Dr. Dake on the new animal models of CCSVI

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Dr. Dake on the new animal models of CCSVI

Postby cheerleader » Wed May 18, 2011 11:20 am

Here is part of his lecture from the Hubbard Foundation conference:
http://www.youtube.com/watch?v=Xp2aWE7W ... re=related

First, Dr. Dake explains how the current model of EAE is created in mice. It is a rather convoluted procedure...then he discusses the new research.

"There's an animal model, but it's not really, unfortunately, like most animal models, it's not really a human model. Basically, you take like a mish of ground up spinal cord and brain from some other species, you mix it with some oily substance, some TB bacilli, and some bordadella pertussis, some whooping cough toxin, and inject into peridium, and what you get is this whopping inflammatory response, and that's good because you get the accelerated disease process, but obviously in humans, it's a much more chronic and progressive thing.

So, what we've done is taken mice and ligated (the jugular veins) and we're going to move now up to marmosets, because that's the next level of the species, and marmosets you can actually partially occlude the veins and keep them open without totally ligating them.

And these mice and their veins, we've got a recipe that we think is right where we want it. We're starting to see not only clinical performance differences between mice that are ligated and mice that aren't ligated, but now there's a way to tomographically, in a little mouse brain, to make these wafer thin micron sections thru the whole brain and we're learning a whole lot. I think it's going to be very interesting as we move up to a larger model to really see....but we think that we're seeing an accentuation of the venous ligation on the disease process."

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Postby Cece » Wed May 18, 2011 11:47 am

This is great news.
What difference might be expected with a partially occluded vein as opposed to a totally ligated vein?
Anyone know the lifespan of a marmoset?
Last edited by Cece on Fri May 20, 2011 1:49 pm, edited 1 time in total.
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Postby Ruthless67 » Wed May 18, 2011 8:14 pm

Cheerleader,

Thank you for sharing this part of the conference. I was grabbed by the last sentence of Dr. Dake's quote,
....but we think that we're seeing an accentuation of the venous ligation on the disease process."


What a great avenue of research. I can't wait to read the published reports that they have indeed proved this line of thought and that we get real solid answers. These are exciting times.



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let's do it...

Postby 1eye » Tue May 24, 2011 7:39 am

Cece tells me Dr. Dake is doing something like this with marmosets. I don't own the book, but I don't think they used marmosets. I don't know how the physiology matches up or if it does, better than other species, but maybe better than dogs...

I would like to propose something involving ligation and real lesions, but leaving out the placebo nonsense, and instead including MRI.

I have mentioned elsewhere in this forum, a book about an experiment that was done on monkeys, using surgery to introduce stenoses into their arteries, to give them real hypertension. The experiment was done so that the investigators could run a test which is a variant of the the Wisconsin Card Test (WCT), measuring the animals for changes
in their executive cognition.

I have also heard and read about a well-known experiment done in the 30's, which involves dogs. In this experiment Tracy Putnam says he saw lesions similar to those of MS. We believe this experiment to have been a true occurrence. Therefore it should be possible, using this same surgery, to tranquilize and anesthetize monkeys, operate on them, and give them the lesions of MS. We should be able to watch these lesions form in real time on conventional MRI.

It should not be necessary, as it was in the hypertension experiment, to use drugs to control heart adverse events. Moreover, it should be possible, using vascular surgery, to reverse the effects of the surgery and make the lesions
disappear from the MRIs (induce remission).

In addition to these things, it should be possible, using PET technology, or MRI techniques, to see directly the effect of this kind of induced hypoxia in terms of delivery of oxygen to the brain either in real time, or directly before and after surgery. The same can be done with any reversals that are achieved.

These same tests can cover measureable (non-placebo-able, what an awful adjective) symptoms such as executive function, hand and foot temperature, oxygen uptake and maybe others.

The veins involved would be the ones discovered to be involved in CCSVI by Dr. Zamboni: the internal jugulars and the azygous. It may turn out that enough similar simian physiology cannot be found to create the same problems. Indeed, since humans have left the trees we have apparently had a significant change in what is common or expected in the valves in these veins. It may be that CCSVI is a kind of missing evolutionary link.

It should be possible, given Dr. Putnam's experience with dogs, who do not even walk on their hind feet, and do not climb trees.
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Postby cheerleader » Tue May 24, 2011 8:03 am

I just transcribed Dr. Dake's lecture, one eye....I don't pick the animals.

Here's part of my transcription, you can listen to the whole thing at the link I posted above.

So, what we've done is taken mice and ligated (the jugular veins) and we're going to move now up to marmosets, because that's the next level of the species, and marmosets you can actually partially occlude the veins and keep them open without totally ligating them.


The rational is probably because 1. these are upright animals 2. they can survive longer with only partial ligation. The problem in the mouse model of CCSVI is that they die too quickly to have that many MS-like lesions develop.

