gray matter affected in earliest stages of MS

[billf]

For all the people who are still seeing MS as an autoimmune attack on myelin (modled by EAE in mice). Wake up!! Times are changing!!
<shortened url>

[bromley]

billf and all,

I too saw this article on the Boston Cure Project web page. It's not written in terms that a layman can understand, but my translation (I might be wrong) is that degeneration / death to cells / nerves is taking place and that this is not necessarily related to the de-myelination. I think this is a subject that we need to explore (all of us) in some depth as there are enormous consequences.

My view (non scientist):

When I was diagnosed I was told by the neuro that ms was an auto-immune disease involving an attack on myelin which could sometimes damage the underlying nerves. As devastated as I was, I was hopeful that if the attacks could be minimised / stopped by dampening the immune system response then this would minimise the damage / disability. Reading up on the subject, I found that most research was focused (almost completely) on the assumption that ms was an auto-immune disease. Future treatments e.g. Antegren would be more effective at reducing relapses / numbers of lesions etc. This would reduce disability in the longer term. Antegren results look very promising and no doubt future similar treatments will seek to improve on the figures. I was also heartened to see that effort was going into looking at ways for re-myelination.

I have become less convinved as my reading into this subject has increased - particularly horrible phrases which I have come across are brain atrophy (and horrible measurements of how much brain volume is lost each year) and something called pre-programmed cell death. I was also disturbed to find out that pretty much everyone with RR ms goes to SP (half within 10 years). At the SP stage the immune system attacks / inflamation play much less of a role. The cells are, in effect, dying. Campath trials on SP sufferers showed this. I have also become very sceptical about re-myelination if the cause for the de-myelination is not known and dealt with - it would be akin to painting a rusty car. The new paint would just come off again.

What if the problem is about the death of nerve cells. They degenerate / die and the myelin falls off (a bit like a house on poor foundations). Given this, the poor old immune system knows that something is wrong and seeks to get rid of the rubbish / repair the damage - the scarring covers the gaps. Attempts by the body to re-myelinate fail as it cannot succeed if the foundation is bad (the dead / dying nerve cells are not giving out the required signals). If this theory (layman's theory - in simple language) is right, then the whole auto-immune / de-myelination theory is wrong. Adjusting the immune system / dampening it down etc can never work nor will re-myelination. How can this be tested. I suppose the proof of the pudding is whether any of the immune treatments stop RR sufferers going to SP / stop disability (I hope they can, but I'm not holding my breath).

Possible implications are that all / much of the research done to date has been a waste of time. £millions have been spent on treatments which have no real effect in the long run (maybe a bit of delay at best).

Does anyone share these concerns / have any thought on this? Are any researchers looking at the problem from the other way round - that the degeneration / death of cells is the starting point - lesions / inflammation / immune system response is a sideshow (not my phrase)? The answer would be to find out why cell death is occuring and how it can be prevented (neuro protectors / stem cells to replace damaged / dead nerve cells). There is hope, but it will be bad news for the drugs companies with the current treatments focused on the immune system.

I woudl welcome views on this layman's interpretation of what's going on.

[BioDocFL]

Bromley,

First, something somewhat positive: in the Nov 9 News@Nature.com http://www.nature.com/news/2004/041108/ ... 108-1.html
spinal cords in mice can be repaired by blocking a protein (EPhA4) involved in scar formation.

Second, there are theories out there which describe how MS (and other so-called autoimmune diseases) can initiate before an immune system response. The problem is that too many researchers have blinders on. Just because they wear white coats doesn't mean they are more intelligent or logical than you, that's for sure.

For something positive to do, I would suggest that you find some of those theories and study them. Learn about the strengths and weaknesses of each theory relative to what we know about MS, ie. does it answer simple questions about the female predominance, the compromising of the blood-brain barrier, etc.
Then contact the executives at NMSS and/or NIH and asked them why those theories are not being funded. Ask them in person preferably. I feel they should already be seeking out new ideas and not continuing with the same old immune system based theories that are not working.

Wesley

[OddDuck]

Hi, guys.

Bromley, yes, what you are locating (information wise) is true (well, what I mean is, is that it appears to be what a lot of us find, also). Wesley's suggestions were great. And what you also might want to look up is Dr. Claudia Lucchinetti's research on the different patterns of MS.

