all things vitamin D

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Re: all things vitamin D

Postby jimmylegs » Mon Oct 28, 2013 6:22 pm

no drama, just clarifying and making distinctions between the context of the studies you're talking about, compared to the studies i'm talking about.
The problem that Hayes protocol addresses is that cells are unable to convert 25(OH)D3 to calcitriol and calcitriol is the master, regulatory hormone of the adaptive immune system.
i'm talking about the potential for zinc to correct that cellular failing. I don't go for approaches that bypass broken systems. I prefer to fix them wherever feasible. when a nutritional deficit common to ms patients is potentially involved, I personally feel it is irresponsible to ignore it in favour of a downstream supplemental substitute for endogenous calcitriol.
Perhaps EAE mice are inherently sufficient in zinc and that may not be true in humans.
I have never heard of EAE mice being matched to the nutritional deficit status typical of ms patients. I can, however, think of at least one published case where researchers used murine nutrient deficiency as a model of human illness (depression), in order to test pharmaceutical solutions. <laughing ruefully while shaking head>
The only point I was trying to make at that calcitriol + D3 worked without zinc supplementation.
understood - at this stage i am hopeful that you see my point as well.
It could be an issue in humans, but not in EAE so it would certainly seem sensible that any trial of this in humans, look for deficiencies in any of the vitD co-factors such as zinc, magnesium and copper and correct them before treatment to avoid having a failure because of a deficiency.
i agree 1000%.
I haven't seen any trials of vitamin D in MS that have done this, but when we are King and Queen of MS Clinical Trials, we shall simply order that it be done or off with their heads!
neither have i. it's a gap that continues to get on my nerves.
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Re: all things vitamin D

Postby Squeakycat » Mon Oct 28, 2013 7:23 pm

jimmylegs wrote:no drama, just clarifying and making distinctions between the context of the studies you're talking about, compared to the studies i'm talking about.

i'm talking about the potential for zinc to correct that cellular failing. I don't go for approaches that bypass broken systems. I prefer to fix them wherever feasible. when a nutritional deficit common to ms patients is potentially involved, I personally feel it is irresponsible to ignore it in favour of a downstream supplemental substitute for endogenous calcitriol.

Laudable goal and fair enough contention, but . . .

If zinc would have the same effect as calcitriol + D3 in EAE and possibly MS, then people with adequate zinc levels shouldn't have MS. Is everyone deficient? Are people who are not deficient free of the disease?

The other question is that studies in other diseases in which CYP27B1 is being blocked are all pointing to TNF-alpha and IL-6 as the culprits.

Will adequate zinc levels deal with them? And if so, is there anything to suggest that this is true in EAE or MS? I don't know the answer to that question. It is a question.


SqueakyCat wrote:Perhaps EAE mice are inherently sufficient in zinc and that may not be true in humans.
jimmylegs wrote:I have never heard of EAE mice being matched to the nutritional deficit status typical of ms patients. I can, however, think of at least one published case where researchers used murine nutrient deficiency as a model of human illness (depression), in order to test pharmaceutical solutions. <laughing ruefully while shaking head>

I now see you are coming at this from a slightly different perspective than I originally thought was the case, but my point that bypassing the problem of conversion to get the immune system back on track worked with calcitriol + D3 and didn't require zinc supplementation still stands.

I see now that you weren't so much questioning that as suggesting that it would be better to deal with a nutritional deficiency than to bypass the problem, even if bypassing it initially fixes the problem indicating to me since there was no zinc involved, that the root of the problem is not likely to be a zinc deficiency.

jimmylegs wrote:understood - at this stage i am hopeful that you see my point as well.

I think I do in terms of your view that you should try to address the problem at the root level of a nutritional deficiency, but I'm not convinced that this is the problem, nor that ensuring adequate zinc levels would fix it.

Squeakycat wrote:I haven't seen any trials of vitamin D in MS that have done this, but when we are King and Queen of MS Clinical Trials, we shall simply order that it be done or off with their heads!

jimmylegs wrote:neither have i. it's a gap that continues to get on my nerves.

