The Travis Corner

[Travis]

I also enjoy your posts. I get the nicotine love. 2 questions - do you take supplements, and why do you eat almonds? Just for Vitamin E I assume.

I had stopped eating almonds months ago, and will now only eat macadamias and coconuts. I have some γ-tocopherol-enriched vitamin E that I take occasionally, yet since it's also found in food I don't get too crazy about it. Besides that I also have selenomethionine, alpha lipoic acid, and potassium iodide. I have citrulline in the mail for detoxifying ammonia, which is the only amino acid that works in circumstances of low ornithine transcarbamylase activity—a liver enzyme inhibited by aspirin. Ornithine would be less efficient because it lies upstream of ornithine transcarbamylase, and arginine would have reduced activity because it needs to become citrulline first—which it can do via iNOS, nNOS, and eNOS—before it can detoxify one mole of ammonia per mole citrulline. Yet since this amino acid acts as a catalyst—i.e. becomes arginine then ornithine, then arginine, indefinitely—one citrulline molecule can actually detoxify more than one molecule of ammonia.

 

[yerrag]

Beta-carotene is very often considered dietary vitamin A, and for good reason. Beta-carotene is essentially two retinol molecules joined at their methyl ends, yet is safer to consume because it's cleavage is regulated under reverse feedback from retinoic acid.

That's true. It is the same reason another isoprene-derived substance with hormone-like effects, vitamin D, is much better off left to the body to produce.

 

[Travis]

@Travis
“However, if you are experiencing pain while taking vitamin D, then your bone mineral status is definitely not normal and your pain proves it. You see, when your bones are seriously depleted of minerals, and you begin to take vitamin d, the vitamin d will help you start absorbing minerals and depositing them into the bones where it is needed. But water always attaches to minerals, and when your bones begin to remineralize, it will also draw water with those minerals.

You know: I had come across that but this explanation just sounds unrealistic and there had been no citations, almost as if they had just confabulated this on the spot to 'explain away' the link. When I had read that paragraph I had found it reminiscent of articles of the The Weston A. Price Foundation, or unsupported explanations that are overly apologetic to industries that support them. The website that contains the paragraph above sells vitamin D, and I don't consider unreferenced chemical mechanisms penned by salesmen trustworthy.

 

[Travis]

On Reye Syndrome/aspirin -

“Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used whenever there is a fever.

In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen (Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)”
Aspirin, brain, and cancer

That's interesting that acetaminophen may cause it too. In America, where aspirin is more common, the association between Reye's syndrome and aspirin is most often near 90%. Could the remaining the 10% that hadn't taken aspirin taken acetaminophen? or had the mothers been too ashamed to report it? Also, acetaminophen is called paracetamol in Australia.

This author below implies that all salicylates can induce this, yet acetaminophen is not even a salicylate though it's also acetylated.

Mortimer, Edward. "Reye's syndrome, salicylates, epidemiology, and public health policy." JAMA (1987)

'A report in this issue of The Journal is the fifth major publication to implicate salicylates in the pathogenesis of Reye's syndrome (RS). This report confirms and strengthens prior observations, and I would recommend that attention now turn to such unanswered questions as the pathogenesis of the relationship and why RS occurs primarily with influenza and varicella and rarely with other infections. The first reasonably conclusive evidence of an association and a tentative warning appeared in 1980, but no definitive action was taken until 1986. During 1981 through 1985, one thousand three cases of RS with 291 deaths were reported to the Centers for Disease Control; it is likely that up to a third of survivors incurred permanent brain damage. In 1985 only 91 cases were reported, probably attributable to a decline in aspirin use for children. Most epidemiologists who reviewed the three initial reports agreed that the apparent association was sufficient to justify a strong warning to parents and physicians, pending further resolution of the question." Finally, in 1986, largely due to efforts of the Public Citizen Health Research Group, the Food and Drug Administration was permitted to mandate a package label warning. Why did it take so long?' ―Mortimer

'Second, some aspirin companies have exploited the inherent weaknesses of retrospective studies to exert pressure on the federal government, the American Academy of Pediatrics, and other organizations to prevent warnings about the risk of RS attendant upon aspirin use.' ―Mortimer

'The assumption of a persistent adversarial position, as taken by some aspirin manufacturers in this instance, delays a reasonable solution and antagonizes the responsible medical community who might otherwise be supportive. The strategy adopted by some aspirin manufacturers was ill-advised indeed.' ―Mortimer​

