pair of consensus sequences, X and Y, is found upstream of all class II genes, and deletion of each of these sequences eliminates expression of transfected genes. Furthermore, the absence of a specific X box binding protein in patients with severe combined immunodeficiency disease whose cells lack class II suggests an important role for these proteins in class II regulation. Here, the cloning of two lambda gt11 complementary DNAs encoding DNA binding proteins (murine X box binding proteins lambda mXBP and lambda mXBP-2) is reported. Both phage-encoded fusion proteins bind specifically to the X box of the A alpha, but not to E alpha or E beta class II genes. These two independent isolates do not cross-hybridize. The lambda mXBP complementary DNA hybridizes to two RNA species, 6.2 and 3.0 kilobases in mouse, that are expressed in both Ia positive and Ia negative cells. By means of DNA blot analysis with the lambda mXBP complementary DNA insert and probes generated from each end of this complementary DNA insert, lambda mXBP was found to arise from a multigene family. These data illustrate the high degree of complexity in the transcriptional control of this coordinately regulated gene family.

PMID: 3140376 [PubMed - indexed for MEDLINE]


If Wesley is on to something (which I believe Robin and I both have an inkling that he is), then epigenetics indeed plays a huge role in MS. The more I allow my mind to ponder on his information, the more it comes to me. Proteins and transcriptions are highly complex. But, if you will notice from the above information, the connection is there. We just have to fit all our musings into one.

And notice the point that Wesley expressed in his earlier post. To our minds, I believe, we can safely say that we have successfully broken through the dogma of MS being an "autoimmune" disease. We'll admit the autoimmune functions are definitely involved, but does MS originate there? I'd say no.

Wesley........Robin?

Deb

EDIT: Oh, yea.....and where does norepinephrine factor into this? (Probably pretty early on in the cascade.) Easy..........as an example.........it fits right here:

J Neuroimmunol. 1988 Jan;17(2):89-101. Related Articles, Links

Norepinephrine inhibits gamma-interferon-induced MHC class II (Ia) antigen expression on cultured brain astrocytes.

Frohman EM, Vayuvegula B, van den Noort S, Gupta S.

Department of Anatomy and Neurobiology, California College of Medicine, University of California, Irvine 92717.

Recent evidence that astrocytes can be induced to express the class II major histocompatability (MHC) antigens suggests that these cells may be involved in the development of intracerebral immune responses. The principal inducer of MHC class II antigen (Ia) expression is a soluble lymphokine, gamma-interferon (gamma-IFN). Normally astrocytes do not express significant levels of Ia antigens despite the fact that agents such as gamma-IFN may be present in the central nervous system (CNS). Here we report that a major neurotransmitter, norepinephrine (NE), inhibits, in a dose-response fashion, the ability of gamma-IFN to induce Ia antigen expression on cultured astrocytes derived from newborn BALB/c mice. This finding may indicate that the brain contains inhibitory modulators that serve to prevent the up-regulation of intracerebral immune responsiveness.

PMID: 2826540 [PubMed - indexed for MEDLINE]
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Postby OddDuck » Mon Nov 22, 2004 6:10 am

Wesley posed an interesting avenue to pursue with his last post:

That demyelination is necessarily an initial event may be another dogma we need to deal with.


That very same thing has been tossing around in my head for a long time, also. Before we can go too far with that, though, maybe we should define "initial event"? Initial event of outward physical presentation of symptoms? Clinical presentation? I need to get a handle on where or at what point we are calling the "threshold", where MS becomes extrinsic or "definable", shall we say.

If we define "initial event" as the first clinical presentation, then I believe myself that demyelination is NOT the initial event. I believe it's with the axons themselves. Right now I'm speaking from "intuition", but I'll refine it more as I go along.

I realize that myelin degradation results in a more visible and clinically traceable event, BUT.........what's the common denominator here? Especially factoring in gray matter now (which doesn't even contain myelin!) Axons. Something dysfunctional lies FIRST in or with the axons (as far as initial clinically measurable event). The use of MRS would/should help confirm that! Doggone it! Is MRI already outmoded in a way? (Well, that's neither here nor there........just a sudden mind "click". :) )

Ok.......I'm off to put THAT one together! :wink:

See you all later, everybody!

