all things vitamin D

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Re: all things vitamin D

Postby jimmylegs » Sun Oct 27, 2013 6:35 am

i'm hunting for a study which I think had to do with vit d3 mostly, which stated in the abstract that failing to conduct annual testing was medically negligent (or words to that effect). anyone able to pull that one up speedily? might have been a vieth or a holick study.. will keep hunting but any help would be appreciated.

in the process of searching I encountered this study, which speaks to me of the importance of monitoring and optimizing key bone mineral cofactors:

Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women
http://jama.jamanetwork.com/article.asp ... eid=185854
"Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures."

I think a more informative final sentence for this abstract could have been something like: "Further research is needed to clarify the interactions between cholecalciferol supplementation and bone mineral cofactors known to be associated with fall and fracture risk".
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Re: all things vitamin D

Postby Squeakycat » Sun Oct 27, 2013 11:06 am

jimmylegs wrote:i'm hunting for a study which I think had to do with vit d3 mostly, which stated in the abstract that failing to conduct annual testing was medically negligent (or words to that effect). anyone able to pull that one up speedily? might have been a vieth or a holick study.. will keep hunting but any help would be appreciated.
JL,
This study doesn't answer your question, but it is probably a good starting point for finding an answer.

Source URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912737/
PMID: 20675513
DOI: 10.4065/mcp.2010.0138
Journal Title: Mayo Clinic Proceedings
Journal Date: August 2010
Journal Issue: 8
Journal Volume: 85
Journal First Page: 752
Abstract URL: http://www.ncbi.nlm.nih.gov/pmc/article ... t=abstract
Article Title: Vitamin D Deficiency in Adults: When to Test and How to Treat
Article Authors: Kurt A. Kennel, Matthew T. Drake, Daniel L. Hurley

Mayo Clin Proc. 2010 August; 85(8): 752–758.
doi: 10.4065/mcp.2010.0138
PMCID: PMC2912737
Vitamin D Deficiency in Adults: When to Test and How to Treat

Kurt A. Kennel, MD, Matthew T. Drake, MD, PhD, and Daniel L. Hurley, MD

Abstract

Recent evidence for the nonskeletal effects of vitamin D, coupled with recognition that vitamin D deficiency is common, has revived interest in this hormone. Vitamin D is produced by skin exposed to ultraviolet B radiation or obtained from dietary sources, including supplements. Persons commonly at risk for vitamin D deficiency include those with inadequate sun exposure, limited oral intake, or impaired intestinal absorption. Vitamin D adequacy is best determined by measurement of the 25-hydroxyvitamin D concentration in the blood. Average daily vitamin D intake in the population at large and current dietary reference intake values are often inadequate to maintain optimal vitamin D levels. Clinicians may recommend supplementation but be unsure how to choose the optimal dose and type of vitamin D and how to use testing to monitor therapy. This review outlines strategies to prevent, diagnose, and treat vitamin D deficiency in adults.

Jimmylegs wrote:Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women
http://jama.jamanetwork.com/article.asp ... eid=185854
"Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures."

I think a more informative final sentence for this abstract could have been something like: "Further research is needed to clarify the interactions between cholecalciferol supplementation and bone mineral cofactors known to be associated with fall and fracture risk".

They did look at calcium levels in a substudy and found no differences between the high, single dose of vitamin D3 group and placebo.

This study has bothered me in so many ways since it came out. I think the only conclusion you can draw from it is that a single annual dose of vitamin D3 may cause problems as far as number of falls and the risk of fracture. It has been suggested that the higher levels of falls may indicate that there was a higher level of osteomalacia in the treated group which was not considered in the study. Otherwise, why would vitamin D3 increase the number of falls? What would it do to cause people to fall more often, setting aside the subsequent question of why would this group have more fractures.

I see a possible explanation for this, but the data to know if it is what happened is not available in the study so it is hard to tell if this is what actually happened.

