JUST TO GET YOU THINKING

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

JUST TO GET YOU THINKING

Postby dania » Mon Sep 19, 2011 8:17 am

Someone posed this question on facebook CCSVI Toronto and it got me thinking.

"One simple question. We know inflammation affects arteries and veins, as in CNS vasculitis. All the blood vessels become inflamed. But MS only affects veins (retinal vein sheathing, perivenous lesions, CCSVI) If MS is truly an inflammatory disease, why are the arteries left alone?"
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Re: JUST TO GET YOU THINKING

Postby 1eye » Tue Sep 20, 2011 7:07 am

One reason might be that arteries have high pressure and no valves. Another might be the direction of blood: in arteries, from large to smaller and smaller vessels, until flow stops being controlled by vessel diameter and smooth muscles, and is now controlled by other cappilary-bed-specific mechanisms. After the consumption of food and oxygen which this arterial flow enables, the "discharged" blood goes through progressively larger vessels back to the heart , where it becomes arterial again, after being pumped through a similar system and transition from larger to smaller diameters and back again, to get the oxygen renewed by the lungs.

On the venous side of the brain's capillary beds, the pressure drops and reflux becomes a possibility.

For all of this, a diagram would definitely help (other organs have veins too -- why not them? Is it just gravity-centric positioning?).
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Re: JUST TO GET YOU THINKING

Postby 1eye » Tue Sep 20, 2011 7:58 am

If any credence is given to that Daflon video and to valves being places where immune cells can assemble or concentrate, then veins would be more likely because of the presence of valves (if you thought the problem might be immune-related). If you think it's shear and adhesion molecules, they must change a lot when blood goes through valves and capillaries.

I am also beginning to think about another possibility. Has anyone seen that video showing T-cells self-locomoting along the outsides of blood vessels? You can also see them squirting down and back up again in and out of the vessels. That made me think about a few things: If immune cells get from A to B on the outside of blood vessels, what propels/informs their movement? Do they sense the flow of blood? Maybe that is another reason why they congregate at valves. Or maybe it is only at valves that the blood slows down enough for them to squirt through. Of course, I don't know enough about fluid dynamics, but my reasoning would be that like water flowing over a dam, it would slow down tremendously at the entrance to the narrow part, and then speed up as it goes through. So the brain side might be the easiest place to squirt through.

The other thing I was thinking is, what if what they were doing was being propelled along by some kind of force from inside the vessel, maybe the same thing that make them stay on the vessel? They are single cells, which cannot think or feel. What motivates them? Perhaps it is charge. Perhaps it is magnetism. Something moving along with the blood. I have read about "affinity" but how does it physically work? How do cells follow sources (trails?) of molecules? They have no brains. Without a brain or eyes, how does any single-celled organism find food? Or, in the case of immune cells, find invaders to attack? I bet they are following charge, which changes with blood velocity and direction, and changes with the presence of unwanted visitors.

Any cell biologists care to comment?

That might explain why immune cells might follow myelin, if it's carrying electricity makes them locomote, and electrical transitions make them try to squirt through, which results instead in demyelination.
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Re: JUST TO GET YOU THINKING

Postby NHE » Wed Sep 21, 2011 6:29 am

1eye wrote:The other thing I was thinking is, what if what they were doing was being propelled along by some kind of force from inside the vessel, maybe the same thing that make them stay on the vessel? They are single cells, which cannot think or feel. What motivates them? Perhaps it is charge. Perhaps it is magnetism. Something moving along with the blood. I have read about "affinity" but how does it physically work? How do cells follow sources (trails?) of molecules? They have no brains. Without a brain or eyes, how does any single-celled organism find food? Or, in the case of immune cells, find invaders to attack? I bet they are following charge, which changes with blood velocity and direction, and changes with the presence of unwanted visitors.

Any cell biologists care to comment?

That might explain why immune cells might follow myelin, if it's carrying electricity makes them locomote, and electrical transitions make them try to squirt through, which results instead in demyelination.


Let's consider the case of one of the simplest cells, a rod shaped bacterium. It's movement consists of two behaviors, tumbles and glides. Think of a tumble as a random reorientation of direction. A glide is a movement in a particular direction uninterrupted by a tumble. The bacterium can sense the change in concentration of a chemical gradient. If that chemical is food for the bacterium, then it will move up the gradient. However, if that chemical represents a negative stimulus, then the bacterium will move down the gradient. Directed movement occurs in this fashion. In the case of a positive stimulus, such as a food gradient, if the bacterium senses that it is moving away from the food source, or down the gradient, the number of tumbles will be increased and the period between glides and the resulting length of glides will be shortened. In contrast, if the bacterium senses that it's moving towards a food source, then the frequency of tumbles will be reduced. By changing the frequency of tumbles vs. glides, the bacterium minimizes the amount of time it spends travelling in the wrong direction.

Eukaryotic cells, anything other than a bacterium, typically have proteins on their cell surface that are used as molecular receptors. A familiar example of how this works is with the drug Tysabri.

Tysabri prescribing information wrote:Natalizumab binds to the alpha-4-subunit of alpha-4-beta-1 and alpha-4-beta-7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the alpha-4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the alpha-4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-alpha-4-integrin antibodies also block alpha-4-mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further act to inhibit the interaction of alpha-4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.


In a nutshell, the Tysabri antibody binds to the cell surface integrin protein on leukocytes and blocks its interaction with the VCAM1 receptor on the endothelium. In the absence of Tysabri, the integrin protein on the leukocyte would be recognized by the VCAM1 receptor on the endothelial cell. This recognition creates a binding event and would signal to the leukocyte that its immune fighting capabilities were needed and the cell would then cross the endothelium. The case of integrin binding to the VCAM1 receptor is just one example. This type of receptor and target activity is quite common.

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Re: JUST TO GET YOU THINKING

Postby 1eye » Wed Sep 21, 2011 3:36 pm

Interesting that if the events in that movie were true, leukocytes don't normally go on the inside of vessels but on the outside. I forget whether they traveled with or against the blood flow, or if it was a different trail they followed.
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