Altered collagen in IJVs in MS-new paper

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Altered collagen in IJVs in MS-new paper

Postby cheerleader » Tue Jul 10, 2012 4:38 am

Altered collagen expression in jugular veins in multiple sclerosis--
"The IJVs of MS patients presenting a focal thickening of the vein wall are characterized by the prevalence of loosely packed type III collagen fibers in the adventitia."

Type III collagen in not usually found in jugular veins--this change to the adventitia happens in chronic venous disease.

http://linkinghub.elsevier.com/retrieve ... 592?via=sd
Last edited by cheerleader on Wed Jul 11, 2012 7:24 am, edited 1 time in total.
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Re: Altered collagen in IJVs in MS-new paper

Postby MarkW » Tue Jul 10, 2012 5:12 am

Thanks for posting the link Cheer. Abstract is below. As Full Paper costs $31.50 I will go to the Radcliffe Library here is Oxford to read it. Sounds fascinating. Questions in my mind, start with:
Does the collegen cause stenosis or stenoses cause collegen build up ?
Does this mean pwMS will require regular procedures to remove stenoses ?
Is altered collegen found in other veins ?
MarkW

Altered collagen expression in jugular veins in multiple sclerosis
Matteo Coen a, Erica Menegatti b, Fabrizio Salvi c, Francesco Mascoli d, Paolo Zamboni b, Giulio Gabbiani a, Marie-Luce Bochaton-Piallat a,
a Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
b Vascular Diseases Center, University of Ferrara, Ferrara, Italy
c Department of Neuroscience, Multiple Sclerosis Center, Bellaria Hospital, Bologna, Italy
d Operative Unit of Vascular and Endovascular Surgery, S. Anna University-Hospital, Ferrara, Italy
Received 8 March 2012. Revised 23 May 2012. Accepted 24 May 2012. Available online 5 July 2012.

Abstract
Introduction
Venous abnormalities have been associated with different neurological conditions, and the presence of a vascular involvement in multiple sclerosis (MS) has long been anticipated. In view of the recent debate regarding the existence of cerebral venous outflow impairment in MS due to abnormalities of the azygos or internal jugular veins (IJVs), we have studied the morphological and biological features of IJVs in MS patients.

Methods
We examined (a) IJVs specimens from MS patients who underwent surgical reconstruction of the IJV and specimens of the great saphenous vein used for surgical reconstruction, (b) different vein specimens from an MS patient dead of an unrelated cause, and (c) autoptical and surgical IJV specimens from patients without MS. Collagen deposition was assessed by means of Sirius red staining followed by polarized light examination. The expression of collagen type I and III, cytoskeletal proteins (α-smooth muscle actin and smooth muscle myosin heavy chains), and inflammatory markers (CD3 and CD68) was investigated.

Results
The extracranial veins of MS patients showed focal thickenings of the wall characterized by a prevailing yellow–green birefringence (corresponding to thin, loosely packed collagen fibers) correlated to a higher expression of type III collagen. No differences in cytoskeletal protein and inflammatory marker expression were observed.

Discussion
The IJVs of MS patients presenting a focal thickening of the vein wall are characterized by the prevalence of loosely packed type III collagen fibers in the adventitia. Further studies are required to determine whether the observed venous alterations play a role in MS pathogenesis.

Keywords - Sirius red; CD3; Remodeling
=========================================
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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Re: Altered collagen in IJVs in MS-new paper

Postby 1eye » Tue Jul 10, 2012 11:44 am

In case you missed it, there was a major thread on this in 2011: http://www.thisisms.com/forum/chronic-cerebrospinal-venous-insufficiency-ccsvi-f40/topic11311.html
There was some attempt to bring related threads together: maybe this new one should go in it.

Of particular notice to me was the statement in a paper that the high levels of ET1 in MS are unconnected to MS "phenotype" or disease course. This is what I have suspected for the disease in general, but never saw any evidence as strong as this.