The mice in EAE are blasted with foreign antigens, bacteria, viruses and the inflammation happens over night, creating the demyelination. But, as we all know by now, that doesn't really look like MS in people....which is a more ongoing, chronic problem. The marmosets live longer, and hopefully, will provide more answers. It's what we need...a modern day animal model...yes, we have Putnam's dogs, but that was an oily solution directly injected into cerebral veins, not extracranial. And we don't use dogs in the US anymore, because of animal rights laws. I'm pretty sure the marmosets are being tested in China, where the rules are more lax. (At least that's what Dr. Dake explained to me...)
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Postby 1eye » Tue May 24, 2011 8:47 am

Maybe what's needed is some parallel development of materials and technology to provide something like my brother's jugular shunt, which he received as a baby and grew up with, having had several versions of it for about fifty years so far.

If we can build a device to implant in an experimental animal, the blood drainage can be closed off in a controlled manner remotely. Then, the effects of the reduction, and of reopening can be determined. They are doing amazing things with technology these days: look at all those eye-pod-pad-ish thingies. I swear the geek squads are driving evolution these days... I am all for animal rights, and hamburgers, and tranquilizers, and capitalism, too. Turn, turn, turn.

I'm not saying redesign the human body and start replacing parts, but in cases like ours it may be a good idea to take an old one over to have it rebuilt by a customization/chop shop.
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Postby Cece » Tue May 24, 2011 9:04 am

If we can build a device to implant in an experimental animal, the blood supply can be closed off in a controlled manner remotely.

That is clever.

I wonder what happens when a marmoset with induced CCSVI undergoes an oxygen deprivation or stress event.

Similar to when a person with CCSVI takes a high altitude flight or hikes at altitude, as I did, with subsequent immediate optic neuritis/MS relapses.

Part of the story for humans is not just the chronic effects on the brain but also one-time events that push the brain past its limits.

Hypothesis would be that healthy marmosets could handle these events without damage but that CCSVI marmosets could not.

Marmosets are monkeys, this is a big step up from mice.
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Postby 1eye » Tue May 24, 2011 9:25 am

Another nifty miniaturized gizmo which might be useful in human replacements is the accelerometer used in cameras and computers now to determine which way is up. That's really the trick that the gyroscopic camera and the human ear and the segway have in common. It's some kind of accelerometer, which might come in handy when controlling a gravity-fed blood valve. If one were designing from scratch... good thing I wasn't around when they were handing out ears, eh?
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Postby 1eye » Tue May 24, 2011 11:18 am

This is the book I was referring to. http://tinyurl.com/44qpb3d It used rhesus monkeys.
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Postby se1956 » Wed May 25, 2011 1:06 am

These new animal models of CCSVI are very interesting but one has to be careful with the interpretation of the data.

With a normal amount of cigarette smoke nearly nobody will get lung cancer but the risk strongly increases (but it remains still low).

With CCSVI and MS, I think, it is the same situation.

The many pro and con discussions often show a misunderstanding of risk factors.

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interpretation of the data

Postby 1eye » Wed May 25, 2011 9:53 am

interpretation of the data

I have no idea what this is driving at, but I think the phrase "nearly nobody" would make a good book, movie, poem, song title. Nearly nobody wins the big lottery jackpot every few days. If you are trying to scare people away from venoplasty, I think you are going to have a pretty hard time, considering this topic is not about safety studies, but about animal models. Your audience is elsewhere if that is what you did have in mind.
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Postby AlmostClever » Thu May 26, 2011 5:53 am

Just wondering - did Dr. Dake ever test the effects of heat on the mice?
If you can't explain it simply, you don't understand it well enough. - Al Einstein
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Re: interpretation of the data

Postby codefellow » Thu May 26, 2011 9:36 am

IMHO: If you give CCSVI to ten monkeys and nine of them get MS, the neuros will claim this disproves the claim that CCSVI causes MS. There is a difference between a CAUSE and a RISK FACTOR.
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Postby 1eye » Thu May 26, 2011 5:02 pm

If the tenth one walked over to the computer and started in typing "To be, or not to be, that is the" I would start to worry. :)
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Re: interpretation of the data

Postby Cece » Thu May 26, 2011 5:16 pm

codefellow wrote:IMHO: If you give CCSVI to ten monkeys and nine of them get MS, the neuros will claim this disproves the claim that CCSVI causes MS. There is a difference between a CAUSE and a RISK FACTOR.

Calling it a risk factor (or a "promoter" of MS, as Dr. Dake called it at ISET) is much easier to prove than calling it a cause. And unlike other MS risk factors like low vitamin D during childhood, being female, growing up in an area with greater incidence of MS, and genetic susceptibility to MS, to name a few, CCSVI is a risk factor that can be treated and removed. What effect that has on the MS also remains to be proven. Can't wait til it is.
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