Summaries of Main Points from Blog Postings in 2009: Part II

More summaries of points from the blog in 2009 (between 12-2008 and 12-2009):

In my opinion, vitamin K supplementation is potentially very dangerous, and I'm actually doubting, at this point, if vitamin K is even essential. It doesn't behave at all like an essential nutrient, in my view, but that's just my opinion. There's research showing that geranylgeraniol, an intermediate in cholesterol biosynthesis, possesses vitamin K activity (see Ronden et al., 1997: (http://hardcorephysiologyfun.blogspot.com/2009/06/squalene-as-potential-cholesterol.html)], and I wonder if there isn't some endogenous ligand for the vitamin K-cycle enzymes. The whole business with squalene 2,3-epoxide being an intermediate in cholesterol biosynthesis and vitamin K epoxide being a vitamin K cycle intermediate seems like it might also suggest that endogenous compounds can be utilized for the gamma-carboxylation of glutamic acid residues on vitamin K dependent proteins. There's also research discussing the extremely low amounts of vitamin K that are required for humans to manufacture clotting factors, and, in fact, the amounts are so tiny as to make the notion of the essentiality of vitamin K more or less "not valid," in my opinion. I don't buy it anymore. The vitamin K nonsense in the literature has bothered me for a long time and defies all attempts to integrate it into anything resembling "nutritional" science. The facts that vitamin K decreases des-carboxyprothrombin levels and under-gamma-carboxylated osteocalcin aren't evidence of essentiality. In any case, vitamin K supplementation has the potential to not only exacerbate thrombotic conditions or lead to de novo thromboses by elevating levels of serum prothrombin and other clotting factors, in any number of disease states, but to also cause thrombogenic effects by exotic mechanisms, such as by inducing osteoclast precursor cell apoptosis, etc. Obviously, one would want to discuss these things with one's doctor, but there's all this research on vitamin K that looks good on paper but just becomes very bizarre on closer examination. Why would an essential nutrient cause osteoclast apoptosis or potentially cause such serious effects? In any case, I don't think it's essential, and this leads into another point. I should note that the vitamin K topics are not pleasant to write about.

In my opinion, coenzyme Q10 can exhibit vitamin K activity, and there's a lot of indirect evidence that it can. Riboflavin, or vitamin B2, can also enhance the activities of vitamin K dependent enzymes by providing the FAD cofactor for vitamin K reductase(s). There's evidence that quinone reductases or other cytosolic enzymes can utilize coenzyme Q10 and increase clotting factor biosynthesis. In my view, these facts seriously compromise the usefulness of CoQ10 or high-dose vitamin B2. I personally do not take coenzyme Q10 and only take a minimal dosage of vitamin B2, and the potential I see for problems with high doses of vitamin B3, vitamin B6, and vitamin B2 has caused me to not even be able to use a B-complex or multivitamin. In the case of multivitamins, all of the copper and zinc and manganese and vitamin A or beta-carotene are also reasons I don't use them. CoQ10 is also a benzoquinone, and benzoquinones are known to be highly reactive. One would want to discuss these things with one's doctor, but, in my view, there are plenty of energy substrates or other "agents" that could potentially substitute for CoQ10 as approaches to dealing with mitochondrial dysfunction in people who do not have mitochondrial disorders that require supplementation with CoQ10.

In my opinion, the large numbers of cases of intracranial hemorrhage in people taking some Ginkgo biloba extracts (GBEs) seriously compromises their usefulness, and there are, potentially, similar risks with high doses of supplemental omega-3 fatty acids. The numbers of case reports showing hemorrhages in people taking GBEs sort of speak for themselves, and there's no way of really evaluating the hemorrhagic risks of any degree of antagonism of platelet activating factor (PAF) receptors by GBE constituents, such as ginkgolide B and ginkgolides A and C and bilobalide. All of those are PAF receptor antagonists, and ginkgolide B is potent enough to be utilized as a pharmacological PAF receptor antagonist in in vitro research, etc. As far as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 fatty acids that are supplied in supplements, I don't know what the answer is. EPA and DHA are really reactive and have been shown to cause problems in animal models of fatty liver disease, but they're obviously essential and can have a lot of beneficial effects. One strategy might be to obtain small amounts of them in omega-3 egg yolk phospholipids, but I don't quite understand why hard-boiling eggs doesn't destroy all of the docosahexaenoyl- and eicosapentaenoyl-containing phospholipids. I also don't understand why egg yolk phospholipids, which supply choline in the form of sphingomyelin, more than phosphatidylcholine, do not cause depression, in my view, but supplemental phosphatidylcholine and other choline-containing compounds have been shown to cause severe depression in some humans. I think it might be that the sphingomyelin is utilized differently or that the elevations in plasma choline that result from egg-yolk phospholipid administration are not rapid enough to flood the brain with free choline and cause ATP depletion or inorganic phosphate sequestration, etc., thereby potentially causing depression. The omega-3 issues are really complex, and I don't really get into them much in my blog.