It just makes complete sense to do this. It makes sense to investigate CCSVI. To check for and deal with potential stealth bacterial infections. To address possibly active EBV.

The calcitriol + D3 does not directly fix any of those things, although restoring the immune system to a healthy state may make it possible for the immune system to deal with them, except of course ,things like venous malformations.

I monkeyed around with a lot of quotes here. Hope I have all that right!
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Re: all things vitamin D

Postby jimmylegs » Tue Oct 29, 2013 7:41 am

If zinc would have the same effect as calcitriol + D3 in EAE and possibly MS, then people with adequate zinc levels shouldn't have MS. Is everyone deficient? Are people who are not deficient free of the disease?

short answer: yes and yes, imo. zinc deficiency is poorly defined. also imho. what we can say with scientific backup is the following: technically in ms zinc is 'low normal'. this is the case for many chronic diseases. if you focus on 'healthy' status, you typically find high-normal serum zinc levels.

optimizing zinc can have marked effects on vitamin d3 status. i *can't wait* for the studies on this type of interaction to come out.
'unpublished case study': my vitamin d3 dose-response *tripled* after i identified and corrected my underlying (outright, documented, no question) zinc deficiency.

The other question is that studies in other diseases in which CYP27B1 is being blocked are all pointing to TNF-alpha and IL-6 as the culprits.
Will adequate zinc levels deal with them? And if so, is there anything to suggest that this is true in EAE or MS? I don't know the answer to that question. It is a question.

yep looks like it will:

Zinc in Human Health: Effect of Zinc on Immune Cells (2008)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277319/
"In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-κB activation, leading to decreased gene expression and generation of tumor necrosis factor-α (TNF-α), IL-1β, and IL-8." "A few investigators have reported that inflammatory cytokines such as TNF-α (tumor necrosis factor-α) and IL-1β, generated by activated monocytes-macrophages, also are known to produce increased amounts of ROS (23,24). Increases in these cytokines are associated with decreased zinc status in patients.

Zinc-suppressed inflammatory cytokines by induction of A20-mediated inhibition of nuclear factor-κB (2011)
http://www.sciencedirect.com/science/ar ... 071000287X
"We confirmed that zinc-induced A20 contributes to downregulation of TNF-α and IL-1β by antisense and short interfering RNA A20 studies."

Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent (2010)
http://ajcn.nutrition.org/content/91/6/1634.short
"After 6 mo of supplementation, the intake of zinc, compared with intake of placebo, increased the concentrations of plasma zinc and decreased the concentrations of plasma high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, macrophage chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), secretory phospholipase A2, and malondialdehyde and hydroxyalkenals (MDA+HAE) in elderly subjects. "

I haven't dug deep enough to see if any studies to date have examined these interactions in ms or eae. but as you can see from the dates we are looking at quite recent academic developments. for the time being i like occam's razor, given that the relatively poor zinc status of ms patients has been established.
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Re: all things vitamin D

Postby Squeakycat » Tue Oct 29, 2013 3:32 pm

Good stuff. Zinc it is!

Along with calcitriol +D3.

Nothing here says that zinc alone will change status in MS, or do you read it that way?
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Re: all things vitamin D

Postby jimmylegs » Tue Oct 29, 2013 5:02 pm

I read it as: optimize zinc first, then test to determine if additional d3 or calcitriol are needed.

since zinc corrects overexpression of TNF-alpha and IL-6 as above, AND zinc fosters proper renal hydroxylation of D3 to calcitriol as per the studies above, AND IF vit d3 status is positively correlated with or even dependent on zinc status (a nice specific study would help here), then zinc alone may result in higher levels of endogenous d3 and calcitriol.

