small-scale Putnam replication?

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

small-scale Putnam replication?

Postby Cece » Sat May 22, 2010 4:44 pm

113. Occlusion of single cortical venules results in decreased blood flow in upstream capillaries
J. Nguyen1, N. Nishimura1, C. Iadecola2 and C. Schaffer1

1Biomedical Engineering, Cornell University, Ithaca; 2Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA

Background and aims: Microvascular lesions in the brain play an important role in the development of cognitive decline.1 While recent animal models of small strokes have investigated the changes in blood flow that result from the occlusion of cortical arterioles and capillaries, the redistribution of blood flow following a venule occlusion remains poorly understood. This is largely due to the lack of an appropriate animal model. To study the consequences of single venule occlusions on cortical blood flow we use nonlinear optical techniques to induce clot formation in targeted venules and to study blood flow changes in upstream capillary beds.

Methods: Through a craniotomy in urethane-anesthetized rats, vascular topology (Figure 1A) and blood flow is measured using two-photon excited fluorescence microscopy of intravenously injected fluorescein-dextran. Blood flow velocity is determined by tracking the motion of unlabeled red blood cells. Occlusions are induced by tightly focusing high intensity, femtosecond laser pulses into a targeted venule. Nonlinear absorption of the laser energy in the focal volume injures the vessel wall, initiating the natural clotting cascade (Figure 1B).2

Results: Measurements of blood flow in brain capillaries were taken before and after the occlusion of an ascending venule, i.e. a venule that brings flow from the cortical capillary beds to a vein on the brain surface (Figure 1C). For capillaries one and two branches upstream from the clotted venule, flow decreased to 20%±3% (average±s.e.m.; 16 clots across 16 rats; P<0.001, one-way t-test) of baseline value, while for vessels three and four branches upstream, speed decreased to 51%±7% (P<0.001) of baseline. Additionly, we observed reversed blood flow in 55% of the capillaries one or two branches upstream from the occlusion (red arrows, Figure 1C).

a.Baseline two-photon image of vasculature. Surface venule and arteriole outlined in blue and red, respectively. Red circle indicates a penetrating arteriole and blue circle represents an ascending venule.
b.Post-clot two-photon image. Red ‘X’ indicates location of clot.
c.Mapped vessel network with flow speed after the clot as a percentage of baseline speed in individual vessels. Red arrows indicate vessels that have reversed flow direction after clot.

Conclusions: This reduction in blood flow speed suggests that occlusion of a single venule perturbs microvascular flow in upstream capillaries over a relatively large vascular territory. Such previously unrecognized reduction in flow can deprive nearby neurons of the nutrients required for normal function leading to cell injury and death, and may potentially play a role in the brain lesions responsible for cognitive decline.



Figure 1 Case study of an ascending venule occllusion. Case study of flow changes in capillaries after the occlusion of an ascending venule.

References

1. Vermeer et al. NEJM 2003;348:1215.

2. Nishimura et al. Nat Meth 2006;3:99.

http://www.nature.com/jcbfm/journal/v29/n1s/full/jcbfm2009153a.html
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Postby belsadie » Sun May 23, 2010 4:04 am

When you read about the impact o f tiny venules on brain health...it's daunting..the complexities that this problem might have on our health. The body surely s a mystery and it seems we've just scratched the surface!
Pray for the researchers........
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Quite different from CCSVI

Postby MarkW » Sun May 23, 2010 4:37 am

This study is interesting but very different from Putnam or CCSVI. CCSVI is about major veins not venules on the surface of the brain. The study was in rats not larger mammals. Please not not fall into the EAE trap and follow a misleading investigation path for years.
For me, the study gives ideas for future research, nothing more.
Kind regards,
MarkW
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Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Postby Billmeik » Sun May 23, 2010 5:53 am

Such previously unrecognized reduction in flow can deprive nearby neurons of the nutrients required for normal function leading to cell injury and death, and may potentially play a role in the brain lesions responsible for cognitive decline.




so they didnt get encephalomyelitis.

I wonder what nutrients they think of in this context? Oxygen?

2006 was well before ccsvi. Same path.
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Postby AMcG » Sun May 23, 2010 9:22 am

Zamboni 2006 is a discussion of the big idea that:

“ iron-dependent mechanisms of inflammation seen in CVD could be relevant to MS”

He writes about lesions in the brain which are like fingers digitating outwards from venocentric plaques into the cerebrum and quotes both Putnam and Charcot as describing the same thing.

As we know Zamboni’s idea is that micro-bleeding (extravasation) from veins into this surrounding tissue deposits the iron and begins the problem.