More of the Exploration of my "Thought" Processes

I was just going to add that, as far as blogging goes, I tend to use these blogs for different purposes at different times and to make not much effort to "map out" my purposes, if any, for writing any given thing. On one day, the blog can be an attempt to practice technical writing and to help myself learn a few new things or remember things I've read. On another day or posting or even part of the same posting, the blog(s) might be more like a kind of "talk therapy" that allows me to make wild, sweeping generalizations and to "rage against the machine" of society. If I do a posting and sound like a Jeckyl-and-Hyde, raving, rage-filled maniac, the reality is that I'm quietly typing as the "Zen master" and lamenting the way the world is set up, for the most part. I'm not someone who would ever hold onto seemingly hate-filled sentiments or anything, but I've noticed that blogging in a relative state of isolation can make me not as aware of these sorts of unconscious sentiments that can seem to be just filled with a vituperative ugliness. In reality, they're not intended to be that, and I'm not thinking that, at the time. But it's like they can sometimes end up being that way and seeming that way, to the extent that I or any other person might read the posting, later on, and feel that the posting doesn't show me at my finest hour. I think the entry of some vague, unconscious associations of some kind into blog postings may just be a result of the amount of writing that can go into a blog. I've sometimes read postings of mine and been shocked by the things that the posting might seem to be saying. In many cases, I wasn't really conscious of those potential implications. It's like writing for a blog causes one to have a sometimes-excessive amount of freedom of expression. But there can also be something about my writing style that can make it seem as if there's some organized, systematic "mayhem" or maniacal quality to the person writing the posting ("me"). The whole thing about blogging being like talk therapy can almost create an alternate persona at times, and I haven't seen much of any need to restrict the extent to which I can silently slip into this sort of altered state. Writing long postings on a blog and exploring lots of different topics can cause one to enter almost a trance or dream state, to a certain extent. I'm just saying that it opens up one's mind.

There are also some other aspects, such as the fact that many postings include this juxtaposition of precise, dispassionate language and discussions with random attempts at humor or wild generalizations that I haven't had much of a need to censor in my blogging. That can make it seem as if the wild statements are a reflection of an organized, inexplicable form of "madness" or something along those lines. In reality, I think I can just organize my sentences in ways that sound intense, when it comes to discussions of anything. I just haven't really had the energy to be extremely conscious of my tone, in some postings, because no one reads the blog and because the blog has always been more about organizing my thoughts on scientific topics and discussing any and every controversial topic that may come up. Another thing is that it has been really difficult to tell who my audience is or should be or needs to be or could conceivably be, etc. As a result, I tend to shut out attempts to shape my postings to specific audiences. I tend to jump around and may, when I try to think of some possible need to include a warning for such and such a reader who might, a year down the road, read the thing, include some statements that might be more of pure scientific interest and others that might be more about logistical or other details. The other thing I was going to mention is that I can sometimes end up communicating, in relation to some topics, like a person would in a debate. It's like I'll start with some vague or simple, generic sentiment and then allow the "debater-type" discussion to evolve or devolve into an argument that may be extreme and be a caricature of my true feelings about the matter. A lot of the complex discussions have always had a "hammed-up" quality on this blog, and that can be bad or good. The result can end up being a mixture of different things, etc. I've griped in generic ways about all sorts of topics on here. Nonetheless, when I see the ways I can end up allowing the less rational and superficially-angry facets of my thinking to mix with rational discussions, I don't, in a lot of these cases, like the things that I see, either in myself or in my postings. When I look closely and explore the issues and the extreme sides of some of the things I see in the world or in medicine, I sort of remember the ways things can just go on and on in the world (or, for example, in my life, in the past) and defy all reason and become devoid of hope, etc. I remember the way it feels and don't like remembering, and the result can be some sort of apparent tirade or seemingly-calculated expression of outrage that may just be mostly a journey into or exploration of some concept or concern. That's not to say that I don't have some thoughts and opinions that can seem extreme, but I haven't really made an attempt to carefully distinguish between statements that reflect my true feelings or perceived motivations (or, upon subsequent analysis, unconscious motivations) for saying things and statements that can constitute a "mixed bag," as discussed above. I generally have assumed that any one or any collection of statements that I've made have not been of much significance to anyone, and, even as that is likely to still be the case, that approach is not necessarily the best one and can lead to things that are troubling for me to see, to say the least.

