"Occult" Calcium and Copper in "Gums" and Other Soluble and Insoluble Fibers: Relevance to the Adjunctive Management of Depression

These articles [Fang et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17910512); Debon and Tester, 2001: (http://cat.inist.fr/?aModele=afficheN&cpsidt=987245); Leroux et al., 2003: (http://cat.inist.fr/?aModele=afficheN&cpsidt=14819835); Nasir et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18267216)] show that gum arabic and other gums (comprising high-molecular-weight polysaccharides and glycoproteins, etc.) contain significant amounts of "occult" calcium (Ca2+) and magnesium, primarily, and also small amounts of copper and zinc. The amounts of zinc and copper listed in the table on page 4 of Debon and Tester (2001) are actually (ug zinc or iron)/(g of "gum") (micrograms Zn or Cu/g gum), not mg/g. The authors mention that in the text on that page, and those values are consistent with the values reported in other articles. Debon and Tester (2001) found that the gum arabic (also known as gum acacia or acacia fiber, etc.) samples contained a mean of 7.82 mg Ca2+/g gum, and the values for pectin, guar gum, and carrageenan are, respectively, 1.53 mg Ca2+/g, 0.79 mg Ca2+/g gum, and 30.3 mg Ca2+/g gum. Fang et al. (2007) found that a 20 % (w/w) aqueous solution (20 g gum arabic/100 g solution) of gum arabic contained 1417 ppm Ca2+. One ppm = 1 ug/g. So that works out to about 7.1 mg Ca2+/g gum arabic. Leroux et al. (2003) found that sugar beet pectin contained 5700 ppm Ca2+, and that's 5.7 mg Ca2+/g sugar beet pectin. That gives one an idea of the amounts of unlabeled calcium that some of these things might contain. If one applies the 7.82 mg/g number, for example, one sees that 30 g of gum arabic might contain up to about 235 mg Ca2+. There's also magnesium, but there's research that implies that some of these gums may sequester magnesium and increase the gums' intestinal (and urinary) excretion [Eby and Eby, 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19944540); Nasir et al., 2008]. Acacia gums of the family Gummiferae (similar to gum acacia, which is from the family Leguminosae) contained mean copper contents of 4.36 and 13.0 ug copper/g of Acacia gum (4.36 and 13.0 ppm) and 6 and 9.5 mg calcium/g gum [Mhinzi, Mghweno, and Buchweishaija, 2008: (http://linkinghub.elsevier.com/retrieve/pii/S0308814607009983)] . That works out to about 131-390 ug copper per 30 g of gum acacia or gum arabic, assuming that the "inter-family" similarities in calcium contents imply that the two families contain similar copper concentrations. Harmuth-Hoene and Schelenz (1980) [Harmuth-Hoene and Schelenz, 1980: (http://www.ncbi.nlm.nih.gov/pubmed/6251185)] found that the endogenous copper concentration in guar gum was 0.40 ppm (0.40 ug/g), and it looks like guar gum might contain less copper than some of these other fibers. In general, however, it looks like some of these soluble fibers might contain smaller amounts of copper (and, perhaps, also calcium) per gram of fiber (insoluble or soluble) than even some of the "best" commercial "whole-grain" "goodness-filled" cereals contain. There's nothing terrible about cereal, but some of these cereals that are "healthy" in relation to their glycemic indices have unsettlingly-large amounts of copper in them, in my opinion. The USDA nutrient tables are useful for estimating one's copper intake (http://www.nal.usda.gov/fnic/foodcomp/Data/SR17/wtrank/sr17a312.pdf), but there's a typo in that document on the copper contents of foods. The numbers given are in milligrams, not micrograms. For example, a number like 0.345 means 345 micrograms (mcg) of copper per mass given, and that's equivalent to 0.345 milligrams copper. (To find the USDA documents for other nutrients/minerals, search on google with the terms USDA copper content" or whatever other nutrient, and the title will be something God-awful, along the lines of "release 18 December 23rd 1993" or the like.) It's appalling that one has to keep trying to check to see what the RDA is now, and I don't even know if they mean for males or females. I personally make every attempt to avoid dealing with numbers that are based on the RDAs, given that, for example, the RDA for copper for adult males is different from the RDA for adult females. The way to use a USDA table is to convert all of the numbers into ug nutrient/g food (mcg/g) or mg nutrient/g food. Take a copper content of 345 mcg or whatever, and divide by the mass of the serving of food in question. When one does that, the numbers are relatively consistent across similar foods. If I'm looking at a nutrition label on a food and can't tell what RDA "thing" the label is referring to, I'll just type the name of the food into google scholar and add the words "copper content" or whatever. The articles usually provide the concentrations in ppm (ug/g) or mg/g or % (w/w) (which is g nutrient/g food, or g/g, unless otherwise specified).