Forsyth, Brian. "New epidemiologic evidence confirming that bias does not explain the aspirin/Reye's syndrome association." Jama (1989)

'Twenty-four case subjects and 48 matched controls were enrolled. Eighty-eight percent of case subjects and only 17% of controls had received aspirin prior to the onset of Reye's syndrome (matched odds ratio, 35). Further analyses demonstrated that the association could not be attributed to the five potential sources of bias.' ―Forsyth

'In Table 4 we display in matched format the relationship of acetaminophen use during the prodromal illness to the risk of Reye's syndrome. For anytime during the prodrome, acetaminophen was used by 38% of the case subjects and 71% of the controls, for an OR of 0.16 that is statistically significant.' ―Forsyth
​

Yet Reye syndrome could be expected with having taken no drugs whatsoever. This is because Reye's is explained generally as extreme cachexia compounded by an impaired urea cycle, or severe febrile hyperammonemia, and I am under the impression that most experts would agree on this. Reye's syndrome is actually somewhat similar to hepatic encephalopathy in effect, yet that condition is never called Reye's syndrome.

 

[Travis]

Sorry, I disagree on this one. In fact, there is a study (below) showing aspirin can protect the liver from the toxicity of acetaminophen. The toxicity of APAP is multifaceted and not limited to glutathione depletion. It involves serotonergic mechanisms as well as direct toxicity (activation of TLR family), resulting in cells spilling ATP, LDH and other intracellular components into the blood.

And yet: this is all quite distinct from the inhibition of urea cycle enzymes, which aspirin has been shown to do. Furthermore, the article you'd cited had not mentioned serotonin, glutathione, or lactate dehydrogenase even once. These scientists had actually defined liver damage both histologically and by the enzyme alanine transaminase, both quite distinct from ornithine transcarbamylase. The pathway outlined in the article you'd cited had involved dNA first activating the toll-like receptor Tlr9 with the subsequent induction of interleukin-1β and interleukin-18, two cytokines implicated directly for causing the liver damage. Using various methods such as dNA injections, Tlr9 knockout mice, cyclooxygenase inhibitors, interleukin-1β antibodies, etc., the authors had deduced that 6 mg/kg/day aspirin given orally could protect against injections of acetaminophen at 500 mg/kg by inhibiting interleukins 1β and 18. Again, this does not support you prior claim of 'acetaminophen being clearly cytotoxic in almost any dose/concentration while aspirin only being indirectly toxic.' I feel I must reiterate the fact that this study says absolutely nothing about urea cycle enzymes.

To my knowledge, aspirin does not do that even in high doses, except for raising the GSSG/GSH by lowering GSH. Human trials with 3g aspirin daily noted no side effects except ototoxicity. The clinically relevant dose of APAP for humans is 3g-4g daily. According to the study below, at presumably safe doses (HED ~36mg/kg) APAP can apparently cause serious hepatoxocity.

That dose it between 2¹⁄₂–3 grams for most American adults, most of whom I'd venture would actually assume it to be veritably unsafe. Regular strength tablets are generally marketed with 325 milligrams of acetaminophen, and I don't know anyone who believes that taking between 8 and 9 of those would be safe.

And APAP was given just once. Imagine what happens with chronic exposure. The study even goes as far as to suggest formulating aspirin and APAP together to protect from the hepatotixicity in cases of (usually intentional) APAP overdose. Given that this study did not use an APAP dose that qualifies as overdose, the aspirin/APAP combo should be even more relevant considering the millions of people around the world that consume such APAP doses on a daily basis.

Well aspirin certainly works to antagonize acetaminophen in rats at a dose ratio of 1∶83—likely by inhibiting interleukins 1β and 18—yet there is good evidence that in higher doses it can inhibit the activity of ornithine transcarbalymase thereby inducing hyperammonemia in people under a high protein load. This can be fatal. Besides being responsible for impairing urea cycle enzymes, aspirin has also been shown to cause macroscopic structural changes:

Iancu, Theodore. "Ultrastructural changes in aspirin hepatotoxicity." American journal of clinical pathology (1976)

