I was going to mention that one way of looking at the age-dependence of the protective effect of "migration" in multiple sclerosis (migration to an equatorial latitude) is that the axonal transport capacity or generalized "robustness" is greater in people who are relatively "younger" than in people who are older. There's also a latitude gradient in Epstein-Barr Virus-associated malignancies (Burkitt's lymphoma, etc.), but it's not clear if that's explainable in terms of the lesser extents to which people living in Subsaharan Africa have access to health care and nutrition, etc. (http://scholar.google.com/scholar?hl=en&q=Burkitt%27s+lymphoma+latitude). That's not a great search. But the point is that that could provide indirect support to the ideas people have had about late EBV infection being associated with abnormal neural development in the offspring of people who have had late EBV infections (see past postings and the articles cited in them). I just don't think one can ignore that epidemiology (the latitude gradient and research on migration) in relation to multiple sclerosis, and I don't think it's written in stone that there's no capacity for protection after age 15 or something (no capacity for protection to occur in response to migration or to the environmental, protective factors(s) that have been associated with migration to equatorial latitudes). I've seen research suggesting, for example, that migration may be protective through age 27 or something. That would tend to imply that migration *could* be protective at later ages but that people's behaviors, related to time spent outdoors or to nutritional factors that would interact with that or to activity levels and all other things, have become ingrained, perhaps, by the time people are 16 or 17. On average, how many people radically change everything about their habits after age 18? I'm talking about drastic changes in UVB exposure, etc. I mean, I'm sorry to say it (and I'm in no way suggesting that people go out in the sun without talking with their doctor), but 10 minutes of sun exposure at noon, on the hands and face, is not likely to increase serum 25-hydroxyvitamin D levels all that much and is not going to have the kinds of immunomodulatory effects that depend on hundreds of billions of neutrophils infiltrating the UVB-irradiated skin and the immunosuppressive cytokine milieu associated with it. In my past comments, the main thing I wanted to convey is that I don't think people should expect magic from UVB exposure and that there are many other factors that come into play in the etiology of multiple sclerosis. But, for example, Epstein-Barr Virus infects keratinocytes (http://scholar.google.com/scholar?hl=en&q=Epstein-Barr+keratinocytes), and I don't have to say what that means. It means that there's the *potential* for the induction of tolerance to EBV latent and lytic cycle proteins on a kind of mass scale, following UVB exposure. But there's also the potential for that tolerance to turn into seriously aberrant, Th2-driven immunity and to worsen matters. It's difficult to control or predict the responses, and that's especially true in disease states (in which there's potential for disastrous effects). But, then again, UVB is known to suppress both Th2 and Th1 immunity (the Th1/Th2 dichotomy is a bit outdated but still has some usefulness as a crude framework for looking at these things). But my point is that the release of Th1 cytokines almost disappears, in some cases, from the lymph nodes of UVB-irradiated animals, and the idea that everything boils down to vitamin D and hands-and-face, anemic, Victorian-Era, parasol-carrying approaches is a bit absurd to me. That said, I can't make any recommendations on these things, because I can't give medical advice and, to say the least, can't make any guarantees whatsoever about safety. Avis et al. (1995) (http://scholar.google.com/scholar?hl=en&q=sudden+death+sun+exposure+%22multiple+sclerosis%22) discussed case(s) of people with multiple sclerosis dying after sitting in the sun.
I think it's telling that thermoregulatory dysfunction features prominently in multiple sclerosis, but I don't claim to know how it relates to the supposed UVB-mediated trigeminohypothalamic thermoregulation that may occur in humans. Part of the difficulty is that, for example, the neuropathological effects of Epstein-Barr Virus, in some extreme case studies, can be highly diffuse, and that could be explained in any number of ways (in terms of "diffuse" B-cell infiltration or latent infection of astrocytes and microglia and other perivascular, monocyte-macrophage-lineage cells). I tend to think it's a result of astrocytic infection by EBV, but that's just my opinion. The relapsing-remitting quality could be explained in terms of the devastating effects that pro-inflammatory cytokines can have on energy metabolism, and that could explain the apparent absence of overt inflammation in some research in multiple sclerosis (I can't say anything more specific without looking at the specific articles that people have cited, and I don't want to do that now).