These types of issues could be relevant to the treatment of depression or other psychiatric disorders, given the potential that exists, in my opinion, for small changes in dietary calcium and copper to produce low-level hemostatic effects and, by that and other mechanisms, in my view, to exacerbate depression or brain functioning in a more general sense, at least in some people. It's worthwhile to note that the soluble fibers can sequester small amounts of metals, and that effect could, in theory, offset the supposed increases in copper or calcium absorption that one might expect to see in response to the ingestion of one or more of the fibers. I was going to discuss some of the research on depression and psychiatric symptoms in relation to copper and calcium metabolism, but this posting is getting too long. One of the points I was going to make is that one could replace a healthy cereal with some source of soluble fiber and conceivably get less copper, less calcium, and substantially more soluble fiber than one would get from the cereal itself, with milk. Another downside of milk is that manufacturers are still adding preformed vitamin A to it, and preformed vitamin A can produce toxic effects on the liver and parts of the brain, among other tissues, in relatively small amounts. Another approach would be to dilute the milk with water. I'm not suggesting that these are likely to be practical approaches for most people, but I just throw the ideas out. As discussed in past postings, there's research that suggests that excesses of dietary calcium can produce increases in platelet activation, either by increasing the rates of calcium influx into platelets or simply serving its functions in the coagulation cascade. In my opinion, excesses of dietary copper have the potential to exacerbate depression, in part by producing hemostatic effects. Copper is incorporated into coagulation factor V and factor VIII during the post-translational processing of those proteins (http://scholar.google.com/scholar?hl=en&q=copper+%22factor+VIII%22+OR+%22factor+V%22&btnG=Search&as_sdt=2000&as_ylo=&as_vis=0), and there's abundant evidence that excesses of intracellular copper have been associated with exacerbaions of symptoms of depresssion and other psychiatric conditions, etc. Essentially, it's well-known, and I'm not going to collect a lot of references at this point. But it's interesting that there's all this research focusing on the increases in platelet activation that can occur in association with depression (http://scholar.google.com/scholar?hl=en&q=depression+platelet&btnG=Search&as_sdt=2000&as_ylo=&as_vis=0), and the assumption seems to generally be that this platelet activation is going to mainly have relevance as an explanation for the association of heart disease with depression [for example, see Nemeroff and Musselman, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/11011349)]. But there's a lot of research showing, for example, that elevations in serum antiphospholipid autoantibody titers can occur in people who have been diagnosed with depression or some other disorder (http://scholar.google.com/scholar?hl=en&q=depression+antiphospholipid&btnG=Search&as_sdt=2000&as_ylo=&as_vis=0); (http://scholar.google.com/scholar?hl=en&q=antiphospholipid+psychiatry&btnG=Search&as_sdt=2000&as_ylo=&as_vis=0)]. Elevations in serum antiphospholipid autoantibody titers are very well known to produce hemostasis and increases in platelet activation or platelet-dependent thrombosis (http://scholar.google.com/scholar?hl=en&q=antiphospholipid+hemostatic+OR+hemostasis+OR+platelet+OR+thrombogenic+OR+thrombosis&btnG=Search&as_sdt=2000&as_ylo=&as_vis=0). Thus, the increases in platelet activation could be a cause of the depression. I want to emphasize, however, that using any old platelet-anti-aggregatory approach is likely to be problematic, at best, and could be disastrous, given the association of a lot of these plant (herb)-derived or other antiplatelet compounds with hemorrhages and whatnot. There's a lot of other indirect evidence that I'm not going to get into now.