I think it is more likely that additional 25(OH)D3 would potentially be needed.. not so much additional supplemental 1,25(OH)2D3.

anyway, I have a deadline at midnight so better pitter patter.
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Re: all things vitamin D

Postby Squeakycat » Tue Oct 29, 2013 7:58 pm

jimmylegs wrote:I read it as: optimize zinc first, then test to determine if additional d3 or calcitriol are needed.

since zinc corrects overexpression of TNF-alpha and IL-6 as above, AND zinc fosters proper renal hydroxylation of D3 to calcitriol as per the studies above, AND IF vit d3 status is positively correlated with or even dependent on zinc status (a nice specific study would help here), then zinc alone may result in higher levels of endogenous d3 and calcitriol.

I think it more likely that if anything, additional 25(OH)D3 could potentially be needed.. not so much additional supplemental 1,25(OH)2D3.
Legs,

No! No! NO ! ! !

Not one of these studies suggests that you can halt MS by maintaining adequate levels of zinc. Not a single one.

Or even any of the other diseases where the problem is that 25(OH)D3 is not being converted to 1,25(OH)2D3.

And I think if it were this simple, someone would have stumbled on this besides you, no offense intended.

The problem that is overcome by a single high dose of calctiriol + D3 is that 25(OH)D3 is not being converted to calcitriol in the CNS. You can have perfectly acceptable levels of both 25(OH)D3 and calcitriol in the blood, and adequate levels of 25(OH)D3 in CSF, but still have a problem if the problem is that CYP27B1 conversion is not working.

It is only EAE and mice, but Hayes' series of studies demonstrate that D3 alone will not effect the course of EAE, but calcitriol + D3 will both stop it and keep it in remission. The calcitriol is key to this happening because it makes it directly available to cells bypassing the conversion problem.

I personally would not waste time on zinc since this works in EAE. If it didn't work, zinc might be something to look at.

I've been discussing this offline in the context of active EBV and it will not completely work there because EBV hides in B-cells and blocks the Vitamin D Receptors so making calcitriol available will not have any effect as far as B-cells where there is an active EBV infection.

If calcitriol +D3 doesn't work in MS, then I can see a reason to test zinc in EAE to see if that alone has the same effect as calcitriol + D3.

Again, I'm not disputing that it would make perfect sense to ensure adequate nutritional status before testing calcitriol + D3 in pwMS to eliminate that as a confounding factor in whether it works.

The studies you cite do suggest that it alone could have an effect in MS, but if that is so, why has this not been investigated in MS or at least EAE?

Is there any evidence that people who attain adequate zinc levels after being dx with MS go into remission? Any?

Here is one study of zinc in EAE. It does conclude that there was a reduction in severity, but compare that to a complete remission which was sustained for the duration of the study in 100% of the mice treated with calcitriol +D3:
Source URL: http://www.ncbi.nlm.nih.gov/pubmed/22350510
PMID: 22350510
DOI: http://dx.doi.org/10.1007/s10534-012-9532-z
Journal Title: Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine
Journal Date: Jun 2012
Journal Issue: 3
Journal Volume: 25
Journal First Page: 529-39
Abstract URL: http://www.ncbi.nlm.nih.gov/pubmed/2235 ... t=abstract
Article Title: Zinc aspartate suppresses T cell activation in vitro and relapsing experimental autoimmune encephalomyelitis in SJL/J mice.
Article Authors: Diana Stoye,Claudia Schubert,Alexander Goihl,Karina Guttek,Annegret Reinhold,Stefan Brocke,Kurt Grüngreiff,Dirk Reinhold

Importantly, administration of a medium range dose of 30 μg/day zinc aspartate [1.5 mg/kg body weight (BW)] in a therapeutic manner led to a significant reduction of the clinical severity of the EAE during the first relapse of the disease. A lower zinc aspartate dose (6 μg/day, 0.3 mg/kg BW) had no significant therapeutic effect on the severity of the EAE, while administration of higher zinc aspartate amounts (120 μg/day, 6 mg/kg BW) led to more severe disease. Taken together, our data suggest that zinc aspartate can modulate activation, proliferation and cytokine production of effector T cells in vitro and in vivo and that activated autoreactive T cells may be potential therapeutic targets of tightly controlled zinc supplementation in autoimmune diseases like MS.

