Epstein-Barr Virus Might Kick-Start MS

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Dunmann
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Epstein-Barr Virus Might Kick-Start MS

Post by Dunmann »

Here's another article outlining EBVs possible influence on MS. With an illustration!

May 01, 2006
Epstein-Barr Virus Might Kick-Start Multiple Sclerosis

Researchers have found that patients with multiple sclerosis (MS) carry a population of immune cells that overreact to Epstein-Barr virus. The virus, which causes mononucleosis and may contribute to some cancers, has long been suspected to play a role in MS. However, the mechanism linking the virus to the disease was poorly understood.

Scientists think that MS—which can cause vision problems, muscle weakness, and difficulty with coordination and balance—is a result of the immune system attacking the body's own nervous system. Not everyone who is infected with Epstein-Barr develops MS, but the results of the new study, published in the June 2006, issue of the journal Brain, suggest that some individuals' unusually strong reaction to the virus may trigger the disease. The findings could lead to new therapeutic strategies for better control of the damage caused in this autoimmune disorder.


“EBNA1-specific T cells from MS patients not only increased in frequency, but also recognized a much broader region of the protein, compared to healthy people who carried the EBV virus. This was an interesting and unexpected finding.”
Nancy Edwards

The culprit, the researchers say, may be a population of T cells that helps boost other components of the immune system in response to the virus. "What we discovered in the peripheral blood of the MS patients were T cells that appeared to be primed for action against EBV," said Nancy Edwards, an HHMI-NIH research scholar at the National Institutes of Health (NIH) and co-author of the paper, which was published in advance online.


This illustrates how Epstein-Barr virus could hypothetically trigger auto-immunity in multiple sclerosis...

Image
Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) thought to be mediated by T cells attacking the insulating myelin sheath of nerve cells. EBNA1-specific T cells (1) or antibodies (2) could falsely recognize and attack CNS auto-antigens, a process called molecular mimicry. Or EBNA1-specific T cells could ramp up the action of auto-aggressive myelin-specific T cells with soluble pro-inflammatory molecules such as interferon-gamma, a mechanism termed bystander activation (3). In addition, latent EBV antigens could sustain the survival of auto-reactive B cells (4), or they could be triggered by auto-antigens that initiate viral replication (5), in turn elevating EBV-specific T cell responses (6). Illustration: Jan Lünemann


HHM-NIH research scholars are medical students who are interested in research. They compete for the opportunity to spend a year conducting mentored research in NIH labs. The program is designed to encourage medical students to consider careers as physician-scientists. Edwards, a medical student at Duke University School of Medicine, conducted her research primarily in the laboratory of noted MS researcher Roland Martin at the National Institute of Neurological Disorders and Stroke.

“The susceptibility to acquire MS is inherited, but environmental insults such as viral infections are thought to trigger the disease, and Epstein-Barr virus is one of the leading candidate triggers,“ said first author Jan Lünemann, a neurologist and immunologist at The Rockefeller University in New York. “Epstein-Barr virus does not cause MS, but the immune response to this virus is different in MS patients, and our hypothesis is that the altered immune response contributes to the development and progression of the disease.”

Lünemann started the research as a postdoctoral fellow at NIH. He is continuing to investigate the role of Epstein-Barr virus in MS in the lab of Christian Münz, a Rockefeller University researcher who specializes in EBV-specific immune responses.

The people with MS, who are universally infected with Epstein Barr virus, showed increased antibody responses to certain EBV proteins in previous studies, Lünemann said. “Very recent investigations have shown that such enhanced responses occur years before onset of clinical symptoms of MS,” he noted, indicating that EBV plays an important role early in the development of the disease.

“Our aim was to investigate what causes these increased antibody concentrations and if T cell responses to EBV are different in patients with MS," Lünemann said. He and Edwards focused on one viral protein, called Epstein-Barr virus-encoded nuclear antigen1 (EBNA1).

