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Posted: **Thu Apr 05, 2012 7:31 pm**

http://www.plosone.org/annotation/listT ... a48d19f3c8

Ligation of the Jugular Veins Does Not Result in Brain Inflammation or Demyelination in Mice

RESULTS INTERPRETATION

Posted by PaoloZamboni on 05 Apr 2012 at 10:16 GMT

This is a very nice article on animal model of MS and CCSVI. The experiment is well conduit and I would congratulate the Authors. The main problem lies in data interpretation. It seems to me that the main purpose is to "hide" a result on the one hand, and to just privilege a single negative on the other.
Let me explain better:

1) the “hidden result” is that only the group of rats with the ligated jugulars develops a problem of cerebral hypoperfusion. This aspect is not measured in both sham and EAE rats. This is a very important result because the cerebral hypoperfusion is a constant feature of human MS, clearly not explained by the autoimmune theory (1). Alternatively, it seems that hypoperfusion in the human being can be rather explained by the CCSVI (1-2). From this point of view the animal model confirms that the stenosis of the jugular veins leads to cerebral hypoperfusion, which is one of the aspects of human MS never reproduced in the animal model of MS. From this point of view this experiment is an important contribution in order to achieve a model similar to the human disease.

2) demyelination and neuro-degeneration occurs only in EAE animals, a fact long known, but in CCSVI or sham did not. Also clinical and neuro-inflammatory parameters were not responsive in CCSVI model. This is not surprising as 3-6 months of slightly reduced hypoperfusion are not likely to be able to determine a damage of this magnitude. It should be more interesting to assess more refined parameters at cellular and axonal level in CCSVI model respect to sham.

REFERENCES

1. D'haeseleer M, Cambron M, Vanopdenbosch L, De Keyser J. Vascular aspects of multiple sclerosis. Lancet Neurol. 2011 Jul;10(7):657-66
2. Zamboni P, Menegatti E, Weinstock-Guttman B, Dwyer MG, Schirda CV, Malagoni AM, Hojnacki D, Kennedy C, Carl E, Bergsland N, Magnano C, Bartolomei I, Salvi F, Zivadinov R. Hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report. BMC Med. 2011 Mar 7;9:22.

No competing interests declared.

Dr. Zamboni responds to the Harvard mouse study. He sees significance in the fact that the mice with ligated jugulars indeed developed hypoperfusion, which is present and otherwise unexplained in MS patients. He points out the limitation of the mice's lifespan. For an illness with the word chronic right in the name (Chronic Cerebrospinal Venous Insufficiency), the mice's lifespan is too short to allow for the chronic damage possible during the much longer human lifespan. CCSVI is suspected to be due to congenital abnormalities present at birth, and the most common age of MS diagnosis is at age 30 years, which is 60 times the duration of 6 months studied in these mice. And I am curious what Dr. Zamboni would think of the point that Dr. Sclafani made, that the dural sinuses in humans drain into the internal jugular veins but in mice the sinuses drain into the retroglenoid veins. IJVs are a more important conduit in humans than in mice.

But what is meant by the more refined parameters at axonal and cellular level that could be studied in the CCSVI animal model? The finding that the ligated mice develop hypoperfusion could be compared to the sham and eae mice. Over a six months duration, what might be the effects that the hypoperfusion might have, on an axonal and cellular level, and how would they be measured?

Posted: **Fri Apr 06, 2012 1:37 pm**

WHEN ARE THESE GENIUSES GOING TO REALIZE WE ARE NOT FUCKING MICE?!!!!!!!!!!!!!!!!!!
http://WWW.THEGREEKFROMDETROIT.COM

how many of you can shit that small?

Posted: **Thu Apr 12, 2012 8:24 pm**

does not cause MS but does cause hypoperfusion, a precursor to MS.

Posted: **Fri Apr 13, 2012 1:00 am**

Billmeik wrote:does not cause MS but does cause hypoperfusion, a precursor to MS.

Hello Billmeik,
Refining your comment:
"ligatures in mice (a proposed murine model for CCSVI) induce hypoperfusion. Hypoperfusion seems to be a precursor to neurovascular diseases in humans"
Science research is usually precise, the conclusions drawn often are not. Drawing precise conclusions from research data was not performed in this paper as Prof Zamboni illustrates.
Kind regards,
MarkW

Posted: **Fri Apr 13, 2012 4:02 pm**

This replicating putnam is taking years.Been three years since we started talking about it here.

I think one of us who is a farmer should get the jugulars on a few cows ligated. Post photos of the brain slices when they're slaughtered.

I mean this hypoperfusion is a step down the road but this could take years. I want results now. We need scientists with ms because we're in a hurry.

Posted: **Sat Apr 14, 2012 6:49 am**

Billmeik, even if one of us followed through with such a plan, what would it prove? It would not be publishable in the medical literature.

I agree about being in a hurry.

Posted: **Sat Apr 14, 2012 7:24 am**

In a weird way this discussion board is as good as he medical literature. Not controlled by special interests, just a direct feed of data to the patient. If those pictures got published here and showed lesions, it would be heard all around the world.(would still need legit replication but would be extremely interesting anecdotal evidence.) I would finally know too.