There were four studies in 2001-2003 about Zn-MT-II in EAE that showed effect, but apparently not enough for anyone to follow up on this.

I think you are suggesting that adequate zinc plus a little D3 will have the same effect as calcitriol + D3 in EAE or maybe MS.

I just don't see support for that suggestion. It might work in MS. It might work in EAE. The studies of zinc in EAE suggest that it is helpful, but not a 100% remission and sustained remission in 100% of the the treated mice so I think what we know based on these studies is that it would not be as effective as calcitriol + D3 in EAE. We still, of course, don't know if calcitriol + D3 will work in pwMS.

I have to believe that there would at least be some anecdotal evidence that the combination of zinc and D3 adequacy would stop progression in MS if this were true. I don't see even that evidence and surely, there must be some pwMS who have tried this?
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Re: all things vitamin D

Postby jimmylegs » Tue Oct 29, 2013 9:07 pm

not sure where the outburst came from, and I don't have time to bother
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Re: all things vitamin D

Postby NHE » Wed Oct 30, 2013 1:55 am

Squeakycat wrote:Here is one study of zinc in EAE. It does conclude that there was a reduction in severity, but compare that to a complete remission which was sustained for the duration of the study in 100% of the mice treated with calcitriol +D3:


The zinc/MS question seems convoluted at best (at least in my mind at this time).

Here's an EAE study that found improvements with zinc & copper chelation...

Copper/zinc chelation by clioquinol reduces spinal cord white matter damage and behavioral deficits in a murine MOG-induced multiple sclerosis model.
Neurobiol Dis. 2013 Jun;54:382-91. doi: 10.1016/j.nbd.2013.01.012. Epub 2013 Jan 27.

    The present study aimed to evaluate the therapeutic potential of clioquinol (CQ), a metal chelator, on multiple sclerosis pathogenesis. Experimental autoimmune encephalomyelitis was induced by immunization with myelin oligodendrocyte glycoprotein (MOG(35-55)) in female mice. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were analyzed. CQ (30mg/kg) was given by gavage once per day for the entire experimental course. CQ profoundly reduced the daily clinical score and incidence rate of EAE mice. The CQ-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and reduced infiltration by encephalitogenic immune cells including CD4, CD8, CD20 and F4/80 positive cells. CQ also remarkably inhibited EAE-associated BBB disruption and MMP-9 activation. Autophagy contributes to clearance of aggregated proteins in astrocytes and neurons. The present study found that EAE increased the induction of autophagy and CQ further increased this expression. Furthermore, the present study found that post-treatment with CQ also reduced the clinical score of EAE and spinal cord demyelination. These results demonstrate that CQ inhibits the clinical features and neuropathological changes associated with EAE. The present study suggests that transition metals may be involved in several steps of multiple sclerosis pathogenesis.

So, has there been a clinical trial of zinc in actual MS patients? I would like to see that paper even if it was just a small phase Ia.
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Re: all things vitamin D

Postby Squeakycat » Wed Oct 30, 2013 7:09 am

NHE wrote:The zinc/MS question seems convoluted at best (at least in my mind at this time).
NHE,
Indeed! Getting rid of metal seems to help in a number of neurodegenerative diseases.

There appears to be a very narrow Goldilocks range for most. Too little is bad. Too much is bad. But just right is therapeutic.
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Re: all things vitamin D

Postby jimmylegs » Wed Oct 30, 2013 7:29 pm

on outright zinc deficiency in ms patients:

Serum level of iron, zinc and copper in patients with multiple sclerosis (2013)
http://jmj.jums.ac.ir/~jumsjmj/files/si ... 0187b3.pdf
Mean serum iron levels were significantly elevated in MS patients (127.04 ± 34.67) compared to these levels in the control group (103.95 ± 33.81). Mean serum zinc levels were significantly decreased in MS patients (10.92 ± 2.114) as compared to these levels in the control group (14.05 ± 3.2). Also, mean serum copper levels were significantly decreased in MS patients (88.58 ± 19.56) compared to the levels in the control group (110.37 ± 37.1).