Potential Approaches to Addressing Complications or Sequelae of Influenza Infections

The stuff related to this (http://hardcorephysiologyfun.blogspot.com/2009/12/multiple-revisions-of-old-paper-of-mine.html) just got really complicated, but that's that. I got the intranasal H1N1 flu vaccine on Wednesday, and the people did do a good job conducting the clinic. It's like the mild symptoms from it are slightly worse than with the seasonal intranasal one but aren't much worse. I was going to mention some approaches to dealing with post-influenza issues or low-level, ongoing effects of influenza, I should say. I've discussed some of the pharmacological issues with antivirals' potential interactions with exogenous purines or sources of inorganic phosphate (via the organic anion transporters and multidrug resistance proteins, as in efflux transporters in hepatocytes and proximal tubule epithelial cells, etc.) (http://eahblog2.blogspot.com/2009/08/discussion-of-influenza.html). I think the use of even relatively low doses of oral purines could be useful in dealing with the kind of ongoing, low-level thrombogenicity that one would expect to see, following an influenza infection, from elevated anti-ganglioside autoantibody titers (or from elevated antiphospholipid autoantibody titers in general) and anti-hemagglutinin antibodies that one would expect to exert thrombogenic/hemostatic effects. There tends to be a perception that something like Guillain-Barre syndrome from influenza is an all-or-nothing event, and it is. But one would expect to see elevated anti-ganglioside autoantibody titers and immunity following influenza infections, and influenza vaccination has produced prolonged but asymptomatic elevations in antiphospholipid autoantibody titers in normal people (for 3-6 months or so). Here's a search that shows some articles discussing the issue in various contexts (http://scholar.google.com/scholar?q=antiphospholipid+influenza+vaccine+OR+vaccination&hl=en&as_sdt=2001&as_sdtp=on). This search (http://scholar.google.com/scholar?hl=en&q=ganglioside+autoantibodies+lipopolysaccharide+OR+antiphospholipid&as_sdt=2000&as_ylo=&as_vis=0) shows that anti-ganglioside antibodies can exhibit cross-reactive binding to lipopolysaccharide(s), which are bacterial endotoxins, and that fits in with this article showing that the injection of viral neuraminidase proteins from influenza viruses causes a rapidly-induced thrombocytopenic response in rodents [see (http://eahblog2.blogspot.com/2009/08/influenza-is-it-big-man-on-campus-is.html); Choi et al., 1972: (http://www.ncbi.nlm.nih.gov/pubmed/5060079)(http://www3.interscience.wiley.com/cgi-bin/fulltext/120727425/PDFSTART)]. That could be explained by some sort of rapid release of IgE from mast cells or something, but mast cells can participate in all sorts of different immune responses and can actually serve as antigen-presenting cells, etc., and all-around "loose-cannons" of the immune system. But it could be that the viral neuraminidase elicits an existing, established, anti-lipopolysaccharide antibody response or multifaceted response that causes cross-reactive, antibody-mediated clearance of platelets. Choi et al. (1972) found evidence that the platelets' membranes were damaged over that short time course. They were being degraded and damaged, and the platelets were being destroyed, if I remember correctly. It sounded like an anti-platelet glycoprotein or antiphospholipid autoreactivity or contact hypersensitivity type of response. Elevations in antiphospholipid autoantibodies generally cause thrombogenic symptoms, with or without bleeding, etc. Here's another search (http://scholar.google.com/scholar?hl=en&q=influenza+ganglioside+autoantibodies&as_sdt=2000&as_ylo=&as_vis=0), but the point is that influenza neuraminidase enzymes cleave sialyl (or disialyl, I think) residues on cell-surface proteins of human cells and allow influenza to enter cells (http://scholar.google.com/scholar?hl=en&q=influenza+neuraminidase+sialic+OR+acetylneuraminic+OR+ganglioside&as_sdt=2000&as_ylo=&as_vis=0). The viral neuraminidase is a sialidase enzyme, and humans have sialidase enzymes, of course. One would expect antibodies to the (anti-influenza) antibodies to the active site or associated residues of a viral neuraminidase enzyme to potentially bind to gangliosides or other phospholipids (and to potentially lead to anti-ganglioside or more generalized antiphospholipid autoreactivity). The viral hemagglutinin proteins agglutinate red blood cells, meaning the red blood cells clump together and produce hemostatic effects or microthrombi that constantly are reforming and being degraded in a dynamic manner. Then that can lead to a big mess of chaotic immune responses, etc.

