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Joined: Sep 11, 2007 Posts: 784 Location: southern California
Posted: Sat Dec 06, 2008 6:49 pm Post subject:
Thanks so much for the Zamboni research, Dignan-
What really struck me about Zamboni's research on iron dysregulation was how impaired venous drainage could impact MS lesions. An outward sign of this damage is varicose veins or the brownish red petechiae (dots) my husband has had on his legs. Iron accumulation can be seen with the eye on the legs, but is much harder to view inside the brain. Zamboni was able to stain human brain tissue to look for iron deposits, and he consistently found it around MS lesions.
It was only Jeff's outward signs which prompted me looking into the vascular system as a cause of MS. Zamboni posits that it is the genetic differences in MS patients which lead some to have migraine, some to have varicose veins or leg ulcers or petechiae....BUT all of these are signs of iron dysregulation in the vascular system.
His Doppler study on venous reflux was really interesting...showing how the blood goes back and forth in the veins, causing cellular adhesion and a breakdown of vessel walls and creation of lesions. This cerebral reflux study ties into the recent studies showing how many MSers suffer from headache and migraine (caused by venous spasm and reflux)
wow....still more questions, but I feel the track is the right one. Hope Zamboni keeps studying the MS brain and leaves the ice machine business to others!
AC _________________ Husband diagnosed RRMS March 2007
pursuing endothelial healing
Copaxone, Swank, supplements, laughter
Cheers is keen to emphasise that endothelium dysfunction occurs because of iron disregulation and i do not doubt this is possible because excess iron messes with nitric oxide but i am convinced that the damage is mostly due to oxidative stress. When the excess iron reacts with oxygen, free radicals are produced. Although free radicals are essential molecules in the body's metabolism, they can also destroy cells.
We already know something like this is happening in Parkinson's, Alzheimers and Friedreich's Ataxia due to iron problems, so why not MS?
In Parkinson's:
Disrupted iron metabolism and excess iron accumulation has been reported in the brains of Parkinson's disease patients. Excessive iron can induce oxidative stress subsequently causing degradation of nigral dopaminergic neurons.
In Friedreich's:
In Friedreich's, poor metabolism of iron leads to an accumulation in the mitochondria of nerve cells resulting in neuropathy, for example, in the optic nerve.
I know that anaemia is common in MS and that some people with MS actually take iron supplements but I am still convinced that faulty iron metabolism is a very likely candidate for what is behind the neurodegeneration. It may not matter whether iron levels are high, low or normal, it is the metabolism of iron that seems to be crucial.
Correct iron delivery to the receptor cells in the mitochondria is essential for correct metabolism. The Egyptian study made the discovery that this is going wrong in all types of MS but not in controls. When metabolism goes wrong oxidative stress follows, whether due to imbalance of iron, oxygen, glucose, nitric oxide, insulin or whatever. A faulty carburettor or ignition will make a car sick, regardless of whether gas is high or low in the tank. This fault could be due to a genetic flaw, viral attack, endothelium problems, insulin, stress hormones... the usual selection, but oxidative stress results.
It is interesting that removing iron from mice with EAE ("Mouse MS") supressed the disease and inhibited active T cell function. I know EAE is not 'real' MS but you'd expect removing most of the iron supply would make those little creatures feel a lot worse wouldn't you?
My mother (70 yrs old) has extreme overproduction of platelets. Upon more testing, the doc found that she has NO iron in her bone, yet she still produces red blood cells. (????) It seems that iron can be at different levels in different places throughout the body. The level in the brain is diff from the blood which is diff from the testes in men, which is diff than the level in the bone, are there more? I can't shake the feeling that her issues might teach me something about my MS if I can make sense of it. After all, I am my mother's daughter.
She is being treated with a fairly high dosing of iron for 4 weeks. then back to the doc for more tests.
Makes me want to have a bone marrow biopsy just for curiosity sake.
Has anyone ever thought about seeing a hematologist for their MS?
Terry
Sometimes the spleen can produce red blood cells too.
I'd be worried about taking too much iron supplement...the body may have depleted it for a reason.
Without a doubt I would take your mum to see a chinese herbalist or someone who is knowlegable in Ayurvedic medicine, plus take a multivitamin, cut out too much fatty food and cakes and I'm sure she'll be fine. ( I take it she doesn't smoke). Salvia (Dan Sheng) and other herbs like Amrit Kalash can do great things to balance blood and stop the risk of clotting but you need to speak to the experts. Vitamin A in high doses has had surprising results in treating leukemia.
Joined: May 24, 2007 Posts: 112 Location: Southwestern PA
Posted: Tue Dec 09, 2008 8:36 am Post subject:
I'm confused on this iron thing. My husband just had blood work because he is on Tysabri. The nurse told him his iron levels are low and to eat more red meat. Also, a week or so ago, we noticed that his one leg is swollen. We have an appt with his general doctor this week. The nurse said it could be something vascular. Okay! Help me understand. Should I give him iron pills or not? What is the connection? You all understand this much better than I do.