MS doesn't appear to be just ONE "disease". According to what Dr. Lucchinetti has found, so far she has mapped four different patterns of MS. Two involve the immune system and two do not. The ones that do not (as far as can be ascertained right now) appear to be the "progressive" types of MS (or so that is what my understanding is. There may be one pattern that she found two different avenues of damage going on at the same time, but at that time, she still wasn't sure what or why).

I believe the reason why you see so MUCH concentration on RRMS (immune system involvement) is because of the statistics. Many more people come down with RRMS, so treatment of RRMS appears to be more focused on because it will help more people right off the bat. If you look back at my prior posts over the months, you will find that I, also, am chagrined that progressive MS seems to not have as much focus on it.

BUT......I will say that if you dig a little farther, you will find that researchers ARE focusing on progressive MS. It's hard to see, though, because the research isn't in layman's terms. The NMSS IS funding research into all sorts of areas. If you look at their PDF format documents on their website that lists what research they are currently funding, you will see all sorts of areas being funded.

I believe, though, that you will find most pharma companies concentrating on treatments for RRMS because that's where the numbers are and where the most money would be.

The problem with ascertaining which research would be applicable to the immune system (as in RRMS) or for progressive MS (and/or axonal damage WITHOUT demyelination), is in the terminology. Look for words like ion channels, calcium influx, GAP 43,..........uh..........well, anything that doesn't appear like it has to do with T cells or the ILs or cytokines. Even though a lot of it overlaps quite a bit, once you get used to the terminology, it is possible to suddenly see the difference between research that is geared directly toward immune system regulation, and research that is not. That will clue you into the likelihood that that particular funding for the described research is not solely focused on immune system.

I truly believe you will then feel better. I agree with Wesley, also, though in that there IS a strong concentration on the immune system, which IS involved in "most" cases, but NOT all! And as you mentioned, bromley, RRMS can evolve into SPMS......but again, not always.

The problem is, they unfortunately do know less right now about what might be causing the damage in the progressive patterns of MS, but they are working on it. The Mayo is working on it, for certain. Dr. Moses Rodriguez is doing some research right now (that the NMSS is funding) on aptamers. To my understanding, that is not directly immune system related, but I'll have to double-check my thoughts on that.

I'm not the "best" at all this by any means, but if you open the pdf file from the NMSS website and start browsing through it, if there are any terms or descriptions of the research that is being funded that may need further explanation..........post it here. That will also give us ALL something to consider and/or discuss. Or if you have any questions regarding terms, etc., (or if any of us do), we can all put our heads together and attempt to figure out what the researchers may be thinking and the avenue they are taking (and why). I will certainly do my best to explain what something actually means (to the best of my ability).

Again, as I said earlier, although the balance is NOT 50/50 on research or emerging treatments for anything other than RRMS, it IS there.

I hope this helps reassure you. (And not to blow my own horn, my research narrative that I posted back in June - although sort of technical - shows some terms that once I put it all down on paper, is why I thought a drug that did what desipramine appeared to do, SHOULD or might prove to be helpful for progressive MS. I mean, maybe the terms used in that narrative might give you some idea of what applies to possible progressive patterns of MS, and not necessarily strictly to demyelination or remyelination.)

Darn..........am I making any sense? Perhaps I could just post an example when I get a chance, huh?



Deb

EDIT: Sorry, folks, I think I've edited this a few times, simply to add clarification or further "thoughts". I think I'm done now.

SECOND EDIT: Nope, I lied! Here's my "oh, yea"........I posted a while back one of my abstract-thinking "here's how I got there" postings that had to do with progressive MS. I think it was some time back in July. Some researchers found some clues to SPMS, etc. If you're interested, it's one that I posted in different colors to separate interesting findings in the abstracts, and then my silly thoughts about it. And not negative thoughts, just the who cares what I think blabbing stuff.

[HarryZ]

Bromley,

Possible implications are that all / much of the research done to date has been a waste of time. £millions have been spent on treatments which have no real effect in the long run (maybe a bit of delay at best).

Well, if you read Dr. P. Behan's Pathogenesis of MS, he more or less subscribes to the abysmal record of MS research for the past number of decades. Like you said, it's pretty much been a waste of time when you look at where it is at today.

Dr. Barrett and Dr. Prineas got a lot of people thinking in a different direction when they autopsied that 14 year old girl who died suddenly from MS. They found myelin destruction without any evidence of the immune system being involved....so what caused that? At this point, nobody knows.