The general idea, in my opinion, is that hemostatic conditions will inevitably lead to some problems with energy metabolism and that the elevated levels of pro-inflammatory cytokines in many different tissues, following the influenza-induced increases in mast-cell density just about everywhere, for example, will also disturb mitochondrial functioning. TNF-alpha and other cytokines rapidly and reliably impair mitochondrial functioning and induce oxidative stress. Antiphospholipid and anti-ganglioside autoantibodies would be expected to produce thrombogenic effects and, basically, low-level neuropathic effects, in my opinion. One approach would be to consider the potential effects of exogenous uridine or triacetyluridine, for their supposed, generalized anti-inflammatory effects and for their potential effects on glucose uptake and energy metabolism (pyrimidines' effects, I mean, on those processes, as discussed in past postings), and to potentially consider the utility of L-glutamine supplementation as a way of addressing the supposed, low-level neuropathy and adverse effects on energy metabolism. Anti-ganglioside autoantibodies would clearly compromise energy metabolism, and, in people without overt Guillain-Barre syndrome, glutamine might help to address a supposed, low-level conduction blockade from elevated anti-ganglioside antibody titers, etc. Glutamine can produce anti-inflammatory effects, and so can uridine, in a lot of different models of inflammation, and glutamine [see Amara, 2008, cited here, for a review of three trials on the use of glutamine in the prevention of chemotherapy-drug-induced neuropathy, implying that it acts as an energy substrate or has some other generic effects (it's likely to basically be acting as an energy substrate/precursor of TCA cycle intermediates, in my view): (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)] and uridine (PN401 = RG2133 = triacetyluridine: cited as ref 32 in Ashour et al., 1996(?); the research exists somewhere, maybe here, as shown: (http://scholar.google.com/scholar?hl=en&q=neuropathy+acetyluridine+OR+RG2133+OR+PN401&as_sdt=2000&as_ylo=&as_vis=0)] have both been used in the treatment of peripheral neuropathy, implying some generic usefulness in addressing neuropathy of inflammatory origins (). There might well be research specifically on glutamine in influenza infections [(http://scholar.google.com/scholar?hl=en&q=%22L-glutamine%22+influenza+supplement+OR+exogenous&as_sdt=2000&as_ylo=&as_vis=0)], but this article [Neu et al., 2002: (http://www.victusinc.com/VictusTecnical_files/Glutamine%20in%20Radioterphy/Docs/09.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/11790953)] cites some of the research showing anti-inflammatory effects of glutamine (elevations in interleukin-10 expression or release, etc.). I'm pretty sure there's research showing that glutamine protects against the adverse effects of lipopolysaccharide on energy metabolism or the cellular redox state. Yeah, there is (http://scholar.google.com/scholar?as_q=&num=100&btnG=Search+Scholar&as_epq=glutamine&as_oq=lipopolysaccharide+endotoxin&as_eq=&as_occt=title&as_sauthors=&as_publication=&as_ylo=&as_yhi=&as_sdt=1.