Normally, vitamin D manages the level of calcium and increased vitamin D increase the uptake of calcium.

But we know with high doses of calcitriol, the bio-active form of vitamin D, that a high dose will suppress PTH which then has the effect of lowering the uptake of calcium.

It may be, though there is not data in the study to back this, that a dose of 500,000 IU suppresses PTH which in turn lowers calcium uptake and that results in softer bones leading to an increased risk of falls and subsequent fractures.

The other possibility is that because this study was done in Oz, people being down under are already struggling to avoid falling off the earth and somehow high levels of vitamin D made that problem worse. :lol:

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Re: all things vitamin D

Postby jimmylegs » Sun Oct 27, 2013 12:07 pm

thx for taking a stab at it. i'll keep looking!

interesting re the calcium substudy. i'd love to see a study or three on magnesium impacts too.

"Between 50 percent and 60 percent of body magnesium is located within bone, where it is thought to form a surface constituent of the hydroxyapatite (calcium phosphate) mineral component. Initially much of this magnesium is readily exchangeable with serum and therefore represents a moderately accessible magnesium store, which can be drawn on in times of deficiency. However, the proportion of bone magnesium in this exchangeable form declines significantly with increasing age (9)."
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Re: all things vitamin D

Postby jimmylegs » Sun Oct 27, 2013 12:10 pm

interesting:

First-principles study of substitutional magnesium and zinc in hydroxyapatite and octacalcium phosphate.
http://www.ncbi.nlm.nih.gov/pubmed/18601385
Abstract
First-principles calculations are performed for Mg(2+) and Zn(2+) substitution in hydroxyapatite (HAp) and octacalcium phosphate (OCP), because the foreign ions are known to play an important role for bone formation. In order to study their possible location in the system of HAp in contact with the aqueous solution, OCP is considered as a structural model of the transition region between HAp and the solution. It is found that, when the foreign ions substitute for Ca sites, the surrounding oxygen ions undergo considerable inward relaxation, due to their smaller ionic sizes than Ca(2+), which results in the smaller coordination numbers with oxygen as compared with those of Ca in bulk HAp and OCP. From the calculated defect formation energies, it is likely that the substitutional foreign ions are quite difficult to dissolve into HAp whereas can be more easily incorporated in OCP. In particular, Zn(2+) can more favorably substitute for the specific Ca site of OCP, as compared to Mg(2+), which is attributed with covalent bond formation between Zn and the surrounding oxygen ions. It is thus considered that zinc may play its role to promote bone formation by being incorporated into the transition region between HAp and the surrounding solution.
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Possible explanation of increase in fractures with high dose

Postby Squeakycat » Sun Oct 27, 2013 4:29 pm

While not proof, this study raises an issue which has recently been found in a test of calcitriol + D3 which shows that in EAE and likely MS, there is a problem converting D3 to the bioactive from of vitamin D, calcitriol.

In this study, a variant in the CYP27B1 gene which manages this conversion was linked to an increased risk of falls and fractures.

There is more and more evidence that this is at the heart of what is happening in MS and a number of auto-immune diseases, particularly Type 1 Diabetes where this has been well studied.

Something in the immune response to an infection or injury sets off a normal pro-inflammatory response, but that response blocks the conversion of D3 to calcitriol leaving the pro-inflammatory immune system cytokines active when normally, with enough calcitriol, they would undergo programmed cell death.

Professor Hayes' study bypasses this problem by making calcitriol directly available to cause programmed cell death. It also seems to unblock the conversion of D3 to calcitriol so that this process begins working again which is how she was able to maintain her mice in remission with D3 alone. It also explains why D3 has shown so little effect: It isn't being converted to the bioactive form, calcitriol.