Rambler on L-Methylfolate and Tetrahydrobiopterin, in Relation to the Brain and to Influenza-Induced Hemostasis

I was just going to mention that the use of L-methylfolate could be another approach to the management of post-influenza hemostatic effects, given that L-methylfolate and other reduced folates appear to be active as cofactors for tetrahydrobiopterin (BH4)-dependent enzymes. It's something that researchers could investigate and that one would want to discuss with one's doctor. I think it might primarily be useful, conceivably, after the acute illness has abated, in part because BH4 is a cofactor for inducible nitric oxide synthase (iNOS) enzymes and not just eNOS. I think the higher dosage range of L-methylfolate might be useful under certain circumstances, such as in the "aftermath" of a viral illness and the oxidative stress that is associated with viral illnesses. Oxidative stress would tend to increase the rate of degradation of BH4 and to potentially increase the neopterin/biopterin ratio, thereby potentially leading to further, functional inhibition of either the formation of BH4 or of BH4-dependent enzymes (eNOS, tyrosine hydroxylase, and tryptophan hydroxylase). For example, Mittermayer et al. (2005) [Mittermayer et al., 2005: (http://ajpheart.physiology.org/cgi/reprint/289/4/H1752.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15964928?dopt=Abstract)] found that the intra-arterial administration of BH4 counteracted the detrimental effects of intravenous endotoxin on eNOS activity, basically (or it might have acted as an antioxidant, without enhancing eNOS activity). There's a large amount of research on BH4 in humans, now, and most of it shows that BH4 does increase eNOS-dependent blood flow responses (http://scholar.google.com/scholar?q=tetrahydrobiopterin+oral+OR+orally+OR+peroral+OR+supplement&hl=en&as_sdt=2001&as_sdtp=on). It's being tested in trials in the treatment of peripheral arterial disease, and maybe it'll be covered by insurance then. It's been approved to treat phenylketonuria, but I checked the out-of-pocket cost of it. It's prohibitively expensive. There's research showing it can pretty dramatically decrease blood pressure in people who are hypertensive. If only they'd started testing it 30 years ago, in 1981 or so, when some of the first research showing its biological effects was published. In the context of Alzheimer's disease, some researchers discussed the potential for an increase in BH4 availability to limit the uncoupling of eNOS activity (and nNOS and iNOS activities) to NO formation (or to uncouple the formation of citrulline, from arginine, from the formation of NO) and thereby decrease peroxynitrite formation [Foxton et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17191137)].