'A percutaneous liver biopsy was obtained from a 9-year-old boy who had elevated serum transaminase levels while receiving aspirin treatment for rheumatic fever. Electron microscopy showed extensive fine-structure changes of the hepatocytes, similar to those induced by hepatotoxic drugs. These included marked dilatation of rough endoplasmic reticulum, proliferation of smooth endoplasmic reticulum, and mitochondrial abnormalities. These ultrastructural changes could be considered evidence that aspirin is hepatotoxic.' ―Iancu​

Yoshida, I. "Sudden onset of ornithine carbamoyltransferase deficiency after aspirin ingestion." Journal of inherited metabolic disease (1993)

'A 15-year-old boy was admitted to Kurume University Medical Center because of deep coma. Initially he was diagnosed as Reye syndrome by the referring physician. After the admission and biochemical investigations including enzymatic study, the diagnosis of this patient was confirmed as OCT deficiency (Mizoguchi et al 1990). Careful history taking revealed that this patient had begun to take aspirin at the onset of prodromal symptoms. ¶ He was born at full term. The delivery was uneventful. He had never shown any symptoms suggesting metabolic disorders for 15 years or any aversion to protein intake. He had been well until one week before admission, when he had fever and headache. At that time, he began to take aspirin. After 5 days, he felt general malaise and showed haematemesis. Next day, he was very irritable, unsettled and crying. This patient was deeply comatose on admission. Physical examination showed anisocoria suggesting brain herniation. The blood level of salicylate at 7 days after first intake of aspirin was 1.7 mg/dl.' ―Yoshida​

'Recently Yamamoto and colleagues (1987) reported that salicylate inhibited mitochondrial OCT processing in vitro.' ―Yoshida​

Brown, Ted. "Transiently reduced activity of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of children with Reye's syndrome." New England Journal of Medicine (1976)

'Since Reye's syndrome is associated with hyperammonemia, we measured the urea-cycle enzymes in hepatic tissue of 13 patients. Expressed as nanomoles of citrulline per milligram of hepatic protein per minute, mean activity of carbamyl phosphate synthetase and ornithine transcarbalymase in Reye's syndrome was reduced significantly when compared to that of 25 "normal" controls.' ―Brown​

Sinatra, Frank. "Abnormalities of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of patients with Reye's syndrome." Pediatric research (1975)

'Urea cycle function was evaluated in liver obtained from six patients with Reye's syndrome and from five control subjects. Reye's syndrome patients demonstrated normal activities for the extramitochondrial portion of the urea cycle. but showed marked abnormalities of the mitochondrial enzymes, i.e., carbamyl phosphate synthetase (CPS) and ornithine transcarbamylase (OTC). CPS activity was reduced to less than 15% of control values in all four patients from whom tissues was obtained during the first 72 hr after the onset of encephalopathy.' ―Sinatra​

Deshmukh, Devendra. "Interactions of aspirin and other potential etiologic factors in an animal model of Reye syndrome." Proceedings of the National Academy of Sciences (1982)

'The aspirin dosage (50 mg/kg of body weight, twice daily) was selected to approximate human nontoxic therapeutic levels and was administered concurrently with the viral infection to mimic the association in RS. Using our conditions, we produced RS-like disorders in ferrets and observed substantial synergism of the aspirin effects with those caused by other pathogenic factors (influenza infection and ammonia toxicity). Ferrets subjected to all three factors experienced a rapidly developing encephalopathy, progressing to coma and usually death. Serum levels of ammonia, SGOT, and SOCTase were greatly elevated whereas serum bilirubin was unaffected. Liver levels of OCTase and of several mitochondrial urea-cycle enzyme activities were depressed, whereas liver lipids and arginase activity levels were increased. These changes mimic those seen in RS. We have reported preliminary studies describing RS-like alterations in hepatocyte ultrastructure in infected ferrets fed the arginine-deficient diet (25). These various similarities and the similar associations with hyperammonemia, aspirin, and influenza infection as potential pathogenic agents suggest that the ferret model may be useful for further studies of RS.' ―Deshmukh​

No need to argue. I am not trying to convince you of anything. Just something to think about.

Likewise.