Source URL: http://www.ncbi.nlm.nih.gov/pubmed/21107545
PMID: 21107545
DOI: http://dx.doi.org/10.1007/s00223-010-9434-4
Journal Title: Calcified tissue international
Journal Date: Feb 2011
Journal Issue: 2
Journal Volume: 88
Journal First Page: 109-16
Abstract URL: http://www.ncbi.nlm.nih.gov/pubmed/2110 ... t=abstract
Article Title: Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly.
Article Authors: Roderick J Clifton-Bligh,Tuan V Nguyen,Amy Au,Martyn Bullock,Ian Cameron,Robert Cumming,Jian Sheng Chen,Lyn M March,Markus J Seibel,Philip N Sambrook

Calcif Tissue Int. 2011 Feb;88(2):109-16. doi: 10.1007/s00223-010-9434-4. Epub 2010 Nov 25.
Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly.

Clifton-Bligh RJ, Nguyen TV, Au A, Bullock M, Cameron I, Cumming R, Chen JS, March LM, Seibel MJ, Sambrook PN.
Source

Northern Metabolic Bone Research Unit, Royal North Shore Hospital, St. Leonards, NSW, Australia. jclifton@med.usyd.edu.au

Abstract

CYP27B1 encodes mitochondrial 1α-hydroxylase, which converts 25-hydroxyvitamin D to its active 1,25-dihydroxylated metabolite. We tested the hypothesis that common variants in the CYP27B1 promoter are associated with fracture risk. The study was designed as a population-based genetic association study, which involved 153 men and 596 women aged 65-101 years, who had been followed for 2.2 years (range 0.1-5.5) between 1999 and 2006. During the follow-up period, the incidence of fragility fractures was ascertained. Bone ultrasound attenuation (BUA) was measured in all individuals, as were serum 25-hydroxyvitamin D and PTH concentrations; 86% subjects had vitamin D insufficiency. Genotypes were determined for the -1260C>A (rs10877012) and +2838T>C (rs4646536) CYP27B1 polymorphisms. A reporter gene assay was used to assess functional expression of the -1260C>A CYP27B1 variants. The association between genotypes and fracture risk was analyzed by Cox's proportional hazards model. We found that genotypic distribution of CYP27B1 -1260 and CYP27B1 +2838 polymorphisms was consistent with the Hardy-Weinberg equilibrium law. The two polymorphisms were in high linkage disequilibrium, with D' = 0.96 and r² = 0.94. Each C allele of the CYP27B1 -1260 polymorphism was associated with increased risk of fracture (hazard ratio = 1.34, 95% CI 1.03-1.73), after adjustment for age, sex, number of falls, and BUA. In transient transfection studies, a reporter gene downstream of the -1260(A)-containing promoter was more highly expressed than that containing the C allele. These data suggest that a common but functional variation within the CYP27B1 promoter gene is associated with fracture risk in the elderly.

PMID:
21107545
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Re: all things vitamin D

Postby jimmylegs » Sun Oct 27, 2013 6:42 pm

i have spent some time on that angle before. interesting interactions.

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419671/
"The synthesis of bioactive vitamin D requires hydroxylation at the 1α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1α-hydroxylation in the kidney ..."

Genetic Disorders and Defects in Vitamin D Action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879401/
"The critical enzyme to synthesize calcitriol from 25(OH)D, the circulating hormone precursor, is 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase)."

1,25(OH)2D response to combined zinc and phosphorus depletion in rats.
"...Zn depletion limits the increase in plasma 1,25(OH)2D concentration associated with P depletion. The mechanism is unknown but may involve an effect of Zn on renal 25(OH)D 1-α-hydroxylase synthetic activity."

The Vitamin D Receptor: New Paradigms for the Regulation of Gene Expression by 1,25-Dihydroxyvitamin D3
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879406/
"The actions of the vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are mediated by the vitamin D receptor (VDR), a ligand-activated transcription factor that functions to control gene expression... the VDR protein is comprised of three distinct regions, an N-terminal dual zinc finger DNA binding domain, a C-terminal ligand-binding activity domain and an extensive and unstructured region that links the two functional domains of this protein together.