Epstein-Barr virus usually persists life-long inside immune system B cells and is kept under control by virus-specific T cells. When B cells divide, the virus produces EBNA1 and uses it to slip its own DNA into the new cell. T cells that target EBNA1 are a crucial component of EBV-specific immune responses in individuals without MS.

Lünemann, Edwards, and colleagues began by collecting T cells from 20 untreated patients with MS and 20 volunteers who had been infected by Epstein-Barr virus but did not have the autoimmune disease. They then isolated from each patient the T cells that specifically responded to EBNA1.

A series of experiments revealed a pattern among the EBNA1 T cells in MS patients that was not seen in the healthy volunteers. “We saw a dual effect—not only was there an increased number of EBNA1 responsive T cells, but these T cells proliferated to a greater extent when they were stimulated by antigens,” said Edwards.

"We also examined T-cell responses to influenza hemagglutinin, antigens derived from cytomegalovirus, and even EBV antigens other than EBNA1," Edwards said. "The T-cell responses to these were all normal in MS patients, indicating a distinct role for EBNA1 in the disorder."

The team then wanted to determine which portion of EBNA1 the T cells were recognizing. Generally, immune cells recognize one small, specific part on a protein, called an immunodominant region. Earlier evidence had pointed to one end of the protein, so the team decided to focus there. Münz supplied a series of 51 peptides—small segments of the EBNA1 protein—that the team added to T cells from MS patients and healthy controls.

As expected, the T cells in the healthy volunteers activated only in the presence of a specific group of peptides. But, Edwards said, “EBNA1-specific T cells from the MS patients not only increased in frequency, but also recognized a much broader region of the protein, compared to healthy people who carried the EBV virus." Immunologists call this phenomenon epitope-spreading. “This was an interesting and unexpected finding,” said Edwards. “At this point, I really believed we had a story.”

Finally, the team discovered that the hyper-reactive T cells belonged to the CD4 compartment of memory T cells and that these cells were strong producers of interferon-gamma, an anti-viral protein that shapes immune responses. “Animal research has shown that pro-inflammatory CD4 cells directed against central nervous system antigens can trigger an MS-like disease,” said Edwards. “So we knew we were looking at the right population of T cells.”

The next step will be to determine how these over-reactive immune cells trigger the destruction of the myelin sheathing that insulates nerve cells. “The broadened response of the T cells could lead them to recognize and attack cells they aren't supposed to, like brain cells,” said Münz. This process, called molecular mimicry, is seen in other autoimmune disorders, such as lupus.

Münz predicted that Edwards, who is returning to Duke University this summer to complete her medical degree, could help bridge the gap between the research worlds of infectious diseases and autoimmune diseases. “It's an exciting new field to which Nancy could greatly contribute,” he said.

Whatever the ultimate cause of MS, Edwards finds the therapeutic implications of her work exciting. “For some reason, MS patients chronically accumulate these hyper-responsive T cells," she said. "And if these cells are indeed involved, either directly or indirectly, in central nervous system injury and inflammation, interfering with them could prove effective.”

Orig link:
http://www.hhmi.org/news/edwards20060501.html
Dunmann.
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bromley
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Post by bromley »

Dunmann,

Good spot - the evidence is certainly building for EBV as a trigger for this disease (or in some cases). I e-mailed it to the UK neuro-immunologist who is running and EBV / MS think-tank later this month. He had already seen it!

Ian
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Post by flipflopper »

That’s very interesting. Thanks Dunmann for the article!

Ian, I am really looking forward to reading your post after you come back from the EBV/MS think-thank!!
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Post by bromley »

Flipflopper,

I don't want to raise expectations from the forthcoming think-tank, but I believe that some very strong evidence will be presented showing (hopefully) a definite link between EBV and MS. There have already been several research papers this year that have pointed to a link.

If EBV is proved to be the trigger in all / most cases of MS then an EBV vaccine in the future, given to children, could possibly prevent MS in future generations.