 

[Dhair]

And yet: this is all quite distinct from the inhibition of urea cycle enzymes, which aspirin has been shown to do. Furthermore, the article you'd cited had not mentioned serotonin, glutathione, or lactate dehydrogenase even once. These scientists had actually defined liver damage both histologically and by the enzyme alanine transaminase, both quite distinct from ornithine transcarbamylase. The pathway outlined in the article you'd cited had involved dNA first activating the toll-like receptor Tlr9 with the subsequent induction of interleukin-1β and interleukin-18, two cytokines implicated directly for causing the liver damage. Using various methods such as dNA injections, Tlr9 knockout mice, cyclooxygenase inhibitors, interleukin-1β antibodies, etc., the authors had deduced that 6 mg/kg/day aspirin given orally could protect against injections of acetaminophen at 500 mg/kg by inhibiting interleukins 1β and 18. Again, this does not support you prior claim of 'acetaminophen being clearly cytotoxic in almost any dose/concentration while aspirin only being indirectly toxic.' I feel I must reiterate the fact that this study says absolutely nothing about urea cycle enzymes.

That dose it between 2¹⁄₂–3 grams for most American adults, most of whom I'd venture would actually assume it to be veritably unsafe. Regular strength tablets are generally marketed with 325 milligrams of acetaminophen, and I don't know anyone who believes that taking between 8 and 9 of those would be safe.

Well aspirin certainly works to antagonize acetaminophen in rats at a dose ratio of 1∶83—likely by inhibiting interleukins 1β and 18—yet there is good evidence that in higher doses it can inhibit the activity of ornithine transcarbalymase thereby inducing hyperammonemia in people under a high protein load. This can be fatal. Besides being responsible for impairing urea cycle enzymes, aspirin has also been shown to cause macroscopic structural changes:

Iancu, Theodore. "Ultrastructural changes in aspirin hepatotoxicity." American journal of clinical pathology (1976)

'A percutaneous liver biopsy was obtained from a 9-year-old boy who had elevated serum transaminase levels while receiving aspirin treatment for rheumatic fever. Electron microscopy showed extensive fine-structure changes of the hepatocytes, similar to those induced by hepatotoxic drugs. These included marked dilatation of rough endoplasmic reticulum, proliferation of smooth endoplasmic reticulum, and mitochondrial abnormalities. These ultrastructural changes could be considered evidence that aspirin is hepatotoxic.' ―Iancu​

Yoshida, I. "Sudden onset of ornithine carbamoyltransferase deficiency after aspirin ingestion." Journal of inherited metabolic disease (1993)

'A 15-year-old boy was admitted to Kurume University Medical Center because of deep coma. Initially he was diagnosed as Reye syndrome by the referring physician. After the admission and biochemical investigations including enzymatic study, the diagnosis of this patient was confirmed as OCT deficiency (Mizoguchi et al 1990). Careful history taking revealed that this patient had begun to take aspirin at the onset of prodromal symptoms. ¶ He was born at full term. The delivery was uneventful. He had never shown any symptoms suggesting metabolic disorders for 15 years or any aversion to protein intake. He had been well until one week before admission, when he had fever and headache. At that time, he began to take aspirin. After 5 days, he felt general malaise and showed haematemesis. Next day, he was very irritable, unsettled and crying. This patient was deeply comatose on admission. Physical examination showed anisocoria suggesting brain herniation. The blood level of salicylate at 7 days after first intake of aspirin was 1.7 mg/dl.' ―Yoshida​

'Recently Yamamoto and colleagues (1987) reported that salicylate inhibited mitochondrial OCT processing in vitro.' ―Yoshida​

Brown, Ted. "Transiently reduced activity of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of children with Reye's syndrome." New England Journal of Medicine (1976)

'Since Reye's syndrome is associated with hyperammonemia, we measured the urea-cycle enzymes in hepatic tissue of 13 patients. Expressed as nanomoles of citrulline per milligram of hepatic protein per minute, mean activity of carbamyl phosphate synthetase and ornithine transcarbalymase in Reye's syndrome was reduced significantly when compared to that of 25 "normal" controls.' ―Brown​

Sinatra, Frank. "Abnormalities of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of patients with Reye's syndrome." Pediatric research (1975)

'Urea cycle function was evaluated in liver obtained from six patients with Reye's syndrome and from five control subjects. Reye's syndrome patients demonstrated normal activities for the extramitochondrial portion of the urea cycle. but showed marked abnormalities of the mitochondrial enzymes, i.e., carbamyl phosphate synthetase (CPS) and ornithine transcarbamylase (OTC). CPS activity was reduced to less than 15% of control values in all four patients from whom tissues was obtained during the first 72 hr after the onset of encephalopathy.' ―Sinatra​