Last edited by MaggieMae on Wed Dec 10, 2008 7:43 am; edited 1 time in total
Joined: Sep 11, 2007 Posts: 784 Location: southern California
Posted: Tue Dec 09, 2008 9:22 am Post subject:
MaggieMae wrote:
I'm confused on this iron thing. My husband just had blood work because he is on Tysabri. The nurse told him his iron levels are low and to eat more read meat. Also, a week or so ago, we noticed that his one leg is swollen. We have an appt with his general doctor this week. The nurse said it could be something vascular. Okay! Help me understand. Should I give him iron pills or not? What is the connection? You all understand this much better than I do.
Oh, goodness. Sorry for your concerns and confusion, Maggie. Go back one page on this thread and read what I wrote. MSers don't need their iron levels raised, it's the transferrin receptor that is off. Have the doc test this before you start iron pills. High transferrin receptor and iron dysregulation could create vascular problems like reflux (as seen in leg petechia, varicose veins and swelling) The blood vessel walls break down and blood is leaks out.
But, his leg swelling may not be vascular. I'd stick to the American Docs Heart Diet, which is low fat, no red meat, high in fruits and veggies. Red meat and saturated fat create inflammation...no good for your husband. You want to calm inflammation and oxidative stress which might be breaking down the blood vessels.
If you want, read my thread on endothelial dysfunction and download the paper...I talk more about the vascular concerns in MS. There's a connection, but docs are confounded by all this, since it doesn't fit with what they've been taught about MS. This might give you more to talk about with your husband's GP. Ours is now behind the program, although she was confused by it all at first.
I hope you figure out his leg issues, and get your husband on the mend.
AC _________________ Husband diagnosed RRMS March 2007
pursuing endothelial healing
Copaxone, Swank, supplements, laughter
Last edited by cheerleader on Tue Dec 09, 2008 9:29 am; edited 1 time in total
Joined: Sep 11, 2007 Posts: 784 Location: southern California
Posted: Tue Dec 09, 2008 9:26 am Post subject:
Terry wrote:
Has anyone ever thought about seeing a hematologist for their MS?
Terry
More and more everyday
Might be a good idea, Terry...if you find someone who understands iron dysregulation and transferrin receptor problems in MS. Hope your Mom's OK.
AC _________________ Husband diagnosed RRMS March 2007
pursuing endothelial healing
Copaxone, Swank, supplements, laughter
careful maggie mae, talk this one over with the doc. i don't have time to investigate cheer's line of research in-depth, which i'm sure has some valid points in certain situations - however, please consider also:
-high ferritin can mean a few different things, including deficiency if the underlying iron levels do test low. in that case, you'd want to get the iron values up.
-chronic inflammation can also cause elevated ferritin values that mask deficiency. in that case, you'd want to take on the inflammation, and get the iron up too.
it's certainly not good to overdo iron, but if ferritin is high, you need to be careful to investigate whether it's in fact caused by deficiency, inflammation, OR transferrin receptors being out of whack.
MS is not one size fits all!
Last edited by jimmylegs on Tue Dec 09, 2008 12:50 pm; edited 1 time in total
Joined: Sep 11, 2007 Posts: 784 Location: southern California
Posted: Tue Dec 09, 2008 10:48 am Post subject:
Jimmy's absolutely right...you want to know the numbers for total iron binding capacity, serum ferritin and serum iron... Especially before starting an iron supplement. Just giving you more questions for the doc.
AC _________________ Husband diagnosed RRMS March 2007
pursuing endothelial healing
Copaxone, Swank, supplements, laughter
Sometimes the spleen can produce red blood cells too
Thanks for that., Gainsbourg. I hadn't figured that one out!
Leukemia has been ruled out for my mom, though it will remain a slight risk in the future. No, she does not smoke. I couldn't get her to go to another doc if I tried. She really worried she wouldn't like this one, and luckily, she does. She is dragging her feet to start the iron, though. Im not sure why. She says she's been too busy to go get it. Hmmm. She'd never have known all this was going on except for routine blood work. She feels fine mostly.
I read lots. I don't retain details at all. (Have you noticed?) I cannot tell you in detail why I think this, but "for now" this is what I'm thinking.
Iron deficiency causes absorption and recycling of iron to change. The iron stores should be pretty even throughout the body. Obviously for some it is not. Not for Mom, not for the MS'ers who store extra in the brain. I can't figure out- once we get to this point, whether adding iron will help or hurt. Does something else need adjusted before we add iron? I guess Mom's tests next month will shed a little light.
Joined: Sep 11, 2007 Posts: 784 Location: southern California
Posted: Fri Dec 12, 2008 11:51 pm Post subject:
Terry...
Iron regulatory proteins seem a wee bit over my head. These proteins function within the cell to regulate iron metabolism. There's an IRP1 and IRP2 and they're made up of amino acids, and they're really small, but large for a protein.