The question is, for those of us with it now, how would the identification of the trigger help us? I don't know the answer, but imagine that it might lead to new targets for drugs. Given that almost everyone gets EBV, but only a small proportion get MS, it might be possible to identify the reasons why some are protected - possibly genes? Maybe also the role of Vitamin D. We will still benefit from neuro-protective drugs which are in the pipeline and, hopefully, some of the work being undertaken to examine the possibility of tissue repair will pay off.

The neuro running the think-tank was the one who told me that a disease is auto-immune until they have found the virus or bacteria. This always made sense to me (as a non-scientist) so I hope the think-tank comes good.

Apologies to all for droning on about EBV as a possible trigger - it just fits my case so well and the other male in my room who was diagnosed a year after me.

Ian
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Post by viper498 »

I am still not convinced. Even though MS affects everyone differently, there is still no definite pattern. I would think if someone had an auto-immunity to their own myelin they would NOT go in to remission. It would be a constant attack with your body trying to rid you of your myelin and you would progress with out remission (like PP MS). It doesn't make sense that your body would all of a sudden stop attacking your myelin and you would heal your self, then all of a sudden start attacking again? So, if they are saying that those who have PPMS could have an auto-immune disease (with EBV being a possible trigger to those who are genetically susceptible to this trigger), then I can see that, but those with RR? I just don't understand how that could be? Please educate me if I am incorrect on something.

Brock
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Makes sense to me!

Post by lyndacarol »

Brock--Your observation makes sense to me. Autoimmunity cannot explain remission! Keep thinking and asking questions! You summed up my thoughts on this very well.

And in about paragraph 9 of the original article posted by Dunmann, I had trouble with this:
The people with MS, who are universally infected with Epstein Barr virus, showed increased antibody responses to certain EBV proteins in previous studies.
I didn't understand the clause--are they saying that people with MS are all infected with EBV? Where is the evidence? I haven't been tested for EBV; I never had mono.

I relish the freedom to throw ideas out there, too.
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Post by Nick »

G day Brock

You're right on with your concerns. In order to achieve a more constant attack on myelin tissue, there must be other factors which com into play.

The molecular mimicry theory postulated by the researchers plays an important role in this respect beyond the EBV. Food proteins also provide a close enough molecular sequencing to act as a mimic and their ingestion provides a daily source of targets for a hyperaggressive immune system.

Throw into the equation a sufficient presence, or lack thereof protective vitamin D3 and your MS prevalence variance with latitude factor is addressed too.

There is superb revidence to substaniate the molecular mimicry of food proteins and self tissue. In Celiac disease part of the gliadin molecule (found in various grains such as wheat and rye), part of adenovirus 12 and part of a gut protein all closely resemble each other and the result of such mimicry is an immune attack on the gut when food containing gliadin protein is eaten.

A similar three way mimicry occurs between a cell wall protein in grains and legumes, part of the Epstein Barr virus and part of the collagen in joints. This leads to rheumatoid arthritis in genetically susceptible people. For type 1 diabetes parts of milk proteins and viral proteins mimic proteins in the insulin-producing beta cells of the pancreas.Of course celiac disease is the most obvious example but there others closer to "home."

Guggenmos et al showed mimicry between self tissue and dietary proteins. See here for a forum discussion of said research.

This recent post demonstrates the parallels between MS and Type 1 diabetes and how milk proteins are inlvolved.

Ian

You comments about an EBV immunization are interesting. We know the effectiveness of vitamin D in autoimmune disease prevention. Why don't you espouse the adaptation of universal vitamin D supplements in amounts known to be adequate yet not toxic? The price if extremely affordable for all and it is very safe and helpful too for prevention of other nasties such as unrestrained cell proliferation (i.e. cancer) and osteoporsis.

For all your posting, you certainly don't do justice to this critical parameter of MS. Not worry mate, nor do the official medical bodies which tend to focus on more sexy, and profitable issues, when it comes to MS.