Now that Paulo and the Boys from Switzerland may be working on this maybe it's time they read a translation of http://www.thisisms.com/forum/chronic-cerebrospinal-venous-insufficiency-ccsvi-f40/topic11311.html

BTW I really miss all those people I saw posts from on that thread. Am I on their "enemies" list, or have they just stopped posting? It can't be my breath, maybe writing style?
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Re: Altered collagen in IJVs in MS-new paper

Postby Cece » Tue Jul 10, 2012 1:10 pm

I still want to know if the collagen can change back if the venous disease is resolved.
The extracranial veins of MS patients showed focal thickenings of the wall characterized by a prevailing yellow–green birefringence (corresponding to thin, loosely packed collagen fibers) correlated to a higher expression of type III collagen. No differences in cytoskeletal protein and inflammatory marker expression were observed.

If inflammatory marker expression is not observed, then these changes in the veins are not likely to be due to inflammation, which would mean it is not a likely result of any inflammatory processes going on in the central nervous system as part of MS.
Fig. 2. Evaluation of the percentage of the orange–red (red bars) and yellow–green (green bars) birefringence/total birefringent area (A) and RI (B) in the different vein specimens. RI=yellow–green area/orange–red area. Untreat.=untreated IJV; treat.=treated IJV.

Has anyone taken a look at Figure 2 yet? Does it show IJVs from patients who have had ballooning for CCSVI, and that is what's meant as treated IJV? Do the untreated and treated IJVs look about the same for collagen, and it's the healthy controls that is the far right figure that shows very different collagen composition?
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Re: Altered collagen in IJVs in MS-new paper

Postby 1eye » Tue Jul 10, 2012 4:11 pm

I can't look at any figures. What would make sense to me would be collagen transformations not as a result of inflammation (maybe genetically determined expression of proteins that changes with age?) but linked firmly to the diseases/conditions/mental states known as CCSVI and "MS".
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Re: Altered collagen in IJVs in MS-new paper

Postby cheerleader » Wed Jul 11, 2012 5:42 am

sorry I didn't post on other thread....travelling and not on computer much, but wanted to share a bit more on this thread...

Here's a great paper on collagen remodeling in venous disease of the legs. Phlebologists are learning more all the time about how the venous wall degrades.
http://www.phlebolymphology.org/2009/07 ... gradation/

Here are the factors phelbologists consider in venous disease of the legs:

Varicose vein disease is expressed very differently from one person to another, in terms of familial background, gender, society, and lifestyle. This is not surprising when we consider the large number of factors that predispose to and promote varicose veins.
Ethnic group: the differences observed tend to be related to types of physical activity, which in this context correspond to the role attributed to prolonged VHT.
Age: acts through the duration factor.
Female gender: the influence of hormones on the venous wall is plausible, although difficult to demonstrate, but women with varicose veins have a later menopause. The role of pregnancy is clear, and emphasizes the need for prevention by compression therapy.
Height and weight: height is a demonstrated risk factor, while obesity is not an independent factor. Nevertheless, excess weight increases the risk of leg ulcer.
Manual work: a relationship exists between VHT and uncomfortable physical activity in a prolonged standing position.
Genetics: a family link has been confirmed in several studies, including a well-known investigation by Cornu-Thénard et al,38 who also reported links to blood group and HLA type.

Hereditary abnormalities in elastin are obviously a cause of varicose veins, as in Marfan disease. There are also abnormal lines of fibroblasts that secrete defective categories of collagen or elastin. Prothrombogenic conditions develop during the course of varicose vein disease, with a propensity to hypofibrinolysis and hypercoagulability.39,40


so, you can see--there are many things to consider in venous disease. Gender, genetics, blood group, lifestyle, etc. But the links to remodeling in the IJVs and MS are striking.
(edited, because I just got paper and posted more below......)
cheer
Last edited by cheerleader on Wed Jul 11, 2012 6:16 am, edited 3 times in total.
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Re: Altered collagen in IJVs in MS-new paper

Postby cheerleader » Wed Jul 11, 2012 6:01 am

OK....just got the paper and am going to quote a wee bit....


The existence of vascular changes in the cerebral veins of MS patients has long been recognized [4], although it has not been ascertained whether these changes play a role in MS pathogenesis [14] or are just secondary to immunological abnormalities [6].

