A new concept and treatment options for MS

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Re: A new concept for MS [I think I found it: This Is MS]

Postby Anonymoose » Wed Feb 20, 2013 6:40 pm

Caveman,

I don't think stress is it. I think it's a cyp450 gene that causes pwms to release extra aldosterone and maybe cortisol in response to stress. All of the complicating individual factors you mention influence levels of cortisol and aldosterone. If you read up on cortisol and aldosterone you will find that a vast number of ms characteristics can be in some way linked to excessive cortisol or aldosterone.

Sorry for the hijack, Leonard. I'm still very interested in your thoughts on this.

NHE, lol! I would not enjoy that test.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby CaveMan » Wed Feb 20, 2013 7:07 pm

Is it a Hijack? I thought the discussion had moved to more general causalities anyway.

Haven't looked at that gene pathway, but I get the same thing on the thyroid autoimmune disease pathways, and yes it's all good valid work and is helping clear up questions on the way,

but they all end in the same place following the switching paths,
Does everyone with MS have this gene and does everyone with this gene have MS?
Is it the only gene controlling the stress response and aldosterone and cortisol levels?

If the answer is no, then this is a predisposition or an aggravating factor, but not the only factor in the expression of the condition.

I don't engage here too often, but I have read through a lot of the big threads, including this one and lots of bits here and there, my knowledge is nowhere near as deep as most here, but it is quite broad.
I am just an interested individual trying to crack the autoimmune nut.
Partner has Graves Disease, 5 years, showing good test results, looking forward to potential remission in the near future.
3 friends have MS, 1 just recently diagnosed, severity 7/10.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby vesta » Thu Feb 21, 2013 3:21 am

Hi Leonard:
Thanks to your posts I realize I have been too preoccupied with the structural vein problems without considering what is happening INSIDE the vein - which can impact blood circulation from the head. I know Diabetes causes blood circulation problems, but what you describe implies you have Diabetes MS , not that Diabetes equals MS. Referrring to your post on morning "wood", how much do you think the improvement concerns the nerves and how much blood circulation? Do you believe using diet, healing toxic gut etc can heal endothelium damage of the veins?

More on stress.

I read somewhere that in Scotland the male/female ratio of MS incidence has widened to the point there are 4 times as many women as men who develop the disease. Why? Because besides being subject to male dominance in general (let's not pretend that misogyny has vanished) the Scotswoman now has success stress fear to deal with, the injunction to succeed professionally while being disadvantaged by gender in the race. And having the triple load of motherhood, home responsibility and work requirements. More stress.
Marc Stecker of Wheelchair Kamikaze reports as well that studies of urbanization in Crete show a rise of MS in women who move to the cities. The most obvious reason for this in my opinion is the added stress of finding work in a more competitive environment. Ah yes, the higher socio-economic strata of society is the most affected. Again Success Stress.

Then look at another study - of MS incidence among various populations in Israel. Same latitude and climate. Israeli born Jews and Jewish immigrants from Europe/North America show the highest MS incidence, of middling incidence are Jewish immigrants from Africa and Asia as well as Christian Arabs, the lowest incidence being among Moslem Arabs, Druze and Bedouin. Forget the sunlight argument and other material factors, the Success Stress Culture strikes me as the most critical factor.
Israeli born Jews are the most afflicted with MS in Israel.. Let's look at this phenomenon again in light of Chinese Medical Theory. Remember, it is said that fear (and cold) "injure" the Kidneys. When their Yang protector the Bladder Meridian mobilizes to protect the Kidneys, the back and neck muscles tense up affecting blood circulation to the head and spine. Israelis don't suffer from a cold climate, it must be the Fear factor. It may be that Israeli children really do grow up with a heightened sense of survival fear which affects their health.

Someone should think of doing an epidemiological comparison of MS incidence among the various religious groups. In other words, study the role of belief and or behavior in the rearing of children. Up to now, I believe one has been too preoccupied with purely material factors - genes, UVB radiation, viruses etc. Stress is as much an emotional/ psychological factor as material. The necks, shoulders and backs of stressed individuals seize up with tension, and it is exactly this phenomonen which I believe damages the vascular system in children leading eventually to adult Multiple Sclerosis.