My wife has SPMS. It progressed to that level back in 1995. She was diagnosed in 1971 and had over 20 years of relatively symptom free life. She took absolutely nothing for her MS and even when the CRABs started to appear in the early 90's, she wanted nothing to do with them.

In June 2000, she started to use the transdermal patch applied Prokarin. She got immediate relief from several symptoms, especially fatigue and her SPMS has not progressed since that time. Her neuro prescribes it for her (originally rxd by her GP in Toronto before we moved to London, ON.) even though he really doesn't believe it. He has seen what it has done for her and fortunately places her health above his convictions.

Now if you don't believe in the immune system theory of MS, it's easy to understand perhaps how Prokarin works for some people. If you do believe in the immune theory, then how do you explain her current health? Those who are interested can go to www.edmsllc.com and click on the "Research" text to read up on the theory behind Prokarin.

This is but another reason why I simply don't believe that MS is a solely caused auto-immune disease. Yes, the immune system does play some havoc when the myelin becomes inflamed but I think it's a "reaction to" as opposed to "cause of" situation.

But at the moment we are sure of one thing....nobody's been able to prove the cause of MS and there certainly isn't anything close to a cure.

Harry

[OddDuck]

But at the moment we are sure of one thing....nobody's been able to prove the cause of MS and there certainly isn't anything close to a cure.

Yea, I gotta say, Harry,..........isn't that the unfortunate truth! That's a big part of why I got so deeply involved myself.

I kept digging thinking that SOMEBODY had to have discovered more about this somewhere!

I keep trying to look on the bright side as best I can. Sometimes it is certainly hard, though, huh?

Deb

EDIT: You know, and that's what makes it all the more difficult, I think........i.e. that so many different types of treatment work for certain people with MS, whereas it doesn't work at all for others. Not being able to find predominant commonalities for MS certainly doesn't help the research! (But I'm always THRILLED when I learn that ANYTHING helps anybody with MS.)

[OddDuck]

Hey, folks!

I know the NMSS isn't on everyone's most favorite list, but aside from that, they did just post a NEW list of the research funded this last time around (Fall, 2004).

Referring to research that might be going on that is NOT completely immune system related, here's an example (I've heard about this hypothesis before, too......glutamate. Wesley! Didn't you just mention something about glutamate, also?!)

"Daniel Pelletier, MD
University of California at San Francisco
San Francisco, CA
NMSS Area: Northern California Chapter
Award: Research Grant
Term/Amount: 10/1/04-9/30/07; $612,478

“In vivo assessment of glutamate in MS
using H-MRS at 3T” Evaluating a molecule
that may over-excite and damage nerve
cells, and correlating findings in different
forms of MS, including primary-progressive
MS.
Although the immune attack in MS is known
to damage the myelin coating that insulates
nerve fibers in the brain and spinal cord, the
nerve fibers themselves are also damaged. In
addition to destructive immune factors, a
molecule called glutamate has been identified
in MS brain lesions. Glutamate helps excite
nerve cells, and some research suggests
that too much glutamate may contribute to
tissue damage in MS.
In a novel attempt to track changes in glutamate
levels in MS lesions over time,
Daniel Pelletier, MD, and colleagues are using
an especially powerful imaging device,
magnetic resonance spectroscopy (MRS), to
measure and compare glutamate in MS lesions
in up to 500 individuals with either relapsing-
remitting MS, secondary-progressive
MS, or primary-progressive MS. The team is
also tracking any progress of clinical symptoms
and will attempt to correlate clinical
findings with observed glutamate levels.
This project should help define the role of
glutamate in MS tissue damage, and may
produce a “marker” that can be traced noninvasively
to determine whether potential
therapies impact glutamate activities."

This is just the first non-immune system related research that I came across in the list, so I posted it. The list is about 62 pages long, though, so if anyone hasn't checked it out yet, you might want to! (Well, wait....the page length depends on which program you are looking at it in. Duh, Deb! In PDF, I guess it's only about 36 pages. I copied it over to Word format, so I could copy and paste, and it just ended up to be 62 pages there. Ok.....so it's been a long day. )http://www.nationalmssociety.org/pdf/re ... search.pdf

I'm looking through it as we speak. It does appear (so far), that a lot more funding might have gone to trying to discover new diagnostic measures and procedures, etc., also! Now that's another area that I found was missing. I personally am glad to see some additional concentration on that, too! (I think I just a couple of days ago mentioned that I wished better diagnostic procedures and tests would come out soon. hmmmmmmmm.........how uncanny!)

