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Dr Trevor Marshall
Foundation Staff
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Posted: Fri Feb 5th, 2010 06:09 |
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scooker48
Member in Phase 3
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Posted: Fri Feb 5th, 2010 19:25 |
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I now report improved eyesight also at my last eye exam of November 2009.
The prescription came down .25 in both my right and left eyes.
Good ole' MP.
Sherry
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Necrotizing granulomas biopsy 10/88; Dx 12/04 Sarcoid liver spleen. 2/2/05: VitD 25/VitD125 62. 11/7/09 D25 at 6, Liver function normal 4/08; Wear NoIRs outside. No K creme used. 5/09 Liver and kidneys normal. ACE still high at 113 on 11/7/09.
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Phillyguy
Guests visiting Phase 1/2/3
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Posted: Mon Mar 1st, 2010 17:43 |
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Frans,
Based upon some prior research that you had posted in this thread on circadian rhythms (and insomnia with TH1 disease) I thought you might find this recent abstract from Robert Wood Johnson interesting. (3/2010)
In vivo endotoxin synchronizes and suppresses clock gene expression in human peripheral blood leukocytes.
OBJECTIVES:: The intravenous administration of a bolus dose of endotoxin to healthy human subjects triggers acute systemic inflammatory responses that include cytokine production and dynamic changes in gene expression in peripheral blood leukocytes. This study sought to determine the state of clock gene expression in human peripheral blood leukocytes, and leukocyte subpopulations, challenged with in vivo endotoxin at two circadian/diurnal phases of the clock. DESIGN:: Clinical and laboratory investigation. SETTING:: University-based research laboratory and clinical research center. SUBJECTS:: Human volunteers. INTERVENTIONS:: Human subjects were administered a standard dose of endotoxin (2 ng/kg) or saline at either 0900 or 2100 hrs. Blood samples were collected at selected time points pre- and postinfusion. MEASUREMENTS AND MAIN RESULTS:: Clock gene expression was determined in human peripheral blood leukocytes, neutrophils, and monocytes by quantitative real-time polymerase chain reaction. The fold change for each gene was determined by use of the 2 method. We show that endotoxin causes profound suppression of circadian clock gene expression, clearly manifested in human peripheral blood leukocytes, neutrophils, and monocytes. Clock, Cry1-2, Per3, CSNK1 ϵ, Rora, and Rev-erb gene expression were all reduced by 80% to 90% with the nadir between 3 and 6 hrs postinfusion. Per1 and Per2 reached an expression nadir between 13 and 17 hrs postinfusion. The levels of plasma interleukin-6 and tumor necrosis factor peaked and then returned to baseline within 6 hrs. In contrast, clock gene expression remained suppressed for up to 17 hrs irrespective of the phase of the clock at the time of the endotoxin challenge. Endotoxin did not perturb the melatonin secretory rhythm. CONCLUSIONS:: Circadian clock gene expression in peripheral blood leukocytes is dramatically altered and possibly uncoupled from the activity of the central clock during periods of acute systemic inflammation. The realignment of the central and peripheral clocks may constitute a previously unappreciated key factor affecting recovery from disease in humans.
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So a comment and a question:
1) Endotoxin disrupts cirrcadian rhythms (unfortunately, we all knew that already)
2) Dr. Marshall, I recall reading the website (which I can't find now) for the nuclear receptor conference that you had attended and seem to remember that there was some emphasis placed on circadian rhythms and how they relate to the expression of various nuclear receptors. I'm wondering if you recall any presentaions relating to this topic.
Last edited on Mon Mar 1st, 2010 17:44 by Phillyguy
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Dr Trevor Marshall
Foundation Staff
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Posted: Mon Mar 1st, 2010 19:52 |
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Ron Evans of Salk spoke about it. But I paid little attention. Any disease which affects the Brain is going to affect everything the Brain does. It is a very complicated, interwoven, and sophisticated organ
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mebauer
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Posted: Tue Mar 2nd, 2010 01:14 |
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I went to the eye doctor in the fall of 2008 after being on the MP for about 8 months...to my suprise the doctor told me my eyesight was getting better...he told me based on the exam that he was going to decrease my prescription by .25! I was shocked because my eyes progressively were getting worse with the symptoms I have...since I became ill I've had vision specks, it looks like I'm seeing rain all day every day, which is annoying but it's been so long I just deal with it. Anyways, the doctor did order me a weaker prescription and I tried it but I couldn't see with them...things were blurry and not crisp. The doctor re-did the exam because he said he makes mistakes sometimes, but he came up with the same results, it was so strange...he said that sometimes people just get use to the strength they have and have a hard time adjusting their eyes to a weaker one. I have an appointment on Thursday this week and wonder what it'll say this time...I can still see fine with my prescription I have now...guess I'll see then! 