CCSVI, a syndrome characterized by an impaired brain drainage due to stenosis or obstruction of the IJV and/or the azygos veins, has been linked to MS [5]; the venous abnormalities have been ascribed to development defects during vascular trunk formation [15]. With the exception of a short report describing macroscopic lesions in the veins of two MS patients [16], at present, the histopathology of extracranial venous wall in MS patients has not been investigated.
Our results show for the first time an involvement of the IJVs in MS patients characterized by an altered proportion of collagen I and III within the adventitia.

Our results demonstrate that extracranial vein lesions of MS patients are characterized by a ratio of collagen type I/III similar to that observed in fibrotic lesions but without the presence of MFs, thus suggesting a local malformative pathogenesis rather than a fibrotic one; these results were confirmed by collagen type I and III immunohistochemistry.

Moreover, since the diseased-treated IJV specimens were sampled from vessel segments distal to the site of previous balloon venoplasty, it is unlikely that the altered collagen type I/III ratio results from local vessel trauma. Although mean age was higher in control compared with MS patients (80.3±2.8 vs. 33.8±3.3), the collagen changes were observed only in the veins of the younger MSpatients; this argues for a disease-associated rather than for an age related process.

A similarly altered collagen distribution has been described in several apparently unrelated conditions: varicose saphenous veins [27], hemorrhoids [28], paraesophageal hernia [29], skin incisional hernia [30], recurring inguinal hernia [31], and recurring hernia after alloplastic repair [32]. It is noteworthy that the venous ECM alterations seen in varicose vein patients are paralleled by similar changes in the dermis connective tissue, thus suggesting a systemic involvement of connective tissue [33]. Lower collagen type I/III ratio has also been associated with impaired anastomotic colon healing after surgery in humans [34] and in a rat model [35] as well as with increased wall stiffness and loss of compliance in dysfunctional bladders [36,37]. Moreover, in the developing bovine bladder, the percentage of type III collagen inversely correlates with bladder compliance [38].

The absence of inflammatory cells within the vein wall lesions suggests that the altered collagen I/III ratio is not secondary to an inflammatory disorder.

We suggest that the alterations observed in the adventitia of the IJVs of MS patients belong to a large group of conditions characterized by an altered collagen type I/III ratio, mainly due to a relative increase in type III collagen deposition.
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Re: Altered collagen in IJVs in MS-new paper

Postby drsclafani » Wed Jul 11, 2012 6:54 am

cheerleader wrote:Altered collagen expression in jugular veins in multiple sclerosis--
"The IJVs of MS patients presenting a focal thickening of the vein wall are characterized by the prevalence of loosely packed type III collagen fibers in the adventitia."

Type III collagen in not usually found in jugular veins--this change to the endothelium happens in chronic venous disease.

http://linkinghub.elsevier.com/retrieve ... 592?via=sd


cheer, correction....the collagen is in the elastic components of the vein. These are the media and advential. The endothelial layer is mostly intimal cells

so the collagen is thickened in the advential layer.

the conclusions are not firm, in my opinion. For example, if the collagen is less elastic, why do the veins dilate above the valvular stenoses? Could the dilation above the valvular stenoses result in deposition of Type III collagen?

Unfortunately, i did not notice any review of the valves themselves. That seems to be the problem in my opinion

S
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Re: Altered collagen in IJVs in MS-new paper

Postby cheerleader » Wed Jul 11, 2012 7:23 am

Hi Dr. S---
I didn't have the full paper when I first posted....
have it now and corrected to:
We suggest that the alterations observed in the adventitia of the IJVs of MS patients belong to a large group of conditions characterized by an altered collagen type I/III ratio, mainly due to a relative increase in type III collagen deposition.

(please remember, I'm only a civilian :)

The researchers noted the collagen switch in all segments in all MS veins, whether or not there was venoplasty, and they state that the switch wasn't due to venoplasty--and they didn't see it in any of the normal control veins. I don't know if this collagen III switch would block dilitation...but it sure might explain restenosis, right?
from the paper---
Moreover, since the diseased-treated IJV specimens were sampled from vessel segments distal to the site of previous balloon venoplasty, it is unlikely that the altered collagen type I/III ratio results from local vessel trauma. Although mean age was higher in control compared with MS patients (80.3±2.8 vs. 33.8±3.3), the collagen changes were observed only in the veins of the younger MSpatients; this argues for a disease-associated rather than for an age related process.