Effect of zinc deficiency on the protein expression of vitamin D receptor and calcium binding protein in growth-stage rats duodenal mucosa
http://www.ncbi.nlm.nih.gov/pubmed/16623997
"Immunohistochemistry demonstrated that the intestinal mucosal expression of both VDR protein and CaBP protein in ZD rats significantly decreased."

Zinc-induced conformational changes in the DNA-binding domain of the vitamin D receptor determined by electrospray ionization mass spectrometry
"...the binding of the first Zn2+ ion to the protein results in very little conformational change in the protein. The binding of a second Zn2+ ion resulted in a significant alteration in the structure of the protein as indicated by changes in both the multiply charged ESI and far-UV CD spectra."

Zinc increases the activity of vitamin D-dependent promoters in osteoblasts.
http://www.ncbi.nlm.nih.gov/pubmed/10777672
To determine whether zinc alters 1alpha,25-dihydroxyvitamin D(3)-regulated genes in cells, we permanently transfected rat osteoblasts with two vitamin D-dependent promoter-reporter systems and examined their responses to 1alpha,25-dihydroxyvitamin D(3) in the presence of increasing amounts of extracellular zinc. When extracellular zinc concentrations were increased in the presence of 1alpha,25-dihydroxyvitamin D(3), there was an increase in the activity of 1alpha,25-dihydroxyvitamin D(3)-dependent promoters with increasing concentrations of zinc. The effect was specific for zinc since metals such as copper failed to increase the activity of 1alpha,25-dihydroxyvitamin D(3)-dependent promoters."

Zinc deficiency, DNA damage and cancer risk
http://www.sciencedirect.com/science/ar ... 6304001408
"Zinc plays a critical role in the regulation of transcription and replication of DNA through zinc finger proteins. Additionally, many DNA repair mechanisms involve zinc. Many proteins involved in both base and nucleotide excision repairs are zinc finger or zinc-associated proteins"
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Re: all things vitamin D

Postby Squeakycat » Sun Oct 27, 2013 7:43 pm

jimmylegs wrote:i have spent some time on that angle before. interesting interactions.
Jimmylegs,

How did I know if I said "Vitamin D," you would say "Zinc." :lol:

But I think I can prove to you that this is not about zinc.

    1. When Hayes gives her mice sufficient calcitriol to raise CSF levels, pro-inflammatory cytokines undergo programmed cell death, without zinc.

    2. Studies, including several by Hayes in EAE show that vitamin D3 has little effect in MS, but calcitriol stops EAE in 100% of her mice without zinc being added.

    3. A number of recent studies show what is blocking the conversion of D3 to bioactive calcitriol is the action of pro-inflammatory cytokines, TNF-alpha and IL-6. These studies are in Alzheimers, IBD and two cancer, not MS, but there is no reason to think this is not the same thing that is happening in MS, and again, no involvement of zinc.

What Hayes has shown is that the reason the immune system is out of control in EAE and likely in MS is that conversion of D3 to calcitriol is being blocked. These other studies show that is because of TNF-alpha and IL-6. Nothing about zinc there and the solution is not more zinc, but providing calcitriol directly. This bypasses the conversion problem by making calcitriol directly available to cells.

It has immediate and measurable effects on cytokines with problematic CD4+ T-cells declining rapidly and anti-inflammatory cytokines increasing. She specifically measured Helios+ and FoxP3 levels as well as CD4+ levels. Again, no zinc in the equation and the results are measurable, not speculated.

I'm not anti-zinc, just don't see it as a major factor in this problem and the studies all show that.

To recap what Hayes found:
    1. Something is blocking the conversion of D3 to the bioactive form of vitamin D, calcitriol.
    2. This allows injurious, pro-inflammatory cytokines to become immortal. Nothing is stopping them from doing damage.
    3. A single dose of calcitriol sufficient to raise CSF levels is enough to trigger programmed cell death of the pro-inflammatory cytokines and stimulate an increase in anti-inflammatory cytokines.
    4. This dose of calcitriol appears to "reset" the immune system such that the conversion process which was blocked now functions properly allowing regular vitamin D3 to keep her mice in remission, without zinc in the equation.