From the standpoint of the effects of methylfolate or BH4 on the brain, I think that L-methylfolate could initially increase, for example, iNOS activity in astrocytes or microglia or even increase nNOS activity excessively and produce effects on mood or cognitive functioning that would initially but not "ultimately" be counterproductive. For example, the administration of L-arginine via microdialysis into the caudal ventrolateral medulla (CVLM) augmented the pressor response to muscle contractions, but the arginine produced the opposite effect when administered into the rostral ventrolateral medulla (RVLM) [Freda et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10320724)]. Those effects could be explained in terms of differences in the anatomical "localization" of nitrergic inputs to glutamatergic neurons that provide excitatory inputs to the preganglionic sympathetic neurons in the RVLM, but most of these articles don't provide many details on the anatomy [Zanzinger et al., 1998: (http://ajpregu.physiology.org/cgi/reprint/275/1/R33.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9688957?dopt=Abstract)]. Another article found a pressor effect of arginine in the CVLM [Rampin and Giuliano, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10899272)] (I just glanced over part of that and thought that was on cardiovascular reflexes only). But the general idea is that nNOS-derived NO tends to be excitatory and to bind directly to NMDA receptors or to otherwise increase glutamatergic transmission, such as by amplifying the excitatory effects of NMDA receptor activation. But that's not really the way BH4 behaves in models of hypoxia or ischemia. There's some research showing that it worsens the damage, but a lot of it shows neutral or beneficial effects. Those parts of the medulla are mainly involved in cardiovascular reflexes, but the same type of concept applies to the nitrergic regulation of the firing rates of noradrenergic neurons in the locus ceruleus or of dopaminergic neurons, etc. BH4 or methylfolate could enhance nNOS activity and, by that mechanism and its function as a cofactor of tyrosine hydroxylase, exert an excitatory influence on dopaminergic and noradrenergic transmission (and serotonergic transmission), but there could be an initial enhancement of nNOS (and eNOS and iNOS) activity/activities and then a subsequent "normalization" of the nitrergic transmission. The increases in NO release, induced by BH4 or methylfolate, could, relatively rapidly, lead to a kind of new, equilibrium state and restore the normal extent to which nNOS-derived (and iNOS-derived) NO produces autoinhibition of nNOS and iNOS activities. For example, these authors [Galijasevic et al., 2003: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=299800)(http://www.ncbi.nlm.nih.gov/pubmed/14657339)] found that the presence of myeloperoxidase, a heme-containing enzyme present in neutrophils and other cell types, could function as a nitric oxide scavenger but paradoxically disinhibit iNOS activity by relieving the constitutive, autoinhibitory influence that iNOS-derived NO exerts on iNOS activity and that is thought to be largely responsible for the maintenance of iNOS activity at between 20 and 30 percent of its maximal rate (Galijasevic et al., 2003). The autoinhibition phenomena is a real phenomenon and isn't just a theoretical mechanism. I actually observed that type of phenomenon (in my opinion) when I took significant dosages of methylcobalamin during infectious mono, and it was mainly apparent when I increased the dosage (these were reasonable but sort of large dosages, as in 10 mg/d, even though there are 15 mg dosage forms of methylcobalamin now) and took it on an empty stomach. It always took 2 hours+ to be absorbed on an empty stomach (apparently because it's all bound to B12 binding proteins or forms some sorts of insoluble complexes?), and it behaved, initially, like a nitric oxide donor but then rapidly ceased to produce that type of effect (the migrating myoelectric complexes that drive gastric motility in the fasted state occur every 1.5 to 2 hours, incidentally, and "reset" upon the ingestion of small amounts of food, meaning it would take about 2 hours for the small amount of food to begin entering the small intestine, assuming it was part of a molecule too large to be transported into the small intestine in solution, by solvent drag or whatever, between the cells). It was possible to tell these things because of all the upregulation of iNOS activity, in response to the viral illness, etc. The point is that nitrergic effects, in response to something like methylfolate, seem to exhibit a kind of tachyphylaxis, and that's consistent with the transience of the inhibitory effects of high dosages of nitrate-derived NO on platelet function. There's an initial inhibition of platelet activation and platelet functions, but there's rapid adaptation/tolerance to the effect. But there still is a nitrergic effect of higher dosages of methylfolate, in the longer term, that's less pronounced than the effects that occur in the short term, in my opinion. In this article on the use of BH4 in the treatment of depression [Curtius et al., 1983: (http://www.ncbi.nlm.nih.gov/pubmed/6131342)], there was a delay of a couple of days until the maximal mood-elevating effect emerged, and the dosage regimes used in the articles on the use of BH4 itself, in treating depression, are bizarre. The authors (Curtius et al., 1983) used a dose that was probably excessively-high (1 g once and then a 100 mg/d maintenance dosage) and that could have compromised the efficacy of the BH4, in my view, given the potentially counterproductive effects that excesses of NO can have on glutamatergic and monoaminergic transmission, etc., in relation to mood or cognitive functioning. But the authors also were using tyrosine at a high dosage, and tyrosine has the potential to worsen depression, in my opinion, particularly at the high dosages that can allow for the autoinhibition of tyrosine hydroxylase activity by tyrosine itself to become significant. But the point is that the 100 mg/d dosage (used in other case reports, also) is similar to the highest dosage (90 mg/d) of methylfolate that's been used in small trials, in the treatment of depression. And the timecourse with which the changes in mood (or, by extension, in something like blood flow, etc.) emerged are consistent with some sort of adaptation to a change in nitrergic transmission. I generally haven't found that Rx L-methylfolate produces any more benefits at dosages above ~50 mg/day, but this hasn't always been the case. I just think that one has to work with one's doctor and try to individualize the dosage in a way that's appropriate for oneself, as an individual. In other words, there may be a significant need to individualize the dosage, and an awareness of some of the mechanisms by which BH4 acts, in the brain, may be useful in...the individualization of the dosage, etc.