Check out the full paper, and it will answer more questions. Would love to hear your thoughts. But I agree, the lack of mention of valves is curious. Studying the valves would surely provide more info.
hope you're doing well!
cheer
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Re: Altered collagen in IJVs in MS-new paper

Postby Cece » Wed Jul 11, 2012 1:33 pm

Lots to think about here. Thank you, cheer, for posting the section from the paper itself. There is a big distinction if we are thinking of CCSVI as a disease of the valves or a disease of the veins and valves.

The altered collagen is found even distal to the the sites of venoplasty. Venoplasty usually covers the bad valve itself as well as a stretch of vein above the valve; although the balloon can be situated so that the shoulder hits the healthy vein just above the valve, this is not common practice. So we are talking about altered collagen that is some distance from the valve. It is not age-related because the comparison veins were from 80-year-olds and the MS veins were from 30-year-olds, and we were the ones who had the altered collagen in our veins, and those spritely 80-year-olds did not. We might have systemic involvement of connective tissue? That's a concern. These collagen abnormalities in the veins are not likely to be secondary to the inflammation of MS, because no inflammatory cells were seen.

Valves themselves are made of collagen, so a systemic collagen disorder could be expected to involve the valves:
In 200 dissections of internal jugular veins, the valves were investigated with regard to their constitution, their macroscopic and their microscopic anatomy. In 88% of the cases, an ostial valve was found. The cusp of each consists of two parts in 77%, of only one part in 16%, and in 7% of three parts. In 12% these valves are not found. The structure, the configuration, the topography of these valves are explained. The stroma of the valve consists of collagen and elastic fibrils. The surface of the luminal and parietal part is covered by endothelial cells with elastic and muscular fibers close to the attachment of the cusp to the vein wall.
http://www.ncbi.nlm.nih.gov/pubmed/3233351

If an internal jugular vein has abnormal collagen ratios, does ballooning soften the vein? If we are dealing with venous disease and not just valvular disease, then perhaps centering the balloon on the valve is better than off-positioning to minimize stretch of the healthy vein by placing the shoulder of the balloon just past the valve. Centering the balloon would stretch the vein itself more. Maybe ballooning the length of the IJV could give some benefit. Remember the research from Taiwan showing that patients who have migraines have reduced distensibility in their veins; if we have an altered collagen ratio, that should mean reduced distensibility in our veins with possible neurological sequellae. But as Dr. Sclafani pointed out, the vein does exhibit distensibility or dilatation right above the stenosis.

Maybe there will be another paper forthcoming that looks at the valves themselves. I am not opposed to talking about venous disease and valvular disease separately if there are observations to be made on both.

Sorry for the long post. I am going to look up systemic collagen disease and see what else that could involve.

Could the dilation above the valvular stenoses result in deposition of Type III collagen?

If so then it would not be likely to be a systemic collagen disease. This would be better news.
It is not good if Dr. Zamboni is proposing this to be a systemic collagen disease and that can be proven wrong. It might cast doubt on his other conclusions and on CCSVI itself. I don't know if the chronic effects of the deranged hemodynamics due to the outflow obstruction could lead to typeIII collagen deposition. I will look for what I can find on this.
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Re: Altered collagen in IJVs in MS-new paper

Postby Cece » Wed Jul 11, 2012 2:35 pm

http://circ.ahajournals.org/content/106/4/479.short
Synthesis of Collagen Is Dysregulated in Cultured Fibroblasts Derived From Skin of Subjects With Varicose Veins as It Is in Venous Smooth Muscle Cells

Abstract

Background— The dilatation and tortuosity observed in varicose veins provide evidence for progressive venous wall remodeling associated with abnormalities of smooth muscle cells and extracellular matrix. The present study was designed to examine if the phenotypic modulations observed in the venous smooth muscle cells of patients with varicose veins were also present in their dermal fibroblasts.