A fuller development of these ideas can be found under the Blog subject Success Stress June 1, 2012 on my site
MS Cure Enigmas.net
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stress and MS

Postby Leonard » Thu Feb 21, 2013 8:01 am

I know that many of you have many questions, I have them too...
and frankly, when we come closer to possible therapeutic options, I hesitate a bit to go into detail...
in the end, I am only one patient, not even a doctor...

On the issue of stress and MS, I think the word 'entanglement' is very well chosen (see refs below). I do not believe that stress is the only factor, but it is a factor. Nor do I believe that stress is necessarily causal; it may well work the other way around where a weak metabolism (e.g. depletion of costisol production after many years of excessive production to deal with an unbalance? - the visceral fat around the belly or the fatty liver is a clear sign of this excessive production!) causes people to become more susceptible to stress and a vicious circle is then established. And of course I do not believe that the neuro-inflammatory issue is primary..

It also occurs to me that not all stress is the same. I remember having read that when Israel was under threat of scud attack in the early 90s, the incidence of MS flares went down. Because people prepared in their minds for a fligth or fight, stimulating some metabolic processes? I also believe that psychological stress is much worse, the stress of unfinished business... George Jelinek expands on this quite well in his book.. Again, pointing to metabolic issues...

Hence, a better title for the article would then have been:
Stress caused adverse entanglement of the nervous system and the metabolism: A case for MS.

Refs:
general-discussion-f1/topic21729.html
http://www.ncbi.nlm.nih.gov/pubmed/23207182
Last edited by Leonard on Thu Mar 14, 2013 1:09 am, edited 2 times in total.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby CaveMan » Thu Feb 21, 2013 2:28 pm

With the Soceoeconomic bias in MS,
There may also be additional factors at play in addition to the stress,
* Sanitation may play a role in early childhood exposure to a greater range of antigens hence a more robust immune system, there seems to be a risk cut off rate at the around 15 yo, one assumes the risk rate where puberty was reached, this fits with the role of the Thymus in immune developement as it is very active and large in childhood and atrophies through puberty. So if one gets a new infection after that age there is a much more severe response as it takes much longer to gear up new antibody blueprints which come from the thymus. One for the supporting factors in the molecular mimicry theory is the rates of MS are much higher in low Hepatitis B regions, which suggests late exposure may be a risk factor for MS.
* Breast feeding may also play into that in the multigenerational level where mothers with higher education levels are more likely to have careers and hence more likely to fall back to formula feeding in early childhood and it is known that this is a risk factor in Type 1 DM, SIDS, and a number of other conditions and this also ties in with the A1 Caesin risk in Milk, which is the primary Dairy variant in European (& US) type cattle whereas the African, Asian cattle are A2 Caesin along with Sheep, Goats and ofcourse Human Milk all being the A2 variant.
* UVB exposure may also be related as there is a similar corrolation with skin cancer rates, where indoor workers and higher socioeconomic classes are at greater risk which has been steadily rising and outdoor workers rates have remained fairly steady, hypothesis is glass, which blocks UVB, but not UVA, UVB is required to produce vitamin D which destroys cancer cells, so basically the higher your status, the more glass you have in your house/office and the more exposure you have to damaging UVA and no UVB/D3 for protection. We need a balanced exposure to direct sunlight during the middle of the day from 10-2 ideally, just when authorities tell you to stay out of the sun, also most sunscreens only blocked UVB, because it is what causes sunburn, but this is just the sign to get out of the sun because you have maxed out on Vitamin D production.
Link on the Skin Cancer thing:
http://fitnessblackbook.com/main/avoidi ... at-advice/

As you may suspect my feelings are all these and many more factors combine to weaken the body and open the door to chronic disease, and correction of as many as possible is the most probable path to healing.
I am just an interested individual trying to crack the autoimmune nut.
Partner has Graves Disease, 5 years, showing good test results, looking forward to potential remission in the near future.
3 friends have MS, 1 just recently diagnosed, severity 7/10.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby Leonard » Thu Mar 07, 2013 7:11 am

If we look deeper into the endocrinological space of our microcosmos, we see an interesting constellation of objects, the family of fibroblast growth factors (FGF).
This review provides a good tutorial on FGFs and a subset called FHFs (fibroblast homologous factors).
http://fvl.vfu.cz/export/sites/fvl/sekc ... review.pdf

The complex is interrelated with similar core structures and (somewhat?) divergent receptor bindings. It regulates a plethora of developmental processes. The FGF 19/21/23 subfamily is endocrine-acting and plays a crucial role in glucose and phosphate homeostasis. The physiology of the FGF19/21/23 complex links the intestine, the liver, the pancreas and the kidneys (see figure 4).