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CFS peripheral neuropathy 125D54 25D18(Feb08) Ph1Feb08 Ph2April08 25D17(April08) Ph3Sept08 25D10(Nov08)25D10 (Nov09) mag ox NoIRs covered up low lux room
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scooker48
Member in Phase 3
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Posted: Tue Mar 2nd, 2010 23:54 |
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I too had my eyes examined and had the prescription decreased .25 in both eyes.
I am happy with the new prescription, and can see fine.
Good ole' MP.
Sherry
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Necrotizing granulomas biopsy 10/88; Dx 12/04 Sarcoid liver spleen. 2/2/05: VitD 25/VitD125 62. 11/7/09 D25 at 6, Liver function normal 4/08; Wear NoIRs outside. No K creme used. 5/09 Liver and kidneys normal. ACE still high at 113 on 11/7/09.
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Dr Trevor Marshall
Foundation Staff
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Posted: Wed Mar 3rd, 2010 00:11 |
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Mel,
Get Doc to check the glasses which were made for you, particularly the inter-pupillary distance, that can be a common problem when glasses seem blurry
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mebauer
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Posted: Wed Mar 3rd, 2010 00:21 |
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| Oh, I should clarify...I wear contacts so he ordered .25 weaker contact lenses...I can't remember what my glasses were...
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CFS peripheral neuropathy 125D54 25D18(Feb08) Ph1Feb08 Ph2April08 25D17(April08) Ph3Sept08 25D10(Nov08)25D10 (Nov09) mag ox NoIRs covered up low lux room
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Bane
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Posted: Sun Mar 7th, 2010 21:52 |
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Convergence of IL-1β and VDR Activation Pathways in Human TLR2/1-Induced Antimicrobial Responses
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686169/
Author Philip T Liu, Ph.D. (cool research focus)
http://www.epernicus.com/ptl
"Taken together, these data demonstrate that TLR2/1L-mediated induction of DEFB4 mRNA is dependent on activation of the VDR."
"The mechanisms by which TLR2/1 activation of monocytes triggers a vitamin D-dependent induction of antimicrobial activity are central to host defense against intracellular M. tuberculosis"
"Upon triggering TLR2/1 with lipopeptide, both human and murine macrophages activate antimicrobial pathways against intracellular mycobacteria. In comparing the human and mouse TLR-induced antimicrobial pathways, it is noteworthy that the human antimicrobial response requires induction of multiple antimicrobial peptides, both cathelicidin and DEFB4, as opposed to the murine antimicrobial response which is dependent upon generation of nitric oxide. It remains to be determined if the cathelicidin- and DEFB4-mediated antimicrobial activity is bactericidal or bacteriostatic. In humans, both the cathelicidin and DEFB4 promoters contain VDREs, VDR activation was required for their induction, as well as TLR-induced antimicrobial activity. In contrast, there are no VDRE sites present in the mouse cathelicidin promoter region, and to our knowledge there are no other known vitamin D-dependent antimicrobial peptides in the murine genome. Interestingly, 1,25D induces nitric oxide generation in murine macrophages, although the role for vitamin D in this murine TLR-induced antimicrobial response remains to be determined."
Last edited on Sun Mar 7th, 2010 22:56 by Bane
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Oral Lichen Planus(mild)/Clubbed Finger (digital clubbing)Last 25D 5.6ng/ml, phase3
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Dr Trevor Marshall
Foundation Staff
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Posted: Sun Mar 7th, 2010 22:55 |
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Excellent article - thanks, Bane
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jlunn247
Member in Phase 3
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Posted: Mon Mar 8th, 2010 06:24 |
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Do they mean both humans and mice use the vdr but mice use it differently.
are primate and human vdrs close to the same?
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emphysema/ cfs/nerve pain/ 125D56 /25D16/Ph1Mar07 ModPh2Jun07/Ph2Nov07/pHase3Feb08/spiriva
dark sunglasses hands & face exposed/light physical herx.jan10
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jlunn247
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Posted: Mon Mar 8th, 2010 06:44 |
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they are showing how mice & deer make excellent carriers of tick born diseases?