Another Commentary on Childhood Bipolar Disorder

http://www.youtube.com/watch?v=a9nScu00E7I

Lactobacillus Bacteremia, Endotoxemia, & Effects of Indigestible Polysaccharides on Bacterial Proliferation & on Liver & Exocrine Pancreatic Function

These are some of the articles [Salminen et al., 2002: (http://toxicology.usu.edu/endnote/Lactobacillus-safety-humans-Fin.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12410474); Land et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15629999); Kunz et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15085028); De Groote et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15750472); (http://scholar.google.com/scholar?hl=en&q=bacteremia+probiotic+OR+prebiotic+OR+yogurt&as_sdt=2000&as_ylo=&as_vis=0)] whose authors have discussed evidence that the use of the preformed, live strains of Lactobacillus bacteria or other bacteria can cause bacterial endocarditis or sepsis, etc. So-called Lactobacillus bacteremia can occur in a person who isn't taking any "probiotic" supplement, but the point is that disease states in which intestinal permeability has been increased could increase a person's susceptibility to this kind of dramatic, potentially devastating event. It's important to realize that portal endotoxemia, in which there's an abnormally-elevated concentration of endotoxin(s) in the portal venous blood but not in the systemic circulation, in many cases, is not something that only occurs in severe disease states, in which a person is falling on the floor and so forth. There's evidence that portal endotoxemia occurs in some obese people and may contribute to nonalcoholic fatty liver disease in people who may or may not be obese [see Brun et al. (2007) and others: (http://scholar.google.com/scholar?hl=en&q=portal+endotoxemia+%22fatty+liver%22&as_sdt=2000)], and some researchers have estimated that 20-30 percent of people in the US have fatty liver disease [Cave et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17296492); (http://hardcorephysiologyfun.blogspot.com/2009/03/nonalcoholic-fatty-liver-disease-nafld.html)]. It's important to note that bacteremia or sepsis or bacterial endocarditis are not minor events but could permanently devastate a person's intellectual capacity, leaving the person mentally disabled, lead to kidney or liver failure leading to death or transplantation, etc.