Cheers
Nick
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DIRECT-MS material

Booklets

Direct-MS produces information booklets on various aspects of multiple sclerosis. These booklets are listed below and a PDF of each one can be opened and downloaded by clicking on the title.
Alternately we can mail you a hard copy of any of the booklets. Just write or email us and let us know which ones you would like sent to you. Don’t forget to include your mailing address. There is no charge for this service.

Booklet #1 Take Control of Multiple Sclerosis
This booklet discusses the main causal factors of MS and, with this information as a guide, it lays out our recommendations for nutritional strategies to help control MS.

Booklet #2 Protect Your Family from Multiple Sclerosis
This booklet emphasizes the high risk for contracting MS of first-degree relatives of persons with MS. It discusses the causal factors of MS with special emphasis on vitamin D deficiency as a primary cause. Finally it demonstrates that adequate vitamin D can likely prevent MS in most cases and provides a recommended supplementation regime.

Booklet # 3 Multiple Sclerosis: The Alberta Disadvantage
This booklet demonstrates that the province of Alberta, the home of DIRECT-MS, has by far the highest rates of MS in the world: Prevalence 340/1000,000; Incidence 20/100,000.
Data and arguments are provided to support the argument that the main reason for the MS Epidemic is that all the main causal factors are present in Alberta, with low vitamin D supply being especially problematic.

Presentations

We have found that a Voiced PowerPoint presentation (‘Webcast’) is an effective way to communicate the science and the recommendations for nutritional strategies for controlling MS and preventing it in the first place.

The first presentation is Prospects for Vitamin D Nutrition. The discussion is narrated by Reinhold Vieth of the departments of Pathology and Laboratory Medicine, Mount Sinai Hospital and Laboratory Medicine and Pathobiology, University of Toronto.

Dr. Vieth addresses the topics of:
Vitamin D and Human Evolution
Clinical relevance of higher vitamin D intakes
Toxicology of Vitamin D

The second webcast is entitled Preventing Multiple Sclerosis and is the second in a series of web casts regarding nutrition and Multiple Sclerosis. The focus of the Prevention presentation is how MS can be easily, safely and inexpensively prevented by focusing on protective factors. This is a must see for those people with MS who have children.

Our first webcast, Nutritional Strategies for Controlling Multiple Sclerosis, addresses similar issues. It presents the probable causes of MS and how to effectively control those elements. A review of the protective factors and how to incorporate them into your lifestyle is also covered.
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Questions for Nick

Post by lyndacarol »

It seems that everything I read lately brings questions to my mind--your turn, Nick. Please take them as simple curiosity, no other intent here.

When you wrote:
Food proteins also provide a close enough molecular sequencing to act as a mimic and their ingestion provides a daily source of targets for a hyperaggressive immune system.
could you give examples of such food proteins? I am limiting my diet severely--no dairy, fish twice a week (otherwise, chicken), green salad for lunch everyday, typical breakfast is fruit and slice of whole wheat bread (my only bread per day), no carbs, no coffee, no alcoholic beverage.

Next question is about insulin (what else!!!) and Vitamin D. I think I've read that sunshine (and maybe even Vitamin D therefore) removes insulin from the body; is this so?

Thanks for any info you can give me.
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Post by bromley »

The issue of remission came up. I'm not so sure that things are as clear cut.

Dr Freedman is a very well respected MS doctor and in an interview about MS treatments said:
Generally speaking, the disease is almost always progressing, but one of our primary concerns is to identify those patients before they experience rapid progression.
Some time ago I posted an article about someone who had attended a presentation where the neuro put up MRI slides of a patient which were taken every six months. On every slide the lesions changed from month to month. The patient was on a DMD and had not experienced a clinical attack.

So I imagine the CNS is under constant attack and the body tries its best to repair itself. At some stage it cannot keep up with the pace of repair and the patient moves into the secondary progressive stage. Even with Primary Progressive the situation is not clear cut, some PPMS sufferers experience attacks later in the disease course. And there is Relapsing Progressive.