Here's a doc who understands them better than me, and has linked iron dysregulation to MS...James R. Conner of Penn State. He spends all his time researching this and trying to figure out how iron ends up in diseased brains. He believes the proteins may provide a pathway to control this dysregulation. Here's what he says....
Quote:
Regulation of Expression of Iron Binding Proteins in the Nervous System
The projects in my laboratory are designed to understand the cellular and molecular mechanisms by which cells regulate their iron status. Iron is essential for normal function but at the same time too much iron can be toxic. Therefore cells have an exquisite system for regulating iron levels. When these regulatory mechanims become dysfunctional either through damage, disease or genetic modification cell behavior is abnormal and they sometimes die. Iron imbalance is associated with a prooxidative stress and a proinflammatory environment. Much of our work has focused on mechanisms responsible for regulating iron in the brain. One basic function in which iron is required in the brain is for the production of myelin. We have shown that too little iron during perinatal development will result in hypomyelination. We have also provided evidence that iron can contribute to Multiple Sclerosis (MS). We have established that there is too much iron in the brain in a number of neurological disorders including Alzheimer's (AD) and Parkinson's Diseases (PD). In contrast, there appears to be too little iron in the brain in a disorder known as Restless Legs Syndrome. What is clear from our studies is that optimal brain function requires a tightly regulated iron supply and that the iron must be delivered in a timely manner. To determine the mechanism(s) for brain iron delivery and the regulation of those mechanisms we have focused on a number of mouse and rat mutants as a model of human diseases in which the ability to acquire, moblize or store iron has been disrupted. In the context of these studies we have generated a very promising mouse line in which the gene for the iron storage protein, ferritin, has been deleted. This model is helping to understand the contribution of loss of brain iron homeostatic mechanisms to those changes seen in the brain with AD, PD and MS. In the course of these studies on ferritin, we found that in addition to the cytoplasmic location, ferritin can be found in cell nuclei under some conditions. This observation has led us to basic molecular studies on DNA binding and protection as well as intracellular trafficking of ferritin. The evidence strongly indicates that nuclear ferritin is associated with tumorigenesis. Another avenue under exploration in the context of homeostatic mechanisms is the analysis of gene mutations that lead to disruption of iron status. We have identified mutations in the Hfe gene as a risk factor for Alzheimer's Disease and Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease). The Hfe protein is thought to limit iron uptake by cells and a mutation in this protein may promote inflammation and oxidative stress. We also have a line of research aimed at understanding mechanisms of iron uptake into the brain. This line of research should provide insight into how too much iron can enter the brain in disease states. These studies have led to one particularly novel and important finding of a new receptor in the brain for ferritin. This receptor is expressed only by oligodendrocytes in the brain. We are investigating the possibility that the selective expression of ferritin receptors on oligodendrocytes may have medically important implications for Multiple Sclerosis.
In regard to function of iron in the brain, one area of focus is the regulation of those proteins responsible for iron management in cells. The iron management proteins are regulated by cytoplasmic mRNA binding proteins that are known are iron regulatory proteins. Our project is to determine how the cytoplasmic mRNA binding proteins find their target mRNAs. The outcome of these studies may help us understand how a cell can become iron overloaded but also will contribute significantly to our general knowledge of post-transcriptional gene regulation. One additional approach which is aimed at understanding the function of iron in cells is gene expression profiling. In these studies we have asked the question: "what does it mean to a cell at the molecular level to be iron loaded or iron starved". So far, we have identified a dozen novel genes and a number of genes not previously known to be iron responsive. These data are relevant to cancer and Alzheimer's Disease and Restless Legs Syndrome.
May God bless Dr. Conner and his research dept. and bestow upon them many grants, and may he figure this iron thing out for us all!!!
Hope your Mom is doing OK, and that the docs are figuring out her iron issues. This is w-a-a-ay too complex for me, but I know there's something here.
AC _________________ Husband diagnosed RRMS March 2007
pursuing endothelial healing
Copaxone, Swank, supplements, laughter
BACKGROUND: the extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have never been investigated.
METHODS: Sixty-five patients affected by CDMS, and 235 controls composed, respectively, of healthy subjects, healthy subjects older than CDMS patients, patients affected by other neurological diseases, and older controls not affected by neurological diseases but scheduled for venography (HAV-C), blindly underwent a combined transcranial and extracranial Color-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. According to the TCCSECD screening, patients and HAV-C further underwent selective venography of the azygous and jugular venous system with venous pressure measurement.
RESULTS: CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29-65, p<0.0001). Subsequently, venography demonstrated in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments; it configures a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of distribution of stenosis and substitute circle. Moreover, relapsing-remitting and secondary progressive courses were associated to CCSVI patterns significantly different from those of primary progressive (p<0.0001). Finally, the pressure gradient measured across the venous stenosies was slightly but significantly higher.
CONCLUSION: CDMS is strongly associated with CCSVI, a picture never been described so far, characterized by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.
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