The other side of the issue is that there are lots and lots of articles showing that Lactobacillus bacteria can reduce endotoxemia in the context of liver diseases or a variety of traumas (http://scholar.google.com/scholar?q=lactobacillus+endotoxin&hl=en&as_sdt=2001&as_sdtp=on). Even though the use of any old oligosaccharide doesn't sound good to me, Wang et al. (1998) [Wang et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9757556)] found that the administration of a "soluble fiber" polysaccharide reduced the liver damage in D-galactosamine-induced liver failure in rats. The polysaccharide doesn't have to leave the GI tract to exert these effects, and Wang et al. (1998) found evidence that the increases in numbers of Bifidobacteria can reduce the numbers of gram-negative bacteria that endotoxin can be derived from. Cherbut et al. (2003) [Cherbut et al., 2003: (http://cat.inist.fr/?aModele=afficheN&cpsidt=15118468)] found that people were able to tolerate gum acacia (from a commercial standpoint, this is the same thing as "acacia fiber," "gum arabic," or "acacia gum," etc.) easily, and gum acacia promoted the proliferation of Bifidobacteria, etc. There are many reasons that acacia gum and, for example, guar gum would be superior to something like inulin, in my view, in many contexts, but that's just my opinion. I've probably been too inclined toward caution with something like "apple pectin" or "grapefruit pectin" (I'm not sure how that differs from apple pectin), but the low-molecular weight fraction might just be glycoproteins or something. I can't imagine how apples would be innocuous and apple pectin would be "poisonous" or "horrendous." There's a ton of research on pectin, incidentally, and some other mechanisms basically have to do with the overlapping of these effects of soluble fibers with the effects of cholestyramine, a resin that sequesters bile acids. Pectin and some of these other polysaccharides can sequester bile acids but can also promote the reabsorption of the bile acids and act as generalized emulsifiers/surfactants/cosurfactants. Cholestyramine is not really a surfacant (http://scholar.google.com/scholar?hl=en&q=cholestyramine+surfactant&as_sdt=2000&as_ylo=&as_vis=0) and has been associated with various side effects, such as steatorrhea (http://scholar.google.com/scholar?hl=en&q=cholestyramine+steatorrhea&as_sdt=2000&as_ylo=&as_vis=0), in which there's malabsorption of dietary fats (potentially as a consequence of the sequestration of bile acids), and hyperchloremic, normal-anion-gap, metabolic acidosis (http://scholar.google.com/scholar?hl=en&q=cholestyramine+%22metabolic+acidosis%22&as_sdt=2000&as_ylo=&as_vis=0). Arginine hydrochloride can also cause that type of hyperchloremic metabolic acidosis (http://hardcorephysiologyfun.blogspot.com/2009/03/arginine-hydrochloride-and.html). Either pectin or cholestyramine can increase cholesterol 7alpha-hydroxylase activity in hepatocytes and increase the overall pool of bile acids [(http://scholar.google.com/scholar?hl=en&q=pectin+hydroxylase+cholesterol+bile&as_sdt=2000&as_ylo=&as_vis=0); (http://scholar.google.com/scholar?hl=en&q=pectin+hydroxylase+cholesterol+bile+cholestyramine&as_sdt=2000&as_ylo=&as_vis=0)]. Pectins can also decrease the activities of bacterial beta-glucuronidase enzymes and thereby lead to a decrease in the rate at which unconjugated bilirubin is formed in the large intestine [(http://scholar.google.com/scholar?hl=en&q=pectin+glucuronidase&as_sdt=2000&as_ylo=&as_vis=0); Kim et al., 1996: (http://kmbase.medric.or.kr/Main.aspx?d=KMBASE&m=VIEW&i=1007519960050020124)], and that effect could reduce the enterohepatic recycling of bilirubin, potentially (http://scholar.google.com/scholar?q=glucuronidase+bacteria+enterohepatic+recycling+bilirubin&hl=en&as_sdt=2001&as_sdtp=on). Only about half of the articles on pectin and glucuronidase activity have shown a decrease. Some of those have shown increases. But increases in the enterohepatic recycling of bilirubin are thought to contribute to the development of some types of gallstones in adults [Brink et al. (1999) and Vitek et al. (2003), shown here: (http://scholar.google.com/scholar?hl=en&q=enterohepatic+bilirubin&as_sdt=2000&as_ylo=&as_vis=0)]. It's important to note that the complex effects of these polysaccharides on bile acid reabsorption could account for those effects, but the research showing that pectin or guar gum, etc., can inhibit gallstone formation or the like, such as in animals or in association studies in humans, could be explained in terms of the polysaccharides' effects on bile acids or on the enterohepatic recycling of bilirubin [(http://scholar.google.com/scholar?hl=en&q=pectin+gallstone&as_sdt=2000&as_ylo=&as_vis=0); (http://scholar.google.com/scholar?hl=en&q=gallstone+pectin+OR+%22guar+gum%22&as_sdt=2000&as_ylo=&as_vis=0)]. There's also the whole pancreatic cancer risk-reduction-association stuff (http://scholar.google.com/scholar?hl=en&q=%22soluble+fiber%22+pancreatic+cancer&as_sdt=2000&as_ylo=&as_vis=0), and some of these soluble, indigestible, high-molecular weight polysaccharides can increase pancreatic exocrine function (http://scholar.google.com/scholar?hl=en&q=pancreatic+exocrine+acacia+OR+pectin+OR+%22guar+gum%22&as_sdt=2000&as_ylo=&as_vis=0). I discussed some of the risks of some of these things in a previous posting (http://hardcorephysiologyfun.blogspot.com/2009/12/potential-effects-of-soluble-fibers-as.html), and those things are worth keeping in mind, in my opinion. But hey, it's no skin off my nose. Have a nice trip, as they say. In any case, the research is a bit chaotic, but there's a large amount of it. The main point is that I think the use of specific indigestible polysaccharides would potentially pose a less extreme range of possible outcomes than the use of the actual bacteria would, particularly since the supplements, as opposed to the foods sold in groceries or whatever, contain larger amounts of bacteria and need to be shipped with ice. I dunno. That doesn't sound so good to me. I used to think the main problem would be the destruction of the bacteria by stomach acid, but apparently it's not even the most important issue, necessarily. Then I thought that the products might be contaminated. That's not even the issue. It's the "good" bacteria themselves that are thought to have entered the bloodstream in some of these cases. The quality control in the realm of the actual baterial supplements seems to be lacking, as discussed in this article [Hamilton-Miller et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/11852901)]. It seems really chaotic to me, in the context of the actual bacterial supplements (as opposed to the soluble fibers that are fuel sources for the existing bacteria). But even some of these lowly foods may pose risks to vulnerable individuals [Presterl et al., 2001: (http://scholar.google.com/scholar?hl=en&q=lactobacillus+bacteremia+yogurt&as_sdt=2000&as_ylo=&as_vis=0)]. A person should discuss this type of thing with one's doctor, however, and I obviously can't make any statements about the safety or lack of safety of any product or supplement.