Ok........I'm heading back to read some more!

Deb

EDIT: Ok....I already found a couple more interesting ones!

Ikuo Tsunoda, MD, PhD “Lesion development from inside (axon) to outside (myelin): Inside-
out models” University of Utah, Salt Lake City, UT, $44,000; 5/1/04-4/30/05

Oh! And this next one should help reassure some folks about non-immune related research, too! This looks interesting, also! Note how they are looking into damage in "myelinated" axons! There's our "ion channels", too!

Shing-yan Chiu, PhD
University of Wisconsin-Madison
Madison, WI
NMSS Area: Wisconsin Chapter
Award: Research Grant
Term/Amount: 10/1/04-9/30/07; $558,155
“Physiology and pathophysiology of potassium
and calcium channels in myelinated
axons” Exploring tiny pores along nerve fibers
whose dysfunction may lead to nerve
tissue damage in MS.

[OddDuck]

Oh, geez.....I'm on a roll now!

For those of you who don't like the "mice" (what's that saying Harry quoted about MS in mice? Darn...what was that, Harry?)

Anyway, I mentioned a while back about them starting to use zebrafish now for some research......and here it is again! HAH! Cool! The NMSS has funded some research into studying myelination via zebrafish! I wonder how that works? Doesn't that sound different, at least, though? (Heck.......I find it fascinating in a way myself. But what doesn't tickle me, huh? Hey....as long as it's a different approach from the same ole, same ole, right?)

Deb

P.S. Ok....I'll quit gabbing now. Sorry....I got carried away again!

[BioDocFL]

OddDuck,
I did mention glutamate, thanks for remembering. My thought was that elevated polyamines locally, perhaps from the chromosomal fragmentation I explained, could interfere with glutamate receptors. This could lead to slow uptake by the abnormal cells and lead to an increase in extracellular glutamate. This can then lead to damage in surrounding cells, normal and abnormal. Usually glutamate is released and taken up quickly in the synapses as I understand it. This interference in the uptake could leave glutamate in the extracellular space where it can start to cause problems. I found a couple of quick references through Google:

http://www.sciencedaily.com/releases/20 ... 064909.htm
http://fensforum.neurosciences.asso.fr/ ... 050_8.html
To quote the last one:
"Likewise, application of glutamate transport inhibitors to isolated adult optic nerves leads to an increase in extracellular glutamate and to glutamate receptor-mediated oligodendrocyte apoptosis. Finally, glutamate transporter inhibitors or glutamate transporter expression knock down in rabbit optic nerve in vivo induces demyelination and axonal damage."
So the polyamines, particularly spermine, could be actiing as a glutamate transport inhibitor when spermine expression is increased.
Perhaps I should send a note to those investigators and ask if they have considered polyamines as part of their project.
I also mentioned serotonin and polyamines. With increased synthesis of polyamines, there would be a decrease in available S-adenosylmethionine for serotonin synthesis. Decreased serotonin could lead to lower nerve signalling rates and be part of the underlying cause of depression in MS and similar diseases.
I'm going to printout the pdf file you mentioned and take a look at it for other projects that might be interesting. Thanks for posting it.

Wesley

[raven]

What I have done is to look at the available treatments for MS (both anecdotal and trialled) and tried to fit them into a model that explains their efficacy. Being a software analyst it's roughly equivalent to the old 'black box' testing.

As a result of this I have come up with a 'straw man' for the pathology of MS. It's very much home-brew science as the only resources that I have are Pubmed abstracts and an overactive imagination but to me it fits much of what is known about MS. The purpose of posting this theory here is so that others can kick holes in it, add to it or merely comment on it.

In my world the process starts with activation of the microglia. Microglia are the brains resident immune cells. This activation may occur as a result of many factors, bacterial, viral, protein etc. One of the best-studied agents in this group may be the bacterial cell wall endotoxin LPS. LPS is a widely used and powerful tool for the activation of microglia and of peripheral immune cells. Evidence for the bacterial cause theory perhaps.