How a virus might drive the disease is for the experts to work out, but infections (viral or bacterial) often preceed an attack.

Nick,

Vit D may well be protective but it's not for me to tell people what to take. I try and get as much sun as possible.

I post articles I see on all sorts of subjects. EBV is of special interest as it fits with my own experience and the neuro undertaking work in this area is higly respected and very driven to seek an end to this disease. I find the viral trigger theory to be convincing given the research undertaken to date. Others are welcome to comment / criticise it.

I find the booklets you flag up rather annoying. lots of stories of individuals who couldn't walk and now run marathons. It's a pity that their neurologists cannot verify the stories. It's also a bit of an insult to the researchers and neurologists who are working hard to crack this very complicated disease.

I am always wary of miracle cures Nick. And the sort of booklets you provide links to, fit right into this. No doubt you were doing badly and are now fine? And your neuro can verify the big changes and the fact that you no longer have MS? A healthy diet is good for everyone, but controlling MS is a big claim.

Ian
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Nick
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Re: Questions for Nick

Post by Nick »

lyndacarol wrote: could you give examples of such food proteins? I am limiting my diet severely--no dairy, fish twice a week (otherwise, chicken), green salad for lunch everyday, typical breakfast is fruit and slice of whole wheat bread (my only bread per day), no carbs, no coffee, no alcoholic beverage.
lc
dairy, gluten yeast, eggs and legumes provide the potential to precipitate autoimmunity against self. Your diet, aside from the bread, is very good with respect to avoiding such foods. Maybe gluten is not problematic for you. If you are feeling well and are stable then carry on.
Next question is about insulin (what else!!!) and Vitamin D. I think I've read that sunshine (and maybe even Vitamin D therefore) removes insulin from the body; is this so?
Not to my knowledge but that doesn't mean it doesn't. The real virtue of vitamin D is its interruption of the immune system's process of autoiommunity (MS, type 1 diabetes, etc.).

Below is an excerpt from Vitamin D Supplementation in the Fight Against Multiple Sclerosis

1) Suppresses antibody production by B cells and the proliferation of T cells in
the thymus.27
2) Upregulates cytokines TGF-beta and IL-4. These proteins, which are produced
by immune cells, act as suppressants of inflammatory T cells.28,29
3) Inhibits production of pro-inflammatory cytokines such as IL-1, IL-2, TNF
and IFN gamma30,31 which also reduces inflamammatory reactions.
4) Interferes with T helper function and inhibits the passive transfer of cellular
immunity by Th in vivo32
5) Inhibits the production of NO (nitric oxide) by immune cells.33 NO has been
identified as one of the most destructive products of the immune system and is an
important factor in demyelination.
6) Inhibits the proliferation of activated and memory T cells.34, 35 Such cells are
the main mediators of the inflammatory autoimmune reactions of MS.
7) Exerts immunomodulating effects in the CNS by inducing a profound
downregulation of antigen expression by both infiltrating and resident antigen-presenting
cells (e.g. macrophages).36
8 ) Inhibits the actions of antigen presenting dendritic cells.37,38

In summary, vitamin D hormone has numerous effects on the immune system and acts within the CNS. All of these effects have the combined result of significantly reducing inflammatory autoimmune reactions from occurring and they readily explain the impressive correlation between MS prevalence and vitamin D supply and why vitamin D hormone is so effective in suppressing a variety of animal autoimmune diseases including EAE (animal
MS).1,16,17


Cheers
Nick
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viper498
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Post by viper498 »

I wish I had EAE dang it!!!!!!!
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Post by ljm »

I've got to second Bromley here. I found the sudden insertion of the entire diet theory and publications library of MS Direct really irritating. This was a thread about EBV. Whats the connection?
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Nick
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Post by Nick »

bromley wrote: Nick,


I find the booklets you flag up rather annoying. lots of stories of individuals who couldn't walk and now run marathons. It's a pity that their neurologists cannot verify the stories. It's also a bit of an insult to the researchers and neurologists who are working hard to crack this very complicated disease.