Methods and Results— Collagen type I (collagen I), type III (collagen III), and type V (collagen V) were compared in dermal fibroblasts derived from the skin of control subjects and patients with varicose veins. The synthesis of collagen I, the release of its metabolites, and the expression of its mRNA were increased in fibroblasts from patients with varicose veins, whereas the synthesis of collagen III was decreased but not correlated with a decrease in mRNA expression and in metabolite release. Matrix metalloproteinases (MMP1, 2, 7, 8, 9, and 13) and their inhibitors (TIMP1 and 2) were quantified in both cell types; only the production of proMMP2 was increased in cells derived from patients with varicose veins.

Conclusions— These findings suggest that the synthesis of collagen I and III is dysregulated in dermal fibroblasts derived from patients with varicose veins. These results are comparable with those observed in smooth muscle cells derived from varicose veins, thus suggesting a systemic alteration of tissue remodeling in subjects with varicose veins.

This was mentioned in Dr. Zamboni's paper, that patients with varicose veins also had abnormal collagen synthesis in their skin as well, thus suggesting a syystemic collagen abnormality. This should be testable in MS patients in the same way to see what the collagen composition of our dermal fibroblasts is. If our skin has abnormal collagen synthesis, that would suggest that we have a systemic collagen disorder. If our skin does not have abnormal collagen synthesis, that would suggest that our issues are more localized to the specific diseased veins. Either way it would add to what is known.
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Re: Altered collagen in IJVs in MS-new paper

Postby 1eye » Thu Jul 12, 2012 11:36 am

we were the ones who had the altered collagen in our veins, and those spritely 80-year-olds did not.
I don't know if we're jumping to contusions or if I don't understand the reasoning. I still see no reason the process could not be age-related. Maybe the chnges happen when you are young. Maybe the things you have to have are youth and CCSVI. Can anybody un-confuse me?
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Re: Altered collagen in IJVs in MS-new paper

Postby Cece » Thu Jul 12, 2012 1:29 pm

1eye wrote:I don't know if we're jumping to contusions or if I don't understand the reasoning. I still see no reason the process could not be age-related. Maybe the chnges happen when you are young. Maybe the things you have to have are youth and CCSVI. Can anybody un-confuse me?

The way I understand it is that these changes are not something that is present in older people who do not have MS. The changes are present in young people with MS. It could still worsen as those young people with MS become old people with MS but it is not in itself age-related because the 80-year-olds without MS did not have the abnormal collagen.

Could a systemic collagen disorder result in abnormal collagen in the blood-brain barrier making it weaker unrelated to any impact by the deranged hemodynamics of CCSVI? We need that skin test done on pwMS to see if it suggests toward or against the idea of a systemic disease. I have always thought of CCSVI as being localized not systemic.
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Re: Altered collagen in IJVs in MS-new paper

Postby Billmeik » Thu Jul 12, 2012 2:04 pm

If inflammatory marker expression is not observed, then these changes in the veins are not likely to be due to inflammation, which would mean it is not a likely result of any inflammatory processes going on in the central nervous system as part of MS.



yes nice catch. A vote for ccsvi->ms not the other way around.
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Re: Altered collagen in IJVs in MS-new paper

Postby 1eye » Thu Jul 12, 2012 4:17 pm

Sounds, from a vague impression, like a localized response to stretching, or the attempt to stretch, which is involved in the seemingly unrelated things. Sounds like it can apply to veins and/or other stretchable tissue. Maybe it involves making the tissue more elastic, stronger due to the possibility that the stretching force will return? The lack of this response to ballooned veins argues against it. Seems to be a common response to hernias. To prevent ripping? But then why not a ballooned area? I have seen pictures of veins that look like they have all ballooned out from excessive pressure above the neck, at Dr. Haacke''s site.

Maybe the collagen is deposited in the BBB due to unaccustomed pressure, and the extra stretch combined with more elasticity makes the sieve have larger holes, allowing things like T-cells to cross more easily? If the stretch is above the stenosis, maybe the direction of blood and refluxed blood matter here?
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