Deshmukh, Devendra. "Interactions of aspirin and other potential etiologic factors in an animal model of Reye syndrome." Proceedings of the National Academy of Sciences (1982)

'The aspirin dosage (50 mg/kg of body weight, twice daily) was selected to approximate human nontoxic therapeutic levels and was administered concurrently with the viral infection to mimic the association in RS. Using our conditions, we produced RS-like disorders in ferrets and observed substantial synergism of the aspirin effects with those caused by other pathogenic factors (influenza infection and ammonia toxicity). Ferrets subjected to all three factors experienced a rapidly developing encephalopathy, progressing to coma and usually death. Serum levels of ammonia, SGOT, and SOCTase were greatly elevated whereas serum bilirubin was unaffected. Liver levels of OCTase and of several mitochondrial urea-cycle enzyme activities were depressed, whereas liver lipids and arginase activity levels were increased. These changes mimic those seen in RS. We have reported preliminary studies describing RS-like alterations in hepatocyte ultrastructure in infected ferrets fed the arginine-deficient diet (25). These various similarities and the similar associations with hyperammonemia, aspirin, and influenza infection as potential pathogenic agents suggest that the ferret model may be useful for further studies of RS.' ―Deshmukh​

Likewise.

Who knew Frank Sinatra knew so much about Reye's Syndrome?

 

[Travis]

Who knew Frank Sinatra knew so much about Reye's Syndrome?

Right? I had just closed-out that article on my browser and saw FRANK SINATRA listed as first author, ostentatiously, and in all-caps. Sammy Davis Jr. also performs laparoscopic surgery, which could perhaps be considered irresponsible on account of completely lacking depth perception with only one eye:

 

[paymanz]

Beta-carotene is very often considered dietary vitamin A, and for good reason. Beta-carotene is essentially two retinol molecules joined at their methyl ends, yet is safer to consume because it's cleavage is regulated under reverse feedback from retinoic acid.

yes but he didnt mention salad or greens.

 

[olive]

Travis I’ve been following your posts regarding acne. Androgens and IGF-1 messing with SERB1 causing thicker sebum resulting in plugged pores. I know you recommend avoiding dietary sources; ie dairy and egg yolks. However how would a menstruating female prevent a monthly breakout due to increased androgens just before her period? Looking to avoid the pill.

 

[Amazoniac]

Travi, is it possible that the adverse experience with vit D is due to having a lot more calcium than phosphorus?

How having a robust or weak metabolism affects phosphorus requirements? What are the effects of stimulants?
Niacin might increase its needs. What about creatine? Calcium carbonate? There are publications of a depletion induced by antiacids.

- Calcirol - Liquid Vitamin D3
- Dr. Hans Nieper, Has No One Heard About His Works?

There are books on nutrition that disconsider it altogether. Fortunately the LPI doesn't:
- Phosphorus

Given that many nutrients in their active form are bound to phosphorus, various supplements can provide some: choline, thiamine, riboflavin, pyridoxine, and so on.

 

[Amazoniac]

avoiding dietary sources; ie dairy and egg yolks

More productive than avoidance is trying to find out how some people manage to not have problems with those at all. After discovering the difference, thinking: am I doomed? What did I do to deserve this? Is it because of my skin color? Is this an extension of my other failures? Will I ever succeed in something?

 

[Nicolas Noyola]

Regarding calcium consumption, how many eggshells do you guys think would be necessary to obtain sufficient dietary calcium intake if one is avoiding dairy and reticent about eating leafy greens. For that matter, how much is too many? I've had 4 full white eggshells the past two days, I havent noticed any adverse effects, but calculating my calcium intake i think i may be overdoing it. An egg weighs 57g according to google, 11% of which is the shell, so the shell weighs 2.5g. Now I've seen the numbers 40% and 95% respectively for the content of calcium carbonate in the shell. so that's 1g calcium per eggshell versus roughly 2.4g calcium per shell. with the former, 4 eggshells a day yields 4g of calcium which I think is fine for me given ample cofactors like vits D, A, K2 and magns. On the other hand, 4 * 2.4 yields 9.2g of calcium, that might be too much...
Moreover how much calcium is actually absorbed?