I think it is important to point out that while this study was of EAE in mice, not humans with MS, it stopped the disease in 100% of the mice and kept 100% in remission.

The mechanism of action here is as relevant to MS as EAE, namely that something is blocking conversion of D3 to calcitriol. Further, a single high dose of calcitriol (no zinc) resets everything halting disease progression and allowing D3 alone to keep it in check in EAE.

There is only one way to find out if this will work for humans with MS and that is to run some trials.

I got pricing on the dose of calcitriol needed and it comes to $1.67, right up there with the price of Tysabri, Gilenya and the other MS drugs and close to the $150,000 pricing for the new drug that Wheelchair Kamikaze just tested.

That is just for the calcitriol and does not include the cost of putting it in a gel cap or shipping, though with a bottle of vitamin D3, if it shipped via Amazon.com, shipping will be free. :lol:

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Re: all things vitamin D

Postby Squeakycat » Sun Oct 27, 2013 7:58 pm

jimmylegs wrote:Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419671/
"The synthesis of bioactive vitamin D requires hydroxylation at the 1α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1α-hydroxylation in the kidney ..."

Genetic Disorders and Defects in Vitamin D Action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879401/
"The critical enzyme to synthesize calcitriol from 25(OH)D, the circulating hormone precursor, is 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase)."
Jimmylegs,
Thought I would separate out the question of vitamin D3 metabolism from zinc.

There are two ways D3 is converted to calcitriol:
    1. Through hydroxylation in the liver and kidneys. This provides serum calcitriol.
    2. Directly in every cell through the action of CYP27B1 as long as there is sufficient D3, or more precisely 25(OH)D3.

I suspect that evolution provided this alternative at the level of the cell because vitamin D is so critical. As a regulatory hormone, it activates and controls the local, adaptive immune response to infection and injury and further, it manages the cell replication cycle to get rid of damaged cells and replace them with shiny new ones.

Hayes shows that there is sufficient 25(OH)D3 available in the CSF and that levels of calcitriol are lower in CSF than in the blood, accounting for the normal difference between CSF and serum levels.
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Re: all things vitamin D

Postby Anonymoose » Sun Oct 27, 2013 8:15 pm

Squeaky...are you going to keep squeaking or try it??!! So far, it's next on my list if rituxan fails. I need to research it more though. It'd be nice if some guinea cat went before me. :P errrr. Do you have ms?
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Re: all things vitamin D

Postby Squeakycat » Sun Oct 27, 2013 8:45 pm

Anonymoose wrote:Squeaky...are you going to keep squeaking or try it??!! So far, it's next on my list if rituxan fails. I need to research it more though. It'd be nice if some guinea cat went before me. :P errrr. Do you have ms?

I don't have MS, but I have offered to try up to 3X the dose to test safety.

I have used calcitriol for 13 years to treat cats with kidney problems and feel very comfortable with my understanding of the risks and see them as minimal and manageable.

I am talking with several medical professionals with MS who are going to try it the next time they have a relapse since that will provide the maximum opportunity to see if it changes things. And there is serious discussion about getting funding to support a proper safety clinical trial.

A friend who is on Rituxan is considering taking calcitriol just before his next two month dose of Rituxan so that the effect of Rituxan is at its nadir. And I have a friend who is a professor of oncology who is looking into whether there would be any contraindication with taking a single, high dose of calcitriol while being treated with Rituxan.

I know you didn't ask for my opinion, but Rituxan will not work. It will kill off your good and bad B-cells, but as they regenerate, the T-cells will again direct them at your myelin. Plus, the standard protocol calls for methylpred and that simply temporarily dampens your immune system without changing anything. Hayes directly tested calcitriol against methylpred and found calcitriol to be far superior on all measures.