Exactly this process has been shown for very small veins in the brains of MS patients using 7Tesla MRI in 2008 in this paper.

“7T MRI: A Powerful Vision of Microvascular Abnormalities in Multiple Sclerosis” b y Y. Ge1, V. Zohrabian1, and R. I. Grossman1

Link: http://www.med.nyu.edu/radiology_resear ... sters.html

“In our two RRMS patients, we were able to demonstrate a total of 80 MS lesions, 58 and 22 lesions independently, and all lesions showed a strict perivascular distribution, following the form, orientation, and course of the vessels, this feature being best noted in small lesions. The diameter of veins associated with lesions ranged from 0.3mm – 0.7mm.”

The veins they imaged were 0.3mm to 0.7mm wide which is very small. Venules are vessels with a diameter of 0.1mm or less; so these vessels are the ones which venules will empty into. If these very small veins were inflamed and swollen they would occlude which would in turn block the venules which Nguyen, Nishimura, Iadecola and Schaffer are talking about. Also these tiny lesions are in the area surrounding these small veins, exactly where the venules would be.

As far as I can see what is presented here fits in perfectly with what Zamboni, Putnam and Charcot were talking about.
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Postby Cece » Sun May 23, 2010 10:32 am

AMcG wrote:As far as I can see what is presented here fits in perfectly with what Zamboni, Putnam and Charcot were talking about.

Yes...I thought it was of interest because it was looking at venous outflow in rats, by different researchers, with the conclusion: blockages in venous outflow, even on a micro level, appear to harm the brain. Also because it mentioned the reverse blood flow.
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Postby AMcG » Sun May 23, 2010 11:55 am

Much more than interesting Cece! A brilliant find ! Well done!
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I failed

Postby MarkW » Sun May 23, 2010 1:10 pm

I tried to caution from jumping to conclusions with small pieces of data but I clearly failed. Unfortunately opinions on this chatroom get treated as facts. They are repeated to Neurologists, who laugh at CCSVI. The good research work being done is lost in the noise of discussion. Sad because this actually hinders the case for CCSVI. We do not need to explain CCSVI to argue it needs to be treated in pwMS.
Kind regards,
MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Postby Billmeik » Mon May 24, 2010 6:53 pm

cece you are doing great work. The papers you have revealed in the last couple of days are great.

Such previously unrecognized reduction in flow can deprive nearby neurons of the nutrients required for normal function leading to cell injury and death, and may potentially play a role in the brain lesions responsible for cognitive decline.



this is the author's conclusion not a tims member.

I think this paper should be filed right next to putnam. Any more?
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Re: small-scale Putnam replication?

Postby malden » Tue May 25, 2010 1:21 am

Cece wrote:113. Occlusion of single cortical venules results in decreased blood flow in upstream capillaries
J. Nguyen1, N. Nishimura1, C. Iadecola2 and C. Schaffer1

1Biomedical Engineering, Cornell University, Ithaca; 2Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA

Background and aims: Microvascular lesions in the brain play an important role in the development of cognitive decline.1 While recent animal models of small strokes have investigated the changes in blood flow that result from the occlusion of cortical arterioles and capillaries, the redistribution of blood flow following a venule occlusion remains poorly understood. This is largely due to the lack of an appropriate animal model. To study the consequences of single venule occlusions on cortical blood flow we use nonlinear optical techniques to induce clot formation in targeted venules and to study blood flow changes in upstream capillary beds.
....
Conclusions: This reduction in blood flow speed suggests that occlusion of a single venule perturbs microvascular flow in upstream capillaries over a relatively large vascular territory. Such previously unrecognized reduction in flow can deprive nearby neurons of the nutrients required for normal function leading to cell injury and death, and may potentially play a role in the brain lesions responsible for cognitive decline.
....


Now we have the whole picture. Main problem is "flow changes in capillaries after the occlusion of an ascending venule".

So, it's not enought to stent or balloone one or two main neck veins, if occlusion still exists upstream: in venulas.

There are about 6 000 000 000 venulas in human boddy. If 1/100 of them is in the brain, its still 60 000 000. Seems practical imposible to me to examin them all, find occlusion, and put stent and/or ballooned them. They are so thin, with a diameter of 0.1 mm or less.