&as_sdtp=on&as_sdts=5&hl=en). This article shows that lipopolysaccharide induces DNA damage and deficits in energy metabolism in macrophages [Zingarelli et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8598485?dopt=Abstract)]. Anyway, there are lots of articles on the anti-inflammatory effects of uridine and on its capacity to protect against neuronal loss or other effects of inhibitors of mitochondrial respiration, such as sodium azide, [see here for a lot of the articles showing protection against the effects of respiratory-chain enzyme inhibitors by triacetyluridine-derived uridine and other pyrimidines: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)]. Some other time, soon, I'll put the links to some of the articles that show anti-inflammatory effects of uridine, but these are some [Uppugunduri et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15251120); Tian et al., 2009 (protection against damage due to cerebral ischemia, meaning it would potentially be useful for the ischemia one would expect from compromised energy metabolism and thrombogenicity per se and all the other mess of influenza): (http://linkinghub.elsevier.com/retrieve/pii/S030439400901180X); Evaldsson et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17570319)]. The article by Evaldsson et al. (2007) showed anti-inflammatory effects of uridine in a model or models of lung inflammation. I haven't looked at the article in awhile and forget the details. Then there's the massive elevations in peroxynitrite formation from activated macrophages, during influenza, and purines (all purines, by more or less similar reactions, interestingly) are peroxynitrite scavengers. But then there's the issue of uric acid competing for efflux with active metabolites of neuraminidase inhibitors or even with M1 protein inhibitors that are excreted unchanged, as in adamantane derivatives. Magnesium would probably be useful, assuming a person can tolerate it, and I'm not finding any easy searches that would explain my reasoning. Magnesium is just depleted strongly by any physiological stress, even exercise, and it produces antithrombotic effects that are less likely to be accompanied by bleeding (just as purines' antithrombotic or anti-cell-adhesion effects are not too likely to be hemorrhagic, in my view), in my opinion, than other antithrombotic strategies. It's hard to convince people of the effects of magnesium. It's like the research is scattered and is so vast that it's hard to convey. Magnesium is really important, in my opinion, as discussed in...past postings. It has crucial effects on energy metabolism (partly as a result of its mild calcium-channel antagonistic effect, as is the case with its antithrombotic effects) and can reduce lipid peroxidation by blunting calcium influx, etc. Here's a hastily-done search that shows some articles on the anti-inflammatory effects associated with magnesium repletion (http://scholar.google.com/scholar?hl=en&q=allintitle%3A+magnesium+inflammatory+OR+inflammation&as_sdt=2000&as_ylo=&as_vis=0). There's a bonus article showing glutamine (or ammonia) can limit the replication of influenza virus replication [Eaton and Scala, 1961: (http://www.ncbi.nlm.nih.gov/pubmed/13725527)]. That's actually a sort of "Saturday-roadkill" type of article, and the effect of ammonia could just be a generalized toxic effect. But it could be that ammonia can serve as a pyrimidine precursor. Who knows.