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emphysema/ cfs/nerve pain/ 125D56 /25D16/Ph1Mar07 ModPh2Jun07/Ph2Nov07/pHase3Feb08/spiriva
dark sunglasses hands & face exposed/light physical herx.jan10
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pgeek
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Posted: Mon Mar 8th, 2010 07:52 |
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Do they mean both humans and mice use the vdr but mice use it differently. are primate and human vdrs close to the same? I think they're saying in humans production of the anti-microbial peptides cathlecidin and defensin B4 depends on vitamin D receptor activation, but this isn't the case in mice. This supports Dr Marshall's view that it's extremely unwise to extrapolate the effects of vitamin D &/ VDR activation from mice to humans. On top of this, the article suggests VDR activation (in humans) is important for antimicrobial activity in a way which hadn't previously been discovered.
I had to look up quite a few things to get the (probably exaggerated) impression that I understood what they meant, so here's an attempt at a potted explanation.
In humans, both the cathelicidin and DEFB4 promoters contain VDREs...
Promoters are sections of DNA before the DNA that describes the protein the gene actually produces. They encourage 'transcription' of that information (ie copying into RNA, which eventually gets 'translated' into that protein.)
VDREs are vitamin-D receptor response elements - parts of the promoter that respond to "things" produced by the vitamin D receptor when it's activated. (As far as I can make out. Not sure what the "things" are called though  )
...VDR activation was required for their induction, as well as TLR-induced antimicrobial activity.
So the VDR has to be activated to switch on the production of cathlecidin and defensin B4 as well as for antimicrobial activity via TLR (Toll-like receptors) - which from the wording appears to have been discovered previously.
In contrast, there are no VDRE sites present in the mouse cathelicidin promoter region,...
The DNA ahead of the cathelicidin gene in mice doesn't have a VDRE, so murine production of cathelicidin isn't dependent on VDR activation.
...and to our knowledge there are no other known vitamin D-dependent antimicrobial peptides in the murine genome.
What's more, in mice, none of the other antimicrobial peptides (proteins which are critical to the functioning of the innate (?) immune system) are dependent on vitamin D either.
So the relevance of vitamin D and the VDR to immunity in mice is totally different - and far less important - than it is in humans, as Dr Marshall has believed for some time...
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Chronic Prostatitis, IBD | Avoiding D | Sunglasses |25D14 (Jan2010)
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jlunn247
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Posted: Mon Mar 8th, 2010 09:30 |
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thanks that helps. i like to plow through info like a sod buster.
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emphysema/ cfs/nerve pain/ 125D56 /25D16/Ph1Mar07 ModPh2Jun07/Ph2Nov07/pHase3Feb08/spiriva
dark sunglasses hands & face exposed/light physical herx.jan10
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DMiller
Member in Phase 3
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Posted: Mon Mar 8th, 2010 12:32 |
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| The Vitamin D supplementation freaks will turn this into further justification to increase the recommended daily intake of Vitamin D. After all, If Vitamin D is this important then more must be better.
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Don: Sarc-Lungs dx Jul 05; DVTs, Factor 5 Leiden dx Aug 2000; Sep05: 1,25D=56 25D=19. Started MP 11/4/05; Started mino 11/11/05; Phase 2: 1/9/06; Apr06: 25D=6; Phase 3: 6/22/06; Non-MP meds: coumadin; 10% NoIRs outdoors, 40% indoors when under flourescent
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mebauer
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Posted: Mon Mar 8th, 2010 14:11 |
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| By the way, my eye exam went well...the doctor said my eye looks to be in perfect physical shape and he also said that my eyes have stayed the same as the last exam in fall 2008. He didn't change my perscription again, however, as he said that we tried that before and it didn't work for me as I like the strength I have and can see best with it...I think it's strange how during the exam my eyes are showing an improvement, but when putting in the contacts of that strength I can't see...I don't get it, but I think the MP is workin on em!
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CFS peripheral neuropathy 125D54 25D18(Feb08) Ph1Feb08 Ph2April08 25D17(April08) Ph3Sept08 25D10(Nov08)25D10 (Nov09) mag ox NoIRs covered up low lux room
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Bane
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Posted: Mon Mar 8th, 2010 14:45 |
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If oral vitamin D doesn't help in the production of cathelicidin in the human body? Lets see if cathelicidin is produced outside the body when we apply 25D to cultured monocytes with workin VDR, in an environment with zero 25D present.