I am always wary of miracle cures Nick. And the sort of booklets you provide links to, fit right into this. No doubt you were doing badly and are now fine? And your neuro can verify the big changes and the fact that you no longer have MS? A healthy diet is good for everyone, but controlling MS is a big claim.

Ian
I'm sorry you feel that way Ian. Your dismay with our literature is the first negative feedback I've received.

We do not promote our regimen as a miracle cure. Quite the opposite. Identifying the cause is not to say anyone with nerve damage will be healed should they incorporate dietary intervention nor will it allow a predisposed individual to never again have to worry about MS should they improve to the point of being symptom free.

We do promote that diet intervention can dramatically slow or completely halt the disease progression. The degree of nerve inflammation/damage an individual has once they incorporate diet revision will to a large degree determine the extent to which they recover.

In the instance of Matt Embry, he utilised diet revision for six months before his symptoms completely abated but then again he was in his twenties at the time and although formerly dx’d did not have severe complications. His compliance with the diet was top notch and I surmise that his symptoms arose strictly from nerve inflammation and that his body was able to heal itself in the absence of the causal food protein consumption. He also recognises that despite his present excellent health his MS will become active again should he return to his former lifestyle.

I was much further progressed with my MS symptoms and was also older then Matt when I incorporated diet revision. Many of my symptoms have either abated or disappeared subsequent to diet revision yet I am plagued though with what I consider nerve damage and this necessitates the use of a cane for my significant limp. I feel great though and have been free of progression for nine years now despite decades of progressively worsening symptoms.

The basis for the dietary theory is formulated from published medical literature. Embry has merely formatted it into a rationale discourse and that is what is presented in our published literature. If that is an insult to researchers and neurologists who are working hard then so be it.

I suppose it is an insult to realize that the solution is so simple and obvious. I posit that our advocacy of diet intervention with MS is a replay of the struggles that Dr. Dicke had to endure in gaining acceptance from the orthodox medical establishment of his radical concept that gluten is the culprit of celiac disease. Whoever said that those who cannot remember the past are condemned to repeat it was right on the money. It’s hard to envision with all of our collective intellect that what was observed in celiac disease during something as recent as WW II has been ignored. But hey, the road to hell is paved with good intentions and that’s where either our well meaning crop of researchers or DIRECT-MS lies.

BTW, what does our material say about the neurologist who has agreed to undertake our proposed clinical trial regarding dietary intervention and MS? Stay tuned for more as I’ll formally announce it when the time is appropriate.

Ian, I not suggesting that you advise people to take vitamin D. I was commenting that, for a guy who obviously spends a lot of time here as evidenced by your 800 posts, your dearth of postings about vitamin D. I would think that for a solitary factor capable of reducing the prevalence of both MS and type I diabetes by 80% you would be a little more, shall we say, buoyant about posting research relevant to vitamin D and its virtues for preventing MS and the like.

Cheers
Nick
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Post by bromley »

Nick,

I don't come across many articles on Vit D. One of the neuros I am in contact with suggested that the way to prevent MS was an EBV vaccine and Vit D supplements.

From my limited knoweldge, I understand Vit D can be gained through exposure to sunlight and I am now making a conscious effort to get more exposure (after years of taking the medical profession's advice and putting on high factor sun cream etc). I have yet to find Vit D tablets in the UK and do not know how many to take - so grateful for any advice.

Like everyone on this site I want to see an end to this disease - my posts are never intended to be personal. But I have seen lots of claims and always challenge them. I hope the research will come up with some good results.

All the best

Ian
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lyndacarol
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Claims need to be challenged

Post by lyndacarol »

Ian, I publicly support your views. Claims need to be challenged! (Even any concerning insulin.) We are all looking for answers, but many "eyes" looking are more apt to find them!

Until the definitive understanding is there, sharing information and ideas is the only course of action I see to get there.
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