Deb
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Postby raven » Mon Nov 22, 2004 6:54 am

Welcome Lurker (does the fact that you've come out and posted mean you have to change your name? :lol: )

I'll just second Deb's comment that our 'discussion' on cognition vs intellect was a side issue, albeit a very important one and probably deserving of it's own thread. Of all the effects of MS cognitive decline is the one that scares me most! 8O

Wesley is probably better placed to answer your question on DNA damage but I can give you a quickie answer. Cells reproduce through mitosis. This is when a cell divides to produce a copy of itself. Sometimes during the process the new cell can receive a slightly corrupt DNA copy. This is exacerbated by the presence of toxins or heavy metals. It isn't about cells dying faster, if the new cell was programmed to die quicker then it would not reproduce itself so often and the mutation would quickly be eradicated. The other side to that is when the programmed cell death mechanism is corrupted and the new cell can reproduce indefinitely. This is cancer. As far as genetics and MS are concerned we (Wesley Deb and I) are discussing epigenetics as a possible mechanism. There is a definition of epigenetics here:

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

For myself I have become convinced that the matrix-metalloproteinases and their inhibitors are central to the pathogenesis of MS (i.e. the process of MS rather than the cause). I, like Finn am convinced that lesion formation is a 'sideshow' rather than the main disease progression. This does not mean that MS is not autoimmune, microglia and astrocytes are components of the immune system specific to the CNS. (although they do have other functions, particularly astrocytes)

There is a model for autoimmune diseases called the 'REGA' model. This stands for 'Remnant epitopes generate autoimmunity' which probably doesn't help you much! There is an abstract explaining it somewhat here:

<shortened url>

The REGA model is the best explanation for autoimmunity that I've seen.

p.s. Deb, notice the mention of MHC's?

Unfortunately it takes a very long time for treatments to go from the theoretical stage to approval. I think there's a very interesting line of research using engineered viruses to express possibly deficient genes (TIMP-1 for example). If there is to be a cure, I believe this is where it will come from. There's an abstract on this here:

<shortened url>


Robin

p.s. Deb, Magnetic therapy is an alternative treatment for MS. I have no idea of it's efficacy though.
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Postby OddDuck » Mon Nov 22, 2004 8:20 am

You know, Robin........a while ago Wesley and I had a brief discussion about the definition of "autoimmune". Right after I posted that this morning, I thought to myself that I hoped everyone understood what I meant by saying MS was not an "autoimmune" disease. I was using the well-known and bantered around definition, which seems to mean "autoimmune" = immune system reaction.

I believe that a major problem in MS is the "self-recognition" process which gets skewed as part of the cascade, which can again mean "autoimmune", BUT..........the problem with labeling MS as "autoimmune" (from my perspective) is that then the research concentrates SOLELY on the "immune system" reaction itself (i.e. all the direct immunotherapy options), as opposed to focusing on the aspects involved in the physiological self-recognition process.

So......basically, we're still on the same page. :wink: Call me "stuck on definitions". hehehe........ Or as you call it, the "model".

I'm going to go check out the REGA model now that you are referring to. Be right back!

Deb

EDIT: Yep, Robin! You're exactly correct! Fits right in! No problemo. AND interestingly enough, IF the cascade can be "interrupted" right at that point that the abstract you posted refers to, you MIGHT be able to get the balance or regulation, if you will, back into balance. (I'm on the back end again. :wink: )
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Postby OddDuck » Mon Nov 22, 2004 8:49 am

Oh, and by the way, Robin..........and I swear this is the honest truth!!! You freak me out! You've AGAIN been reading my mind and thoughts that I was mulling over all morning after I posted (even down to my thoughts about finn's musings AND the more prevelant aspect of toxins at specific time periods throughout life).

And regarding the toxin subject, the introduction of toxins during specific time periods might thereby skew a person's already existing genetic predisposition (probably due to other various epigenetic influences in the beginning, also) closer toward actual disease presentation. Viral influences and their resultant mutations over time, comes in second, in my mind, as the next "trigger".) 8O :P

Simultaneously, the first epigenetic influence has caused the chain reaction to branch off, resulting in several things happening simultaneously. Some developing more slowly and others happening fairly quickly. BUT, again..........even at this point, it would be very difficult to trace and measure clinically. hmmmmmmmm..........

So far, then, in the middle, Robin (after Wesley's hypothesis has started, let's say), and correct me if I'm wrong, we have isolated as the earliest need (that is within our immediate probable availability) for intervention in MS, (1) the need to help preserve axons and continue to stimulate their growth (myelin degradation is a later occurance), (2) inhibit TNFa and IL1b, (3) increase IL10 (to stengthen the BBB), (4) reduce ion calcium influx, (5) inhibit or regulate MHCII in some manner, and (6) regulate the expression and reuptake of norepinephrine (which will assist the glial and microglial cells among many other things).