Brief Summaries of Main "Theses" from Past Groups of Postings: Part I

In the next few days or weeks, I'm going to try to summarize some of the main points from the postings I've made over the last year. In some cases, each summary encompasses hundreds of pages of writing and numbers of articles, articles and pages that I've explored in horrendous, "rock-and-roll-ice-storm" ways over the last year. Here are summaries of some of the groups of postings.

In my opinion, zinc and copper supplementation can be very problematic and inadvisable in many cases, in the absence of medical supervision. There are hundreds of reports of neurotoxicity visible on MRI and degeneration of the brain and spinal cord in humans who have taken excessive supplemental zinc, and the mechanisms that regulate the amount of neurotoxic free zinc and, also, copper are not very reliable, from a physiological standpoint. Copper transport in the blood and even in cells is messy and poorly-regulated, and many foods, including many breakfast cereals, have more than enough copper and also have enough zinc (as well as manganese, for example).

In my opinion, vitamin A or beta-carotene supplementation has the potential to cause serious neurotoxicity, and there are many reports of neurotoxicity or "pure" psychiatric disorders caused by vitamin A or beta-carotene supplementation. One important mechanism is, in my opinion, the toxic effects that retinoids, including vitamin A and beta-carotene as a precursor of vitamin A and retinoic acid, etc., exert on epithelial cells of the choroid plexuses that form cerebrospinal fluid and are crucial in the regulation of other brain functions, such as glutamate efflux, etc. Retinoids, including vitamin A and its precursors, can elevate the intracranial pressure by causing toxic effects on the choroid plexuses at extremely small dosages in some people, and those elevations in the intracranial pressure and associated venous ischemia or venous sinus thrombosis could be important causes of the psychiatric manifestations that vitamin A or beta-carotene supplementation have been associated with. In some cases, people who have done nothing but eat one of the relatively few foods high in preformed vitamin A (i.e., carrots or liver or fish, conceivably, as in fish liver, etc.) have developed severe psychiatric disorders that remitted upon discontinuation of the carrot-eating-induced psychosis or suicidality. The nutrition tables do not differentiate between beta-carotene and preformed vitamin A and only provide information about "retinol equivalents," but even eating a lot of beta-carotene in foods could conceivably produce adverse effects, given that an increase in beta-carotene intake can increase vitamin A (and that elevations in intracranial pressure have been shown to occur across miniscule increments in serum retinol, etc.).

In my opinion, all of the therapeutic effects of oral S-adenosylmethionine, in every disease state it has been used in, could be replicated by oral adenosine monophosphate or adenosine triphosphate. Both of those are sold, and each would be expected to exhibit much higher bioavailability (meaning entry into the brain or other extrahepatic tissues) than many oral SAM-e preparations would, in my view. These disease states include liver disease and osteoarthritis, etc. SAM-e has been researched heavily in many different contexts. The adenosine (and other purine metabolites from it) derived from the SAM-e is likely to be, in my opinion, the only significant mediator of the therapeutic effects of SAM-e. The extreme rapidity with which adenosine is utilized, by any of several pathways, precludes, in my view, a mass-action, inhibitory effect of the extra adenosine or other purines derived from it, on S-adenosylhomocysteine hydrolase activity. Nonetheless, the adenosine derived from SAM-e can increase the intracellular ATP and cAMP levels, and increases in ATP availability can be a determinant of the rate of formation of SAM-e. Increases in the cAMP/AMP ratio or in cAMP levels of cAMP in relation to other purines can influence the activity of S-adenosylhomocysteine hydrolase. One could use a methionine adenosyltransferase inhibitor in an experiment, but the use of that would not allow one to rule out, at all, the contribution of adenosine, derived from SAM-e, to the endogenously-produced SAM-e (via the utilization of adenosine for ATP formation, etc.). Adenosine has been used to treat liver disease in animal models and is thought to enhance hepatic blood flow and to maintain hepatocellular ATP levels and to ameliorate portal venous thrombosis (effects that could account for its therapeutic effects, especially along with pyrimidine nucleotides, in animal models of liver disease), and adenosine is thought to mediate the therapeutic effects of low-dose methotrexate, for example, in rheumatoid arthritis. Thus, there is reason to think that increases in purine availability, in response to exogenous adenosine nucleotides, could influence those conditions by the same mechanisms that SAM-e may influence the conditions. Adenosine could also influence DNA methylation by elevating SAM-e levels (via adenosine-induced increases in ATP levels), and exogenous SAM-e could influence DNA methylation not by increasing the ratio of SAM-e to S-adenosylhomocysteine but by increasing ATP levels (via the conversion of SAM-e to adenosine to AMP, ADP, and then ATP, which is a substrate of methionine adenosyltransferase) or by adenosine receptor signalling, etc.