Once activated microglia produce a number of neurotoxic factors.

These include the cytokines tumor necrosis factor- (TNF) and interleukin-1 (IL-1), free radicals such as nitric oxide (NO) and superoxide, fatty acid metabolites such as eicosanoids, and quinolinic acid. Studies using cell culture and animal models have demonstrated that excessive quantities of individual factors produced by activated microglia can be deleterious to neurons (Boje and Arora, 1992; Chao et al., 1992; McGuire et al., 2001). Furthermore, individual factors often work in concert to induce neurodegeneration. For example, Chao et al. (1995) reported that the combination of IL-1 and TNF, but not either cytokine alone, induced the degeneration of

cortical neurons. Jeohn and colleagues (1998) have shown that the combination of IL-1, TNF, and interferon-y work in synergy to induce degeneration of cortical neurons. Recently, Xie et al. (2002) showed that peroxynitrite, possibly a product of superoxide and NO, is a major mediator of neurotoxicity induced by lipopolysaccharide (LPS) or -amyloid peptide (1-42).

This may explain the apparent neuron apoptosis (programmed cell death) occurring before, and separately from major immune mediated inflammation. The presence of TNF and IL-1 in the brain parenchyma cause the endothelial cells (BBB) to express P-Selectin. P-Selectin begins to recruit immune cells from the bloodstream through the BBB.

Experimental autoimmune encephalomyelitis (EAE) is mediated by inflammatory cells recruited from the circulation to the CNS. We used intravital microscopy to investigate the mechanisms of this recruitment. No leukocyte rolling and very little adhesion was observed in healthy control mice. In contrast, both rolling and adhesion was observed in brain postcapillary venules before onset of physical symptoms of EAE. Rolling and adhesion remained elevated for 2 wk and returned to near normal levels by 5 wk postsymptom onset. Consistent with a role for P-selectin in recruitment to the CNS, P-selectin protein was detected in the brains and spinal cords of EAE mice. Expression was highest before symptom onset and decreased over the next 2 wk. The importance of alpha(4)

integrin increased with time as anti-alpha(4) integrin blocked approximately 20, 50, and 60% of leukocyte rolling 2 days before disease onset, 5 days and 2 wk postonset of symptoms, respectively, and 85% of rolling 5 wk postsymptoms. Addition of anti-P-selectin to alpha(4) integrin Ab-treated mice blocked all remaining rolling at each time point. Interestingly, however, alpha(4) integrin-mediated rolling appeared to be entirely dependent on P-selectin as anti-P-selectin alone was able to completely block all leukocyte rolling. In the absence of rolling (with P-selectin Ab), a 70% reduction in adhesion was noted. A very similar reduction was seen when mice were treated with alpha(4) integrin-blocking Ab. In conclusion, we describe increased leukocyte trafficking in

the brains of EAE mice with important overlapping roles for both P-selectin and alpha(4) integrin in mediating leukocyte-endothelial cell interactions.

Note the role for alpha-4 integrin (evidence for antegren effectiveness). In addition the beta interferons reduce IL-1 expression which may explain their efficacy.

Once the central immune system cells are recruited MBP specific T cells (possibly caused by a genetic flaw in susceptible individuals) begin to attack the neuronal myelin sheath. A relapse is born. Administration of immuno-modulating drugs such as cortico-steroids will at this point reduce the T cell mediated attack and ameliorate the relapse.

Note that the above treatments do not impact the microglial activation so although somewhat lessened the progression of disability continues through neuron apoptosis.

Microglial activation can be lessened by nalaxone (naltrexone) and also by Minocycline which may give an explanation for some of the anecdotal treatments. Interestingly the very small Canadian clinical trial of minocycline found that no reduction in brain parenchymal volume occurred during the treatment. This is evidence that the apoptosis of neurons has been interrupted by the antibiotic, which the front-line treatments are unable to do.

The more progressive forms of the condition may be due to the microglial activation cascading without recruitment of T cells from the bloodstream. This would result in neuron apoptosis without the corresponding T cell mediated inflammation.

As I said at the start this is very much home-brew stuff and the theory isn't even half-baked at this point but it's a starting place for comment and ridicule

Robin

[OddDuck]

Wesley: Absolutely! I'd encourage you to contact other researchers for sure!