I just don't understand why there would be such resistance to the consideration of all the mechanisms at work. I've seen articles make statements that there's no problem with energy metabolism in the brains of people who have multiple sclerosis. That makes no sense, in my opinion, because axonal degeneration implies profound problems with energy metabolism. And if one buys into the idea that a lot of pro-inflammatory cytokines are being released from activated T-cells infiltrating the CNS, then one would expect major problems with energy metabolism from that. Here's a not-very-good search that shows some of the vast amounts of research showing rapidly-induced mitochondrial dysfunction induced by TNF-alpha and other pro-inflammatory cytokines (http://scholar.google.com/scholar?hl=en&q=TNF+mitochondrial+dysfunction+astrocytes). There's one article, there, in which the authors probably discuss the concept that, in my opinion, optic neuropathies are frequently associated with mitochondrial dysfunction and can be caused by that. The energetic demands of neurotransmission in the optic nerve fibers are enormous. I'm not saying that reducing pro-inflammatory cytokine production by T-cells or other cell types doesn't have the potential to improve energy metabolism. I just think that it would help to acknowledge the deficits in energy metabolism that are very likely to exist in a neurodegenerative disease, such as multiple sclerosis, and to try to develop therapeutic strategies for addressing those deficits in more direct ways. These are just my crude, unrefined thoughts on some of these topics, and I'd strongly urge anyone to discuss things with one's doctor before doing anything.
I'm deliberately discussing some of these things from an idealistic, somewhat impractical point of view, because dogged pragmatism and dogma haven't seemed to be all that beneficial. Even something like parenteral guanosine could be viewed as an energy-metabolism-based strategy, because de novo purine biosynthesis is metabolically costly (and the brain has very little capacity for de novo purine biosynthesis). Also, anticonvulsant medications and adenosine receptor activation or modulation are known to be able to increase or preserve the phosphocreatine to creatine ratio and the adenylate charge. Additionally, purine nucleotide availability is likely, in my opinion, to be a limiting or nearly-limiting factor in mtDNA replication and in other aspects of mitochondrial functioning. I'm not saying guanosine would be a cure-all, but I'm just saying that there are many ways to address energy metabolism.
Elevating uric acid (UA) levels intracellularly, in neurons and astrocytes, such as through the administration of exogenous, parenteral purine nucleotides, would, in my opinion, have the potential to be therapeutic as a result of, among other mechanisms, the UA-mediated improvements in mitochondrial functioning (as a result of peroxynitrite scavenging). That article I cited awhile back, on UA in relation to the sympathetic nervous system and goal-oriented behavior, found intramitochondrial UA levels of 60 uM or something. That's very significant, in my opinion. The peroxynitrite scavenging effects of UA may not look all that special or unique in some articles, but one has to consider the fact that the suppression of nitric oxide (NO) output from activated macrophages, by UA, can occur in the face of these massive increases in the output of iNOS-derived NO. I forget what the variable was--NO output or NADPH oxidase activity--that increases the most dramatically. I think the mRNA or protein content of iNOS can increase 20-50 fold or something, in activated macrophages, and I think the NO output can increase by something like 1000-fold or even more. Some articles show these little graphs of the effects of UA (suppression of NO output by cultured monocyte-macrophage-lineage cells, etc.), and the graphs don't capture what's going on. The UA can suppress NO output drastically at physiological concentrations (of UA), and that's no small feat. NO and peroxynitrite produce strongly detrimental effects on mitochondrial function [a lot of these articles show, rather incidentally or in a manner that doesn't showcase the effects of UA, that UA can ameliorate peroxynitrite-induced mitochondrial dysfunction in various cell types: (http://scholar.google.com/scholar?hl=en&q=mitochondrial+peroxynitrite+urate+OR+uric)].
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