Potential Effects of Soluble Fibers as Adjunctive Therapies for Kidney or Liver Diseases: Strategies to Help Avoid "Horrors"

The authors of these articles [Bliss, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15293038); Al-Mosawi, 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12042902)] and similar articles have discussed the therapeutic effects that some soluble fibers, such as gum acacia or guar gum, have produced in people with chronic kidney disease that hasn't been life-threatening or in people with liver disease. Those types of very-high-molecular-weight polysaccharides can't be hydrolyzed by human enzymes but can be by the enzymes of bacteria in the colon, primarily, that use the breakdown products as substrates for the energy production that drives the cell division of the bacteria, etc. The oral administration of guar gum or gum acacia, among other soluble fibers, have reduced serum urea, serum phosphate/phosphorus, and serum creatinine in people with kidney disease, and the explanation has been that the bacteria use nitrogen-containing compounds for their cellular functions and proliferation. The effects on some of these parameters are not small or minor, really, in many of the articles, and, in my view, the research has validity. The idea has been that the soluble fibers provide the "fuel source" and cause, as a consequence, the bacteria to incorporate more of the nitrogen-containing compounds in the intestinal luminal fluid into their cellular processes.

Before I write the rest of this, I should mention that I think inulin, as a "probiotic," has the potential to be very problematic, and one of the reasons is that inulin can cross the intestinal barrier in the jejunum of the rat, apparently by passive diffusion in between the epithelial cells [Ma et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/2035637)]. That "paracellular" ("alongside" the cells) mode of absorption is not uncommon, and inulin has a very low molecular weight (it's ~5000 or so (Ma et al., 1995)). The colon is also permeable to inulin [Ma et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7806033)], and Ma et al. (1995) discussed the fact that the colon had generally been thought to be impermeable to compounds more than 6 angstroms in diameter. The "cross-sectional diameter" of inulin is 15 angstroms, and so inulin "broke the rule," so to speak. Yeah, this is a really, really serious issue, in part because of the way inulin behaves in vivo. I discussed some of my concerns in past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/disturbing-articles-on-inulin.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-inulin.html)]. Another reason the inclusion of inulin in more and more products, all over the place, is worrisome is that gamma-inulin, apparently a conformational isomer of inulin, is an immune adjuvant that's been researched for use in potentiating anticancer treatments (http://scholar.google.com/scholar?hl=en&q=cancer+gamma+inulin&as_sdt=2000&as_ylo=&as_vis=0). [Cooper, 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7551236)], and oral inulin or pectin or oligofructose reduced the growths of tumors at sites outside of the intestinal tract [Taper and Roberfroid, 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10395627); (http://jn.nutrition.org/cgi/reprint/129/7/1488S)]. One could make the argument that the inulin served as an adjuvant and activated dendritic cells, which are antigen-presenting cells in the intestinal tract that are in contact with the luminal fluid, exclusively in the intestinal tract, leading to some kind of 'totally safe,' indiscriminate activation of the immune system or to antigen-specific, pathological T-cell responses to epithelial antigens in the colon (thereby leading to some sort of cross-reactive anti-tumor immune response), etc. Even if inulin were confined to the luminal fluid, that effect would be pathological, in my opinion. But it seems possible, to me at least, that inulin was simply absorbed into the extracellular fluid or portal venous blood or reached the mesenteric lymph nodes, etc. It's interesting that the molecular weights of some components of pectin are as low as 300-400 Daltons [Fishman et al., 1991: (http://cat.inist.fr/?aModele=afficheN&cpsidt=5472774)], and others are less than 7,000 Daltons, etc. I'd be very wary, personally, of any soluble fiber that is of those types of low molecular weights and that could conceivably cross the intestinal barrier. It sounds really bad to me.