The principal target of FHFs are the intracellular domains of voltage-gated sodium channels.

One important function of FGF1 and FGF2 is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures. They thus promote angiogenesis, the growth of new blood vessels from the pre-existing vasculature. FGF1 and FGF2 are more potent angiogenic factors than vascular endothelial growth factor (VEGF) or platelet-derived growth factor (PDGF).

FGFs are also important for maintenance of the adult brain. Thus, FGFs are major determinants of neuronal survival both during development and during adulthood.Adult neurogenesis within the hippocampus e.g. depends greatly on FGF-2. In addition, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory, at least in the hippocampus.
http://en.wikipedia.org/wiki/Fibroblast_growth_factor

In some way connected to FGF21 in lipolytic processes is Carnitine. Carnitine, produced endogenously in the kidneys and liver, interferes with the processing of food i.e. fats for energy production. It plays on essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation.
http://en.wikipedia.org/wiki/Carnitine
http://emedicine.medscape.com/article/942233-overview

Is this where the secret of the Swank low-fat diet lies? That the transfer of long-chain fats is deficient because of Carnitine deficiency, and that gates to the cells are being jammed for that reason? How does Carnitine relate to FGF/FHF?

There are many questions on the glucose/fat metabolism, including on the underlying concepts themselves. But my intuition tells me that this constellation of FGFs, FHFs, Klotho, Carnitine is central to our problem...
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Re: A new concept for MS [I think I found it: This Is MS]

Postby Leonard » Sat Mar 09, 2013 11:48 am

CaveMan wrote:As you may suspect my feelings are all these and many more factors combine to weaken the body and open the door to chronic disease, and correction of as many as possible is the most probable path to healing.


@Caveman, I am sure you are right.
I saw your posting on Linda's thread from a year or so ago on Carnitine. Carnitine intrigues me..

I searched a bit more on Carnitine. And found a link to testosterone, and in particular on the use by the cells of testosterone. Now my explanation for the different incidence of MS between men and women is the testosterone hormone, so clearly there is this link to MS. I think that Carnitine could well play a central role in the sense that the use of free testosterone becomes more effective and hence boosts "cellular nutrition" with higher levels of Carnitine. I think body builders (using Carnitine) don't have more cells, the cells themselves just get bigger. And we know from this thread that MS is all about cellular nutrition.

Is it true that Carnitine production is induced by the hunger hormone FGF19/21/23? Is this a potential regulatory mechanism? Is this a pathway where our metabolism is going wrong (I talk here only about the second progressive phase)? I would be interested in your views..
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Re: A new concept for MS [I think I found it: This Is MS]

Postby NHE » Sat Mar 09, 2013 5:11 pm

If I remember correctly, carnitine helps transport fats into the mitochondria where they can be used as fuel in beta-oxidation.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby Anonymoose » Sat Mar 09, 2013 7:54 pm

Leonard wrote:Is this a pathway where our metabolism is going wrong (I talk here only about the second progressive phase)? I would be interested in your views..

I've been chasing carnitine, malonyl coa and malonyl dialdehyde for hours. I should have done the most obvious search in the first place. "MS and carnitine" Sigh. This study is small and doesn't say which form of MS participants had, but apparently in some form of MS, carnitine is not an issue.
http://www.ncbi.nlm.nih.gov/pubmed/9014230
Serum carnitine and disabling fatigue in multiple sclerosis.
Fukazawa T, Sasaki H, Kikuchi S, Hamada T, Tashiro K.
Source
Hokuyukai Neurology Hospital, Sapporo, Japan.
Abstract
The serum concentrations of total, free and acylcarnitine were compared in 25 patients with multiple sclerosis (MS) and among age- and sex-matched normal controls by the new enzymatic cycling method in order to clarify whether the fatigue in MS might be due to possible carnitine-related fatty acid metabolic abnormalities in the mitochondria of skeletal muscles. Patients with MS were divided into those with and those without excessive fatigue. Levels of total and free carnitine were not significantly different between MS patients and normal controls. Levels of acylcarnitine, whose decrease in chronic fatigue syndrome has been reported, were also similar between MS patients and normal controls. There was no difference in these carnitine levels between MS patients with and without excessive fatigue. We argue that acylcarnitine deficiency and fatty acid metabolic dysfunction in mitochondria are not relevant to the excessive fatigue in patients with MS, and further explanatory investigations are to be sought.
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We need endocrinologists