adding zinc would work to bring the iron levels back into line.

ooo, minerals hitting the mainstream (not sure why vit d3 would not be listed here):

Consensus guidelines for the diagnosis and treatment of multiple sclerosis (2013)
http://informahealthcare.com/doi/abs/10 ... 013.787979
"Nutritional deficiency/toxicity: Vitamin B12, copper, zinc, ceruloplasmin, folate, heavy metal screen."

there is no question whatsoever in my mind that addressing deficiency would be beneficial, and that not doing so would be negligent.

the single study I can think of off hand where ms zinc levels were higher than controls, looked at erythrocytes. the altered distribution of zinc in that situation actually is another indication of underlying deficiency.

since we can anticipate correction of 25(OH)D3/1,25(OH)2D3 endogenous synthesis in the mix, so much the better to correct any zinc depletion issues that are found in patients. even leaving aside the 25(OH)D3/1,25(OH)2D3 side of things, there are always the other 300+ enzymes and 1000+ processes that require zinc.
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Re: all things vitamin D

Postby Squeakycat » Wed Oct 30, 2013 7:39 pm

jimmylegs wrote:there is no question whatsoever in my mind that addressing deficiency would be beneficial, and that not doing so would be negligent.
Jimmylegs,

Agree COMPLETELY.

When we win the lottery, we can fund the ultimate study that looks directly at counts for all the different immune cells implicated in MS and see what happens to them when you increase zinc levels.
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Re: all things vitamin D

Postby jimmylegs » Wed Oct 30, 2013 7:44 pm

had a look at the full text of the EAE chelation study. from the title the researchers appear to be manipulating nutrient levels via clioquinol, but they do not appear to have measured serum zinc or serum copper before or after. at the start of their study they have not matched the nutritional status of a typical ms patient.
for the clioquinol study results to be meaningful applied to ms patients (which is assuming a lot considering it is a murine EAE study), researchers should have started with measurably zinc deficient mice. (the mice should have been low in copper to start too, for that matter).
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Re: all things vitamin D

Postby ribeye » Thu Nov 07, 2013 1:34 pm

Hello,
Wondering how the human male dose for calcitriol and d3 regimen can be calculated. 400ng for a mouse would be how much for 100kg man. My GP is interested in this study and is willing to let me try it. He just wants a figure before dosing me.

Having a bit of a flare now and not a huge fan of prednisone.

Thanking all of you for this wonderful forum. Peace to all.
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Re: all things vitamin D

Postby THX1138 » Thu Nov 07, 2013 1:59 pm

Just remember to supplement sufficiently with magnesium also, as vitamin D uses up magnesium. There are several posts about this on this website.

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Re: all things vitamin D

Postby Squeakycat » Thu Nov 07, 2013 2:18 pm

ribeye wrote:Hello,
Wondering how the human male dose for calcitriol and d3 regimen can be calculated. 400ng for a mouse would be how much for 100kg man. My GP is interested in this study and is willing to let me try it. He just wants a figure before dosing me.

Having a bit of a flare now and not a huge fan of prednisone.

Thanking all of you for this wonderful forum. Peace to all.


A rough figure for the weight of a mouse is 25 grams so the ratio to the weight of a 100 kg human is 100x1000/25 = 4000.

4000 x 400 ng = 1,600,000 ng = 1,600 mcg. Maximum Tolerated Dose for calcitriol is between 74 mcg and 120 mcg.

120 mcg was the lowest effective dose in female mice so may be sufficient to have an effect.

Calcitriol will have to be compounded since the maximum shipping dose is 0.5 mcg. It is available from most scientific chemical suppliers such as Caymen Chemicals who I know manufacturers in the US as opposed to Chinese white powder suppliers.
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