In any case, my point is that the effects of guar gum, for example, and perhaps some of the other high-MW polysaccharides (the MW of guar gum is between 2 and 20 million Daltons or something like that) have these effects, such as on bile acid reabsorption and probably on the enterohepatic circulation of unconjugated bilirubin, on liver function that could explain their beneficial effects on renal function. Researchers have found that guar gum, for example, increased the reabsorption of bile acids in the small intestine, after their entry, in the bile from the liver, into the duodenum via the common bile duct, also increased the amounts of bile acids entering the large intestine, and nonetheless led to a net loss of sterols via the large intestine [Moundras et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9187619)(http://jn.nutrition.org/cgi/reprint/127/6/1068.pdf); Favier et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9307936)]. Those articles show similar effects. One way of looking at their effects might be to say that they act as cosurfactants/surfactants in the small intestine (gums, such as guar gum and gum arabic, have been used as surfactants in emulsions), thereby enhancing the reabsorption of bile acids in the ileum by reducing the interfacial energy and promoting their binding to the ileal transporters (or something like that), and probiotic "fuel sources" in the large intestine. I don't have time to go through more articles, but increases in the reabsorption of bile acids in the ileum can tend to reduce the enterohepatic circulation of unconjugated bilirubin. If some of the different bile acids remain in the large intestine "too long," they can solubilize unconjugated bilirubin, a hydrophobic or fat-soluble molecule, usually (in the absence of visible or UVA light, for example), and allow for its reabsorption, with potentially damaging consequences for the liver, given the cytotoxic and respiratory-inhibitory effects that very high concentrations of bilirubin can have. Also, the loss of bacteria in the colon was shown to produce major increases in the serum bilirubin concentrations of rats (from mean values of 186 to 289 uM) [Vitek et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15664250)], and the idea with that is that there's a decrease in the rate of consumption of unconjugated bilirubin by the bacteria (because the bacterial counts are very low). So more bilirubin is available for reabsorption in the ileum or along all parts of the intestinal tract, as it turns out, and for ongoing enterohepatic recycling. Excess concentrations of bilirubin can promote portal endotoxemia by interfering with the sequestration of endotoxin by bile acids or something like that (http://scholar.google.com/scholar?hl=en&q=bilirubin+portal+endotoxemia&as_sdt=2000&as_ylo=&as_vis=0). I forget, but another element is that bile acids can be cytotoxic to bacteria in the colon. So there can be this vicious cycle of deteriorating liver function, increases in the enterohepatic recycling of bilirubin, loss of bacteria in the colon due to pathologically-increased levels of cytotoxic bile acids in the luminal fluid of the intestine, due in part to impairments in the ileal reabsorption of bile acids, and so on. It's obviously much more complex than this, and increases in the availabilities of some bile acids to the liver can be cytotoxic to hepatocytes and cholangiocytes and other liver cells, etc. There's also the impact that the activities of glucuronidase enzymes in bacteria and enterocytes might have on bilirubin recycling. One might say that the "extra" bacteria would deconjugate conjugated bilirubin and increase the amounts of unconjugated bilirubin that would be available for ileal reabsorption. The glucuronide conjugates of bilirubin are hydrophilic (water-soluble), and I'm forgetting why this is normally not an issue, if I'm remembering correctly that it isn't an issue. I'll have to read some stuff on that.

Another issues is the fact that some guar gum preparations can be of low quality. Guar gum shouldn't form a "rubber cement" type of "epoxy-resin-like" material as soon as it comes in contact with water, in my opinion. It should be somewhat dispersible and shouldn't just form these pieces of hard @#$&#@# plastic in a glass of water. But hey, that's just my opinion. I'm joking, but that's "not the way it was meant to be." Additionally, xanthan gum has the potential to be problematic, in my view, and can form "rubber cement" types of aggregations almost instantly in water. Some animal research (a lot, I guess) has shown that xanthan gum is more or less the same as guar gum or the like, but it doesn't seem like they're very similar. Most of these are available as individual supplements. Hydrolyzed or modified gums could contain polysaccharides of relatively low molecular weights and might, conceivably, have more potential to be problematic. It's possible that the low-molecular weight components of something like pectin are not problematic or are present at very low concentrations. I don't know. At least pectin is present in foods, but I'd wonder about that type of issue with very low molecular weights. I'd personally be wary of it. Also, there are cases of esophageal obstructions (blockages in the esophagus) from guar gum, and there's one report of anaphylaxis from guar gum. There are many more reports of allergy from psyllium, incidentally, and there's only one report for guar gum, from what I can tell. If it's non-"rubber cement" guar gum, this esophageal obstruction business seems rather unlikely, in my view, but one is supposed to drink it with adequate water and discuss the issues with one's doctor.

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.