Vitamin d-directed rheostatic regulation of monocyte antibacterial responses.
http://www.jimmunol.org/cgi/content/abstract/182/7/4289
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)(2)D from precursor 25-hydroxyvitamin D(3) (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (<75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D(2) twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D "insufficient" conditions the TLR2/1 ligand 19 kDa lipopeptide or the TLR4 ligand LPS, monocytes showed increased expression of the vitamin D-activating enzyme CYP27b1 (5- and 5.5-fold, respectively, both p < 0.01) but decreased expression of hCAP mRNA (10-fold and 30-fold, both p < 0.001). Following treatment with 19 kDa, expression of hCAP: 1) correlated with 25OHD levels in serum culture supplements (R = 0.649, p < 0.001); 2) was significantly enhanced by exogenous 25OHD (5 nM); and 3) was significantly enhanced with serum from vivo vitamin D-supplemented patients. These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes.
Last edited on Mon Mar 8th, 2010 17:03 by Bane
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Oral Lichen Planus(mild)/Clubbed Finger (digital clubbing)Last 25D 5.6ng/ml, phase3
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Bane
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Posted: Mon Mar 8th, 2010 18:08 |
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Vitamin D controls T cell antigen receptor signaling and activation of human T cells
http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.1851.html
http://www.physorg.com/news187187075.html
"For the research team, identifying the role of vitamin D in the activation of T cells has been a major breakthrough. "Scientists have known for a long time that vitamin D is important for calcium absorption and the vitamin has also been implicated in diseases such as cancer and multiple sclerosis, but what we didn't realize is how crucial vitamin D is for actually activating the immune system - which we know now. "
http://www.telegraph.co.uk/health/healthnews/7379094/Vitamin-D-triggers-and-arms-the-immune-system.html
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Oral Lichen Planus(mild)/Clubbed Finger (digital clubbing)Last 25D 5.6ng/ml, phase3
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Bane
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Posted: Mon Mar 8th, 2010 21:30 |
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continuation
im not sure how much of the paper i'm allowed to post?
"To further investigate whether the induction of PLC-γ1 is dependent on 1,25(OH)2D3 and VDR, we stimulated T cells in the presence or absence of ketoconazole, an antagonist of the hydroxylase CYB27B1. CYP27B1 is required for the intracellular conversion of the inactive vitamin D precursor 25(OH)D3 into active 1,25(OH)2D3. In turn, 1,25(OH)2D3 stabilizes the VDR and inhibits its degradation. Thus, inhibition of CYP27B1 should result in less 1,25(OH)2D3 and VDR. We found that treatment of T cells with ketoconazole inhibited VDR expression as well as PLC-γ1 induction. This inhibition was reversed by the exogenous addition of 1,25(OH)2D3 but not by the addition of 25(OH)D3, which supported the idea that 1,25(OH)2D3-VDR signaling is required for PLC-γ1 induction."
"in contrast to naive human T cells, naive mouse T cells have substantial PLC-γ1 expression, and therefore VDR-induced regulation of PLC-γ1 expression does not seem to serve a role in functional avidity maturation in mouse T cells. In agreement with those observations, naive mouse T cells have VDR expression similar to that of primed mouse T cells. In addition, although the development of natural killer T cells and CD8αα+ intraepithelial lymphocytes is disturbed in VDR-knockout mice, T cell activation does not seem to be affected much. The evolution of different mechanisms for the regulation of PLC-γ1 activity in human and mouse T cells parallels the development of divergent VDR-dependent and VDR-independent antimicrobial pathways in human and mouse macrophages"
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Oral Lichen Planus(mild)/Clubbed Finger (digital clubbing)Last 25D 5.6ng/ml, phase3
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Frans
Member in Phase 2
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Posted: Sun Mar 14th, 2010 17:14 |
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Dr Trevor Marshall wrote:Incidentally, somebody has validated in-vivo (in rats, sadly) my in-silico prediction that 1,25-D will directly affect the Thyroid receptors. Here is their paper (where they cite me by name)
http://www.ncbi.nlm.nih.gov/pubmed/20097959
Trevor,
I was wondering if there were papers like Wang's, listing genes transcribed by other receptors.
Especially the receptors (like the thyroid receptors you mention above) that get knocked out by rising D-levels in the cell could be of interest for us, I think ?
Frans
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Burn-out/nervous breakdown Jan01 125D 48 25D8.48 Ph1Nov06 ModPh2Jan07 Ph2Apr08 Cipramil Seroquel NoIRs lite exp r/t work cover up 25D3.9(Oct07)
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