Postby Leonard » Tue Mar 12, 2013 7:10 am

The sector analysed the buckets of water in great detail but forgot to look at the course of the river. I think this is true as well for the above study on Carnitine. A broad picture emerges that is complex and includes many facets including fundamentally different mechanisms underlying RR and SP MS, the time constants involved in the metabolic processes are long, and so are time spans for useful trials, the regulatory pathways and loops are unclear, contradictory or inconsistent, …

It is clear to me that MS in its second progressive stage is a metabolic disease. Where I think the FGF21 hunger hormone is central and potentially induces many things, as starvation response, including proteins, enzymes, and catalysers and promotors, gene-gene interactions etc. I think possibly affecting transfer and 'handling' of (very) long-chain fatty acids (related to saturated fats) by the (mitochondria of) the cells.

http://www.pnas.org/content/106/26/10853.full
http://www.everydayhealth.com/senior-he ... -life.aspx
http://www.mendeley.com/catalog/fgf21-i ... n-respons/
http://www.molmetab.com/article/S2212-8778(12)00016-6/abstract
http://en.wikipedia.org/wiki/Fatty_acid ... cid_chains
http://en.wikipedia.org/wiki/Fatty_acid
http://edrv.endojournals.org/content/29/7/939.full
http://www.medicinenet.com/script/main/ ... ekey=23820
http://www.ncbi.nlm.nih.gov/pubmed/3318 ... t=Abstract

Some key words: The physiology of fibroblast growth factor 19 (FGF19), FGF21 and FGF23, pgc-1α, "long-chain fatty acids", Pro12Ala SNP, VLCFAs are too long to be metabolized in the mitochondria and must be metabolized in peroxisomes, carnitine palmitoyltransferase as the enzyme regulating the transport of long-chain fatty acids into mitochondria, hepatic lipid metabolism (LIPC), higher liver fat and insulin resistance, the pathogenesis of type 2 diabetes and lipid metabolism, the upstream transcription factor usf1s2 G/A SNP which is associated with familial combined hyperlipidemia and atherosclerosis, FGF21 inhibit FGF-1, FGF23 regulates phosphate absorption and vitamin D biosynthesis via its actions on the kidneys, hydroxylase so as to reduce the levels of activated vitamin D, GLUT1. The Nature Review paper and Figure 4 elaborate..

But a search on Google also revealed a connection to: Th17 key to MS immune reaction!, RAR and RXR (and VDR?).

http://en.wikipedia.org/wiki/Th17
http://www.jbc.org/content/285/21/15668.full

There is critical need for a re-conceptualisation, to clarify the course of the river. Top endocrinologists should urgently and altruistically enter the space of MS...
Last edited by Leonard on Fri Mar 15, 2013 3:28 am, edited 2 times in total.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby Anonymoose » Tue Mar 12, 2013 7:41 am

Go Leonard! You've gotten me all riled up. :) You're onto something...

I think MS progresses from one endocrine dysfunction to another.

The Th17 (upregulated by aldo and stimulated by salt) isn't really a big player in spms, is it? I thought by that point inflammation was less of an issue.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby positive » Tue Mar 12, 2013 5:35 pm

Very interesting!
Hyperinsulinemia would explain the initial lower blood glucose levels during this phase of pre prediabetes and increase in cellular insulin resistance (insulin the storage hormone, also fat into fat cells).
I find Barometric pressure changes (weather changes) and stress I find are big things -? Vascular affect or hormone release?
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Re: A new concept for MS [I think I found it: This Is MS]

Postby lyndacarol » Tue Mar 12, 2013 6:54 pm

Welcome to ThisIsMS, positive! I like your thinking!

I believe insulin is a major player in MS, as folks here know; I think diet can be an effective treatment for some people and should not trigger insulin production. In my opinion, this diet should be a very low-carb diet --remove ALL trans fats; remove all sugar (including beer, wine, etc. which have sugar), remove all artificial sweeteners, including sugar alcohols like sorbitol, xylitol, etc. (These promote insulin production, too.), and remove white flour, white bread, white potatoes, white rice (in fact, all carbs so far as possible). Although I have not been able to reduce my insulin level with diet alone.