(While we go through this, go take another look at my first narrative regarding the drug desipramine.........just for kicks and giggles.) And again, I'm not referring to a "cure", but just how close MIGHT we REALLY be without realizing it to maybe even already having some pretty effective treaments/therapies for MS? Keep in mind also, though, if you do peruse it, that since writing that, I have even found some additional effects such as how it reduces calcium influx, thereby helping to preserve and protect the axons from damage, etc. - actually something is triggering the axons (in my mind) to cause a reverse reaction that damages themselves!

Now, everybody should keep in mind that "reversal" of damage will and is a totally separate discussion in and of itself, which is not being addressed at this point in time herein. That's a later debate. :wink: Just to throw something in there to put in the back of your mind, I have also found where there is a best-case "window of opportunity" time-wise when trying to produce or influence damage reversal. But.....back to the main path - pathogenesis.

Ok......Robin.........I'm going to go refresh myself on MMP9 again. It's been some time since I've reviewed that piece of the puzzle.

Later!

Deb
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Postby OddDuck » Mon Nov 22, 2004 9:31 am

Oh, boy! That didn't take long (sorry for the ongoing back to back posts folks....I'm truly not trying to "hog" the floor...I'm just on another roll.)

Robin and Wesley:

Go to <shortened url>. Type in "MMP9" into the search box there, and you'll get a list. Choose the first one (number 1), you'll get another list of abstracts. Guys, check out number 26 abstract. The title alone gave me a thrill! :lol:

Ok.....in a nutshell, MMP9 correlates mainly (in my mind) with inflammation and viral influences, for example:

J Neuroimmunol. 2004 Oct;155(1-2):13-20. Related Articles, Links

Inhibition of MMP-dependent chemotaxis and amelioration of experimental autoimmune uveitis with a selective metalloproteinase-2 and -9 inhibitor.

El-Shabrawi Y, Walch A, Hermann J, Egger G, Foster CS.

Department of Internal Medicine, Medical University, Graz, Austria. yosuf.elshabrawi@meduni-graz.at

The chemotaxis of inflammatory cells depends on proteolytic disruption of extracellular matrix components. The metalloproteinases (MMP)-2 and -9 enable T-lymphocytes to pass through basement membranes. Selective inhibition of only MMP-2 and -9 almost completely abolished the ability of lymphocytes to digest collagen. The chemotaxis of lymphocytes was reduced 40%. In our in-vivo model of experimental autoimmune uveitis (EAU), 46% of the animals in the treated group remained disease-free, whereas all animals in the control group developed EAU. The mean activity of the disease was also statistically significantly reduced. The data suggest that selective MMP-2 and -9 inhibition might be a treatment option. Copyright 2004 Elsevier B.V.

PMID: 15342192 [PubMed - indexed for MEDLINE]


UNTIL I got to this part:

<shortened url>

Anticancer Res. 2004 Jul-Aug;24(4):2309-18. Related Articles, Links

Epstein-Barr virus LMP1 status in relation to apoptosis, p53 expression and leucocyte infiltration in nasopharyngeal carcinoma.

Shao JY, Ernberg I, Biberfeld P, Heiden T, Zeng YX, Hu LF.

Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) infection. EBV-encoded LMP1, expressed in most of NPC, has been suggested to have an important role in the pathogenesis and development of NPC and its expression correlates with poor prognosis. MATERIALS AND METHODS: Eighty-seven NPC biopsies were analyzed by immunohistochemistry for expression of markers of cell proliferation, apoptosis, infiltrating T lymphocytes and macrophages in relation to the LMP1 status. RESULTS: Our findings indicate that the p53 accumulation in NPC was significantly correlated to LMP1 and MMP9 overexpression in NPC cells. The frequency of apoptotic cells in NPC, as analyzed by TUNEL labeling, correlated to Fas-L and caspase-3 expression, and inversely to LMP1, p53 and MMP 9 expression. CD8+ T cell infiltration was predominately seen in nests of cancer cells with a high level of EBV-LMP1 expression, but these CD8+ T cells showed low expression of CD25 and TIA-1, indicating that they were not activated. CONCLUSION: Our observation suggests that the heavy infiltration by lymphocytes in LMP1-positive NPC tumors does not appear to counteract tumor growth by cytoxicity as indicated by the low apoptotic index. Thus, LMP1 seems to enhance survival- and proliferation-related signals in NPC. In analogy with other tumors, both the infiltrating T cells and the accumulated p53 may be inactive.

PMID: 15330177 [PubMed - indexed for MEDLINE]


Guys...........note the "p53". There's our toxin connection, too! Go back to a previous thread of mine wherein I talk about p53. HAH! http://www.thisisms.com/modules.php?nam ... opic&t=476

Oh...this is getting way too easy!

Deb
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