In my opinion, L-methylfolate has a lot of potential usefulness as an adjunctive antidepressant and as a way of normalizing cognitive functioning or assisting in the treatment of circadian rhythm abnormalities, and its supposed effects in any of those disease states would probably be a result of its enhancement of noradrenergic and dopaminergic activity (via nitrergic mechanisms, secondary to its supposed effects as an analog of tetrahydrobiopterin (BH4), and by the "methylfolate-as-BH4-analog-dependent" increase in tyrosine hydroxylase activity). In my view, as discussed over maybe 150 postings or something, L-methylfolate and other reduced folates are likely to be not toxic or damaging, in theory, at the 30-50 mg/day range, or thereabouts, but I'd advise anyone to obviously use reduced folates under a doctor's supervision. The augmentation or counteracting of the effects of psychiatric medications could be dangerous in some people & could exacerbate the courses of psychiatric disorders. At high dosages, methylfolate and other reduced folates have generally been much safer than folic acid and less neurotoxic. In my view, L-methylfolate, which is available over-the-counter or by Rx, has less potential to produce adverse or unpredictable nitrergic side effects than, for example, L-arginine and is likely to produce more reliable or predictable or consistent effects than something like L-arginine, from the standpoint of effects on the brain.

In my view, creatine supplementation can be problematic at dosages higher than about 1.2 to 1.5 grams/day, over the long term, and low but not high dosages have been used as adjunctive approaches to treating depression in at least two trials (with other trials showing less clearly-defined effects on mood). Obviously, these are all just my opinions.

More Ramblings from Hardcore

The other thing I meant to add is that I've generally thought that it's probably for the best that not many people read the blog, to a large extent, and I make sort of a big effort to assume that people aren't reading it and to make my assessments as independently as possible. Even though I value tremendously my ability to speak independently, as far as the science goes, I'm always re-evaluating my thoughts on things and trying to think more carefully about the aspects of things that go beyond science. I can say I'm speaking objectively and independently about something and feel that I am, at any given time, but still end up being human and having my own silly sense of pride about things. The thought of being some kind of guru in any of these areas or having people trust my statements, without going to the science and looking it over themselves, is repugnant to me. It's like my thought is, "don't trust me a lot, or I might disappoint you the way I disappointed myself for the first ten or twelve years I read about physiological approaches, etc. And it's probably best that no one read the blog, given that the statements about the research will probably disappoint people, also." I feel like there's a strong, strong distinction between the science and the people who do the science. That's probably not realistic, but I'd be paralyzed and wouldn't be able to write on most topics if I didn't look at the science as being a separate thing, as much as possible. I have a tendency to take that too far, but I've just seen, in this disturbing way, how devastating the consequences of the dearth of critical expression and thought has been in just these few areas that I've written about on the blog. In a lot of cases, research can go on for thirty and forty years along these terrible avenues and can sort of just wither away, year after year. It's not exactly devastating in every area, but it can be kind of appalling to see. It may be the fact that I've been very near to death, for different reasons and in different "disease states," on a couple of occasions in my life that has shaped my view of things, too. It's like it changes you and makes you see the strings behind the puppet show or something. The human body just doesn't impress you, in a lot of ways, after seeing medicine fail you (me) in ways that were appalling to me, at the time, and it's like the models of diseases seem to cease to have any intrinsic validity. I'm not meaning to make any kind of big point in this posting or anything, but I thought I could sort of try to sum up my thought processes, in a not-too-effective way, on the anniversary, here. I just tend to think that it's possible to think and evaluate critically in a dynamic way, and I've re-evaluated my thoughts in a lot of different areas on the blog, as I've read more. For example, I used to think that vitamin B6 wouldn't cause peripheral neuropathy (or even autonomic neuropathy, given that it can cause that, too, at high dosages) at dosages below about 100 mg/day, but I now think it could, potentially, cause neuropathy in susceptible individuals at dosages as low as, say, 25-50 mg/day or less. Neuropathy can cause all sorts of different pathologies in just about any organ and can severely disturb bone remodeling, as in Charcot foot disease, or severely exacerbate liver disease, by shutting down the neurogenic regulation of gallbladder contractions, as in diabetic neuropathy, etc. It's not really possible to easily evaluate those potential manifestations of neuropathy in a person. Anyway, that's about all I can think of to talk about. I don't get very many page hits per day. I get an average of about 10 or so, I'd say, and I have no way of evaluating whatever numbers of people are using any of the hundreds of RSS readers to check or look over the blog. I doubt it's very many, though.