And since corticosteroids raise the blood sugar, I believe that steroids eventually have an adverse affect on MS.

My suspicion is that Fatty Liver Disease is also involved in MS (one can be "skinny fat" – slender with interior fat), since visceral fat (belly fat) secretes cytokines (like poison to the internal organs), which lead to increased insulin, which leads to inflammation which leads to more visceral fat… And the cycle goes round and round. Diet is important; in fact, you may find the account of Dr. Terry Wahls and her dramatic improvement in MS interesting (http://www.TerryWahls.com).

All the best to you.
My hypothesis: excess insulin (hyperinsulinemia) plays a major role in MS, as developed in my initial post: http://www.thisisms.com/forum/general-discussion-f1/topic1878.html "Insulin – Could This Be the Key?"
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Re: A new concept for MS [I think I found it: This Is MS]

Postby Anonymoose » Fri Mar 15, 2013 9:15 am

Leonard,

Could we, rather than having lower than average energy-creating-components, have a higher demand for them?

Energy failure in multiple sclerosis and its investigation using MR techniques
http://link.springer.com/article/10.100 ... -7?LI=true

If you click "look inside" you will find possible explanations.

If the brain is using sodium to compensate for neuronal/myelin damage (which would explain sodium accumulation that increases with progression), our demand for energy would increase proportionately with neuronal damage.
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Re: A new concept for MS [I think I found it: This Is MS]

Postby Anonymoose » Fri Mar 15, 2013 1:41 pm

Leonard,
Since this frame of thinking is all new to me, I was wondering if you think this has something to do with the change from RRMS to SPMS and/or onset of PPMS...
http://www.scielo.br/scielo.php?pid=S01 ... ci_arttext
Energy deficiency and dysfunction of Na,K-ATPase are common consequences of many pathological insults and stress. Glutamate through cyclic guanosine monophosphate (GMP) and cyclic GMP-dependent protein kinase (PKG) has been shown to stimulate α2/3-Na,K-ATPase activity in the CNS (58). Thus, a slight impairment of this pathway may amplify the disruption of ion homeostasis in the presence of a non-lethal insult. Studies in rats suggest that basal age-related decline in sodium pump activity is a consequence of changes in different steps of the cyclic GMP-PKG pathway. On the other hand, age-related reduction in glutamate-positive modulation of cerebellar α2/3-Na,K-ATPase is linked to a defective PKG signaling pathway (59). The loss of the ability of α2/3-Na,K-ATPase to respond to glutamate through a cyclic GMP-PKG cascade could be a failure in an important mechanism for rectifying ionic disturbances that may be present in aging processes and may predispose to or potentiate an effect of stress in the manifestation of age-related degenerative disorders. In fact, chronic predictable and unpredictable stress decrease the neuronal Na,K-ATPase activity and high levels of glucocorticoid have been detected in 24-month-old rats (Munhoz CD, Scavone C, unpublished results), which could induce a further reduction of ATP levels during a neurological insult. It is interesting to note that the aging process (30-month-old animals) induces up-regulation in constitutive NFκB binding activity in the frontal cortex, which in the presence of glucocorticoid levels could potentiate LPS-induced NFκB activation and an increase in mRNA of proinflammatory genes (9). In addition, rats with increased HPA reactivity induced by prenatal stress or by the absence of neonatal handling show an early decline of cognitive functions associated with the hippocampus, as well as increased propensity to self-administer drugs such as amphetamine and cocaine (55). In addition, exposure to both chronic restraint and unpredictable stress increased cocaine-induced locomotion and basal corticosterone plasma levels and chronic unpredictable stress also displayed the largest locomotor response following a challenge dose with cocaine compared with control and chronic restraint stress groups (60). Drug abuse is associated with changes in brain function and neurodegenerative processes, which, for some drugs, have been shown to be associated with the induction of apoptotic/necrotic cell death (Lepsch LB, Munhoz CD, Kawamoto EM, Lima LS, Scavone C, unpublished results). Thus, life-long patterns of HPA function are probably important to determine the susceptibility of the body to stress or insults during the aging process.
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