Rituxan is suppressing part of your immune system, B-cells. Calcitriol is your immune system controller so by taking a high dose, you are supporting the immune system, not suppressing it.

PM me with your email addy and I will send you the relevant papers on using calcitriol plus D3.
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Re: all things vitamin D

Postby NHE » Sun Oct 27, 2013 10:51 pm

jimmylegs wrote:Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419671/
"The synthesis of bioactive vitamin D requires hydroxylation at the 1α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1α-hydroxylation in the kidney ..."


This might be of potential interest. Several supplements, such as CoQ10 and curcumin, are sold with piperine which is an extract of black pepper. It increases the absorption of these supplements. However, it does this by inhibiting the cytochrome p family of enzymes. Taking supplements with piperine may be reducing the efficacy of vitamin D3 supplementation.

natural-approach-f27/topic18613.html#p181912

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Re: all things vitamin D

Postby Anonymoose » Mon Oct 28, 2013 6:46 am

Squeakycat wrote:
Anonymoose wrote:Squeaky...are you going to keep squeaking or try it??!! So far, it's next on my list if rituxan fails. I need to research it more though. It'd be nice if some guinea cat went before me. :P errrr. Do you have ms?

I don't have MS, but I have offered to try up to 3X the dose to test safety.

I have used calcitriol for 13 years to treat cats with kidney problems and feel very comfortable with my understanding of the risks and see them as minimal and manageable.

I am talking with several medical professionals with MS who are going to try it the next time they have a relapse since that will provide the maximum opportunity to see if it changes things. And there is serious discussion about getting funding to support a proper safety clinical trial.

A friend who is on Rituxan is considering taking calcitriol just before his next two month dose of Rituxan so that the effect of Rituxan is at its nadir. And I have a friend who is a professor of oncology who is looking into whether there would be any contraindication with taking a single, high dose of calcitriol while being treated with Rituxan.

I know you didn't ask for my opinion, but Rituxan will not work. It will kill off your good and bad B-cells, but as they regenerate, the T-cells will again direct them at your myelin. Plus, the standard protocol calls for methylpred and that simply temporarily dampens your immune system without changing anything. Hayes directly tested calcitriol against methylpred and found calcitriol to be far superior on all measures.

Rituxan is suppressing part of your immune system, B-cells. Calcitriol is your immune system controller so by taking a high dose, you are supporting the immune system, not suppressing it.

PM me with your email addy and I will send you the relevant papers on using calcitriol plus D3.

Thanks squeaky. I appreciate any and all info/opinions I can get. I didn't do the standard rituxan protocol. I did 4 weekly doses iv and it with solucortef (12-24 hr half life I think) and I'll be starting valtrex Tuesday. My war on ebv. Still have hope something different will happen.

The calcitriol phenomena is very intriguing. Although eae isn't ms...you can't discount that an immune system is an immune system and there is a chance humans may respond in a similar way to calcitriol. If they cure ms in the next 25 years, it will be a lucky, not completely understood happenstance. Why not calcitriol?

I'd love to read the papers you've got. I'll pm you my email. Thanks!
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Re: all things vitamin D

Postby jimmylegs » Mon Oct 28, 2013 1:20 pm

1. When Hayes gives her mice sufficient calcitriol to raise CSF levels, pro-inflammatory cytokines undergo programmed cell death, without zinc.

2. Studies, including several by Hayes in EAE show that vitamin D3 has little effect in MS, but calcitriol stops EAE in 100% of her mice without zinc being added.