M.
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Re: small-scale Putnam replication?

Postby sbr487 » Tue May 25, 2010 4:24 am

Malden wrote:
Cece wrote:113. Occlusion of single cortical venules results in decreased blood flow in upstream capillaries
J. Nguyen1, N. Nishimura1, C. Iadecola2 and C. Schaffer1

1Biomedical Engineering, Cornell University, Ithaca; 2Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA

Background and aims: Microvascular lesions in the brain play an important role in the development of cognitive decline.1 While recent animal models of small strokes have investigated the changes in blood flow that result from the occlusion of cortical arterioles and capillaries, the redistribution of blood flow following a venule occlusion remains poorly understood. This is largely due to the lack of an appropriate animal model. To study the consequences of single venule occlusions on cortical blood flow we use nonlinear optical techniques to induce clot formation in targeted venules and to study blood flow changes in upstream capillary beds.
....
Conclusions: This reduction in blood flow speed suggests that occlusion of a single venule perturbs microvascular flow in upstream capillaries over a relatively large vascular territory. Such previously unrecognized reduction in flow can deprive nearby neurons of the nutrients required for normal function leading to cell injury and death, and may potentially play a role in the brain lesions responsible for cognitive decline.
....


Now we have the whole picture. Main problem is "flow changes in capillaries after the occlusion of an ascending venule".

So, it's not enought to stent or balloone one or two main neck veins, if occlusion still exists upstream: in venulas.

There are about 6 000 000 000 venulas in human boddy. If 1/100 of them is in the brain, its still 60 000 000. Seems practical imposible to me to examin them all, find occlusion, and put stent and/or ballooned them. They are so thin, with a diameter of 0.1 mm or less.

M.


I think the author seems to clearly suggest that such venule defect can lead to microscopic brain injuries resulting in cognitive impairement.

I think MS injuries are much more pronounced and more physically noticeable and probably results in more symptoms than just cognitive issues.

I think the first one is due to aging and not classical MS
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Re: small-scale Putnam replication?

Postby malden » Tue May 25, 2010 4:56 am

sbr487 wrote:I think the author seems to clearly suggest that such venule defect can lead to microscopic brain injuries resulting in cognitive impairement.

I think MS injuries are much more pronounced and more physically noticeable and probably results in more symptoms than just cognitive issues.

I think the first one is due to aging and not classical MS


I am not differ big/small cognitiv/notcognitiv part of brain... there can be occlusion venules everywere. And iron deposits as a result of decreased blood flow (according to CCSVI theory)

M.
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Postby mshusband » Tue May 25, 2010 5:25 am

No, not true Malden ... because the body WILL find a way.

Think about every time you cut your skin and bleed. Cutting a blood vessel is likely the cause. Yet the body doesn't heal that blood vessel, it shuts it OFF and builds a new one around. Same goes for the brain.

Just look at all the collateral veins trying to divert bloodflow around the IJVs in persons with stenosis. That is the body trying to build a way and find new paths! Same thing will go for those many small brain vessels you SPECULATE are causing damage. If they aren't working properly, the body will shut them down and build new ...

Your point isn't necessarily valid.
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Re: small-scale Putnam replication?

Postby sbr487 » Tue May 25, 2010 7:58 am

Malden wrote:
sbr487 wrote:I think the author seems to clearly suggest that such venule defect can lead to microscopic brain injuries resulting in cognitive impairement.

I think MS injuries are much more pronounced and more physically noticeable and probably results in more symptoms than just cognitive issues.

I think the first one is due to aging and not classical MS


I am not differ big/small cognitiv/notcognitiv part of brain... there can be occlusion venules everywere. And iron deposits as a result of decreased blood flow (according to CCSVI theory)

M.


Not sure if I agree with what you say (if I have understood your point).
I still feel venule occlusion is not related to MS.
If that was the case, how to you explain the fact that Dr's have seen blood flow restoration immediately after opening the veins?
Not one touched those venules, so what really happened?
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Postby malden » Tue May 25, 2010 8:33 am

mshusband wrote:No, not true Malden ... because the body WILL find a way. Think about every time you cut your skin and bleed. Cutting a blood vessel is likely the cause. Yet the body doesn't heal that blood vessel, it shuts it OFF and builds a new one around. Same goes for the brain.

Just look at all the collateral veins trying to divert bloodflow around the IJVs in persons with stenosis. That is the body trying to build a way and find new paths!


Ok, I agree, we don't need surgery, the body WILL find a way.

mshusband wrote:Same thing will go for those many small brain vessels you SPECULATE are causing damage. If they aren't working properly, the body will shut them down and build new ...

Your point isn't necessarily valid.


I am not SPECULATE, article:

113. Occlusion of single cortical venules results in decreased blood flow in upstream capillaries
J. Nguyen1, N. Nishimura1, C. Iadecola2 and C. Schaffer1
1Biomedical Engineering, Cornell University, Ithaca; 2Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA

that Cece quoted says that, not me.

M.
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