One-Year Anniversary of the Blog's Inception

I started this blog a year ago, as of tomorrow, and I put the whole year into a pdf file that's a horrendous 1,021 pages (http://www.mediafire.com/download.php?itnnu4ye3km). It seems like the same type of freedom that allows me to link to articles and make quick assessments of things can become a sort of slavery to my unconscious and netherworld of associations. That mixes together with the rational aspects of the science & everything, and the results can be good and bad. It's been strange to do a blog, partly because I've gotten three comments and four or five emails, total, the whole year. Maybe it's the 500-word legal statement at the top of the page that creates the atmosphere (the "Earth, Wind, and Fire" feel). Anyway, it's back where it all began, "Out of the cradle endlessly rocking."

Summer & Fall; Perferryl Heme "States" and Ferryl Heme and General, Free-Flowing Discussion

I added a caption to the screen snapshot of that diagram of compound II, for this posting, as discussed below. My main point with those postings was that I didn't like the way the whole process with this work (http://hardcorephysiologyfun.blogspot.com/2009/12/multiple-revisions-of-old-paper-of-mine.html) went. I did the first two last summer and then made some more revisions again, within the last two weeks or so. But it got so that the focus on the content with that type of thing seemed to not matter, really. So it's like I couldn't communicate freely on this blog, and the amount of work or the degree of validity of the things I'd worked on seemed to be of little consequence. Anyway, the work on heme has been going well, and it tends to be the case that it takes time to be able to shorten and condense things that I've recently tried to get up to speed on. I can write about something but still sort of require time to digest the material and be able to separate the wheat from the chaff. When I learn new things in an area, I tend to write long things and then be able to shorten them. The content on heme is still too long and has been for the last month or so, but I'm sure I'll be able to finish shortening it, here, etc. My main reason for getting into the electron configuration content was to see how I could draw and keep track of structural diagrams of reactions involving heme. It's like the bookkeeping of electron transfers between inorganic and organic elements, in organometallic compounds, is sort of shrouded in mystery still, more from the standpoint of the theoretical framework of chemistry than the experimental data that's reported in chemistry journals, but it's been interesting to sort of scratch the surface of. All the diagrams might have a sort of rock-and-roll quality to them, but the chemistry is just really complex. I still don't have a good understanding of what the different factors are, besides the apparently-slow, proton-coupled electron transfer reactions that can drive radical migration within a protein, but it's like amino acid residues are being protonated and deprotonated dynamically, due to small pH gradients or something like that, and that helps to dictate, as a slow process of "equilibration," the progression of this continuous and rapid electron tunneling that nonetheless is able to slowly progress toward equilibrium and allow for the existence of long-lived tyrosyl radicals. The main, "big-picture" things I've gotten (things that may or may not be relevant or things to include) are that free perferryl heme can, according to at least four or five articles, exist and that the iron(IV) Fe=O moiety of heme with a protein radical is, itself, inclusive of the radical, perferryl heme. Iron(IV)-heme with a protein radical that's mobile is perferryl heme, and so is iron(IV)-heme with a pi-cation radical on the porphyrin ring. But iron(IV)-heme with a closed-shell, nonradical porphyrin ring and no protein radical is ferryl heme, and, even though the diagramming may tend to suggest that the Fe=O moieties are the same in ferryl and perferryl heme, ferryl heme's Fe=O moiety is less oxidized than the Fe=O moiety in either of those states of perferryl heme. And when the amino acid residue harboring the mobile radical is reduced by a reductant, the oxidation state of the Fe=O oxygen changes, and the whole path and potential path of the mobile radical, within the protein (the whole protein, in effect), acts like an extension of the porphyrin ring. There's a change in the electron configuration or distribution that's translated through one or more of the axial ligands of the protein-bound heme. That's one thing that took awhile to recognize (see de Montellano, 1987, cited in past postings, and other articles). It gets so it wasn't really possible for me to discuss the topic in a way that made sense to me and that would make sense to others, in the absence of that information. In some cases, there are descriptions of "ferryl heme" with a protein radical present, but that overall heme-bound protein is, itself, perferryl heme, given that the radical is delocalized across its entire path, in effect. That's my understanding of the way it works, and the oxene-type electron configuration of perferryl heme isn't the same as the one in ferryl heme. Anyway, I've done most of the content on here, related to heme, to allow me to be able to talk about things in a way that makes sense to me, etc.