3. A number of recent studies show what is blocking the conversion of D3 to bioactive calcitriol is the action of pro-inflammatory cytokines, TNF-alpha and IL-6. These studies are in Alzheimers, IBD and two cancer, not MS, but there is no reason to think this is not the same thing that is happening in MS, and again, no involvement of zinc.
What Hayes has shown is that the reason the immune system is out of control in EAE and likely in MS is that conversion of D3 to calcitriol is being blocked. These other studies show that is because of TNF-alpha and IL-6. Nothing about zinc there and the solution is not more zinc, but providing calcitriol directly. This bypasses the conversion problem by making calcitriol directly available to cells.


i'm not arguing the importance of calcitriol and I am not talking about zinc interactions with calcitriol. the studies I posted are about zinc's capacity to facilitate proper conversion of 25(OH)D3 *to* calcitriol via various mechanisms including for example the activity of the critical enzyme 25-hydroxyvitaminD-1α-hydroxylase, and the structure of the VDR receptor.

regarding pro-inflammatory cytokines:
Zinc in Human Health: Effect of Zinc on Immune Cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277319/
"We have reported recently that in both young adults and elderly subjects, zinc supplementation decreased oxidative stress markers and generation of inflammatory cytokines."

given that ms patients are low in zinc it seems most prudent to correct that problem first before worrying about downstream issues..
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info: www.whfoods.com, www.nutritiondata.com
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Re: all things vitamin D

Postby jimmylegs » Mon Oct 28, 2013 1:32 pm

Jimmylegs,
Thought I would separate out the question of vitamin D3 metabolism from zinc.
There are two ways D3 is converted to calcitriol:
1. Through hydroxylation in the liver and kidneys. This provides serum calcitriol.
2. Directly in every cell through the action of CYP27B1 as long as there is sufficient D3, or more precisely 25(OH)D3.


bringing it back. re your item 1 for starters. the hydroxylation in the liver gets you to 25(OH)D3. The hydroxylation in the kidney (via the critical enzyme 25-hydroxyvitamin D 1α-hydroxylase) gets you to calcitriol.
Genetic Disorders and Defects in Vitamin D Action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879401/
"The critical enzyme to synthesize calcitriol from 25(OH)D, the circulating hormone precursor, is 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase)."

zinc status is linked to calcitriol status, possibly via interactions with 25(OH)D 1-α-hydroxylase synthesis in the kidneys:
1,25(OH)2D response to combined zinc and phosphorus depletion in rats.
"...Zn depletion limits the increase in plasma 1,25(OH)2D concentration associated with P depletion. The mechanism is unknown but may involve an effect of Zn on renal 25(OH)D 1-α-hydroxylase synthetic activity."
my approach: no meds so far - just nutrient-dense anti-inflammatory whole foods, and supplements where needed
info: www.whfoods.com, www.nutritiondata.com
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Re: all things vitamin D

Postby Squeakycat » Mon Oct 28, 2013 2:57 pm

Jimmylegs,

Peace. I didn't mean to come across as challenging you or showing a disdain for zinc. Really.

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.

What I was trying to communicate was that Hayes's treatment works by bypassing the conversion problem and making calcitriol directly available to cells. That results in the dying off through programmed cell death of pro-inflammatory cytokines and the proliferation of anti-inflammatory cytokines.

At that point, conversion works, likely because there is a reduction in TNF-alpha and IL-6 which seems to be what blocks conversion in other diseases where this has been studied. They may well do that by manipulating zinc. I don't know.

The process works because by administering calcitriol directly, no zinc-dependent conversion process is needed.

D3 then maintains remission which is a sign (among some others) that conversion is then working. Perhaps EAE mice are inherently sufficient in zinc and that may not be true in humans.

The only point I was trying to make at that calcitriol + D3 worked without zinc supplementation. Maybe it would have worked even better with it. Maybe that will be an issue in humans even though it doesn't appear to be one in EAE.

It is not that zinc is unimportant in vitD metabolism, but that the treatment with calcitriol works without zinc supplementation.

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 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!

Again, did not mean to come across as argumentative, but was just making the point that zinc was not a factor in Hayes' experiments and they worked well without looking at zinc.

Ed
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