Posted: **Mon Apr 16, 2012 2:41 am**

Billmeik wrote:This replicating putnam is taking years.Been three years since we started talking about it here.
I think one of us who is a farmer should get the jugulars on a few cows ligated. Post photos of the brain slices when they're slaughtered.
I mean this hypoperfusion is a step down the road but this could take years. I want results now. We need scientists with ms because we're in a hurry.

Hello Billmeik,
I agree with the need for haste. Unfortunately medical research is not fast. This is why I advocate 'reversing the symptoms of CCSVI' before the research 'what is the link between CCSVI and MS' is done. This approach is not popular with many CCSVI advocates in North America. In UK we are allowed by NICE to have the procedure in the context of research. I hope this will lead to progress in knowledge about the procedure and the impact on pwMS.
Kind regards,
MarkW

Posted: **Mon Apr 16, 2012 7:46 am**

I cannot think of any advocates in North America who have not put their money where their mouth is, so to speak, and gone ahead and had the procedure! While we cannot make decisions for other people, the decision I made for myself was that there was enough research (barely) and more than enough logic and a low enough risk that I went ahead with the procedure. It was successful in reversing symptoms of CCSVI such as cogfog, fatigue, bladder issues, reduced visual acuity, color desaturation, arm numbness, insomnia, and balance.

Having had the procedure, I would like to see more awareness of CCSVI among patients and accurate information being disseminated by neurologists. I would like to see the research hastened because I would like to know more on a personal basis of what to expect from the disease course of my MS now that I've had CCSVI improvements, and because I'd like to see the procedure available to all who want it, fully covered under insurance or government health care, and because I would like this to move toward being the standard of care for patients with MS and/or CCSVI if it warrants being the standard of care.

Here in this forum, I am not always being an advocate, I am often just being myself, and since I did not have complete resolution of cogfog and fatigue especially, I am interested in discussing things such as glucose metabolism as I am always looking for what more I should be doing. And I have appreciated your efforts, Mark, to drive home the importance of IVUS and your focus on what needs to be done.

Posted: **Mon Apr 16, 2012 8:09 am**

I'm not saying these guys are stupid just annoyingly methodical. I mean we're a bunch of laymen, and the thought three years ago was' they'll probably try replicating putnam on mice. Even though Putnam used dogs...
mice won't live long enough.' It's proven true and x many msers have progressed to being in wheelchairs because these jokers did not get on with it. I mean laymen predicted this it's not rocket science. These guys are so cowed by their ivory towers
and professional code of conduct that they are afraid to do the obvious. I say shame on them.Shame them. Show results on dogs of pigs(or cows) right now. Perhaps people will suffer less because of your lawlessness.

Posted: **Mon Apr 16, 2012 10:42 am**

MarkW wrote:.....I advocate 'reversing the symptoms of CCSVI' before the research 'what is the link between CCSVI and MS' is done. This approach is not popular with many CCSVI advocates in North America.

Not you Cece. I count you as a IVUS advocate.
MarkW

Posted: **Mon Apr 16, 2012 12:32 pm**

I think there are problems with lifetimes in mice versus biochemical processes that can take decades in humans. I think there are problems with the procedure. Though as Dr. Zamboni says it does reproduce a key feature of "MS"/CCSVI, it uses a mechanism which I think is never present in mice or humans, for long enough to develop either: complete ligation of jugulars. The method seems intended to exaggerate some 'results' at the expense perhaps of others. Putnam did not do this, though the dogs were probably not pleased, any more than the mice were. Total ligation of the wrong veins in an animal thousands of times smaller, which does not walk the same way, or sleep at the same time or intervals, is bound to provide misleading, conflicting, wrong results in a study seeking to model human circulation problems or chronic human conditions.

Posted: **Mon Apr 16, 2012 1:32 pm**

Yes, I am curious if there is a different effect from complete ligation than from partial blockages.
Remember there is research on marmosets going on at Stanford. And marmosets are more similar to humans than mice, pigs or dogs. I looked up lifespan of a marmoset after a previous discussion, but I've forgotten, let's see.

http://www.thisisms.com/forum/chronic-c ... ml#p166104
Here's a quote from Cheer, paraphrasing Dr. Dake:

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.

So there they are looking at partial occlusion as opposed to total blockage.
With my own jugulars, I had near total blockage (99% on one side, 80% on the other) and there are people with partial blockages who were hit by worse MS than I've had so far (knock on wood). My thought is that total blockage slows the flow, but partial blockage allows for faster flow, which allows for a higher hypertension when the incoming flow meets the reflux flow (you add the pressure of both to get the pressure peak when the two waves combined).

Lifespan of a marmoset is 6 - 15 years. Way better than the mice. But it might take 6 - 15 years for the data to come in?

Posted: **Mon Apr 16, 2012 2:07 pm**

But it might take 6 - 15 years for the data to come in?

I think putnam's dog's showed lesions after 10 months. I scanned the old paper from 1927 and I have it on my server if you can't find it anywhere else.

Posted: **Mon Apr 16, 2012 3:10 pm**

Ten months sounds right, BillM. I never have read Putnam's paper and probably should.
My thought was that they might wait until autopsying the marmosets before publishing. But that would be a long time. In the Harvard mouse research (from page one of this thread), didn't they use MRIs on the mice? Hard to imagine. The marmoset research is initiated by Stanford but being conducted in China, due to more relaxed animal research laws or environment. I don't know if MRIs for marmosets is on the docket. And there are tests of walking and other things that could be done along the way.

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