Robin: Hey, your home baked brew isn't too far off from mine, ya know! So, if you ask ME, I'd say you are onto something. Like I've always said "it's all in the balance and the timing". I found very similar types of things as you have found, but then just went one step sideways in linking those hypotheses with any drugs that may provide beneficial effects for those very issues you expressed. (Actually, I came in from the opposite direction, also. I had the drug first and wondered why in the world it appeared to work so well, and then when I did comparisons of what it affected in the body with what I learned when researching the many hypotheses regarding the pathogenesis MS, is how I arrived at the things I have.)

Anyway, I also mention over and over TNFa and IL1b . [Word has it that Betaseron does inhibit VLA-4 somewhat, also - but provides a little bit of a balance by its other mechanisms of action; and of course as I'm always hammering home, the pet drug I want researched and tested specifically for MS does those three things also (in addition to others). The VLA-4 interaction, though, again is balanced out with other possible beneficial affects and is merely "inhibited" not blocked and is done via a different pathway. Add a small amount of VLA-4 inhibition with raising IL-10 and you've got (to ME anyway), a much safer and more solid method of strengthening the BBB.]

Holding TNFa and IL1b "in check", I personally have found over and over should prove to be highly beneficial in MS. Again, though, I will say we need SOME TNFa and IL1b to do some of its beneficial work in the body, but in MS it needs to be "regulated" and not allowed to go haywire.

That is another reason why I found any success in "selective" targeting of immune regulation pretty exciting! If they can find ways to "selectively" affect certain or ANY processes in the body, then a treatment for MS may be able to be "taylored" to FIT MS more precisely.

I won't go on about your other thoughts, as I again personally support your conclusions on those, also!

So..........poke holes in your findings and correlations? Not ME, that's for sure!!



Deb

[OddDuck]

billf,

I was doing a little investigative search into the gray matter subject that you originally posted here, and just from a quick look, what I found was that the gray matters consists of unmyelinated axons! WAIT: Let me say that exactly. I'll quote:

"Gray matter- areas of the brain that are dominated by cell bodies and have no myelin covering (in contrast to white matter)"

Tell me that doesn't ring a bell, huh? (i.e. cell or axonal damage without demyelination) And most of the gray matter controls movement. Well, I'll be!!!!

If that's true (that MS, or even some patterns of MS) DO strike the gray matter, whereas it was never thought to do so in the past, MIGHT that lead us down a different avenue and MAYBE one that might open up some new thoughts and ideas from researchers?

Hey............this week appears to producing some new avenues and spur some hope that maybe FINALLY, the researchers might begin to really "think out of box", as they say!

Deb

P.S. Oh........while doing this quick exercise this morning regarding gray matter, I ran across a really neat glossary that I posted on a different thread here. Anyway, I thought it was neat.

[HarryZ]

Deb,

For those of you who don't like the "mice" (what's that saying Harry quoted about MS in mice? Darn...what was that, Harry?

You mean that poor MS mouse? The one that has MS that isn't anything like MS in a humans but keeps on getting mentioned in possible therapies!

You know, the mainstream MS research community defines MS as a demyelinating disease that is caused by the detsruction of myelin in the brain. The study mentioned earlier says that there is evidence of damaged cells and nerves in the gray matter, where there is no myelin!! So now they have discovered that something is causing MS symptoms in an area of no myelin....giving credence to Drs Prineas and Barrett's autopsy discovery.

Again, too many questions and certainly not enough answers.

Harry

[raven]

Phew! Thanks Deb.

I expected a volley of rotten fruit to come my way after posting my theory What I may well do is write the whole thing up properly, I have much more to add and many more references but didn't want to clog the thread up with an epic post.

I have an appointment in January with a Professor of neurology. He is at the forefront of stem cell research for MS. In fact he has just been granted a bunch of money by the NMSS for his research. I may well chuck my findings at him and see what he says.

Why do I feel that he won't be interested?

Robin

[BioDocFL]

Robin,
Write your hypothesis up into an article and send it to Medical Hypotheses or Journal of Autoimmunity or Lancet. They all publish hypothesis articles. Writing it into an article format, whether you submit it or not, helps you think things through and explain them fully. That will help get it across to the neurologist or whoever you show it to. Once you have explained the same thing over several times in different wording, you find the expressions that get each idea across best.
Systems analyst, eh? That was my background too. I think it is good training for tackling human systems.

Wesley