VM69/VM013: Concepts of Eggshell Quality
Chicken eggshell as suitable calcium source at home. - PubMed - NCBI

 

[tara]

That dose it between 2¹⁄₂–3 grams for most American adults, most of whom I'd venture would actually assume it to be veritably unsafe. Regular strength tablets are generally marketed with 325 milligrams of acetaminophen, and I don't know anyone who believes that taking between 8 and 9 of those would be safe.

Where I am, aspiring tablets come in
- little daily 'heart health' size of 100mg or less
- ~300mg regular (adult dose is 2 x 300 mg)
~500mg extra strength (adult dose is 2 x 500mg)

Acetaminophen tablets only come in 200mg tablets, adult dose is 2 x 200mg = 400mg.
Also syrups for children a couple of different strengths for different age ranges.

I don't know anyone who sounds like they are reckless about acetaminophen dosing, but I've heard it's one of the most common causes of poisoning in children.

 

[energyandstruct]

I had liked it, and think it's a very useful study to consider. The author had also been interesting, and I liked his use of the term 'diagnostic odyssey.' I can almost picture Odysseus getting fatigued, building a gοddamn ship, and the sailing around the Mediterranean to consult with doctors at ports—those with cool robes and scepters of course.

'Complex diseases like CFS are often difficult and expensive to diagnose. Although individual tests may be affordable and possibly covered by medical insurance, many patients undergo a diagnostic odyssey that results in substantial personal expenditures that can exceed $100,000 over years of searching, absence.' ―Naviaux​

This was a great article yet with one exception. He also says the following:

'If capillary delivery of oxygen to the cell is unchanged, the concentration of dissolved oxygen rises in the cell like water in a bowl [?] in response to instantaneous decreases in mitochondrial oxygen consumption.' ―Naviaux​

I somehow feel that 'water in a bowl' is not a very intuitive analogy for describing a cellular increase in oxygen, and I'll even so far to say that it's a blatantly horrible one. I wouldn't imagine there would be significant volume increases as a function of physiological O₂ concentrations, so I think it would actually make more sense with the analogy omitted:

'If capillary delivery of oxygen to the cell is unchanged, the concentration of dissolved oxygen rises in the cell like water in a bowl in response to instantaneous decreases in mitochondrial oxygen consumption.' ―Naviaux​

And you know, I think it's such a bad analogy that it could even be more appropriate to state things this way:

'If capillary delivery of oxygen to the cell is unchanged, the concentration of dissolved oxygen rises in the cell like water in a bowl a race-riot after the Rodney King Trial in response to instantaneous decreases in mitochondrial oxygen consumption.' ―Naviaux​

But seriously, the article makes a person wonder why sphingolipids are increased in chronic fatigue. Yet this is actually in accordance with my theory on the condition, as is the increase in arginine and proline. The decrease in bile salts are also immediately explicable, and I think I may use this study in the article I am writing.

there's an earlier study by this guy on the Cell Danger Response. he says some things that seem to accord with peat and I liek that he's a deep systematic thinker , but there are things that don't really jive with peat, like talking about PUFAs being replaced by SFAs in cell membranes ! due to stress.

But then in this CDR thing, he calls mitochondria an "electron sink" which very much sounds like Ling's language of cardinal adsorbents . https://www.sciencedirect.com/science/article/pii/S1567724913002390



If you're looking at this whole area, there's this paper: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome that indicates impaired pyruvate dehydrogenase function in CFS.

What do you think can be done treatment-wise with any of these findings? Of course they don't really offer any conclusions, but I have had some thoughts, around high dose thiamine, niacinamide, etc...

 

[Travis]

Travis I’ve been following your posts regarding acne. Androgens and IGF-1 messing with SERB1 causing thicker sebum resulting in plugged pores. I know you recommend avoiding dietary sources; ie dairy and egg yolks. However how would a menstruating female prevent a monthly breakout due to increased androgens just before her period? Looking to avoid the pill.

It does seem that bodybuilders prove exogenous androgens can cause acne, yet the high rates adolescent boys also prove that endogenous ones can contribute Lycopene has been shown capable of reducing the synthesis of cholesterol and the androgens in males, a inhibition it appears to accomplish through mimicking squalene—the direct cholesterol precursor. Autopsy studies show that lycopene distributes at the highest concentrations in the testicles, at least in rats, explaining the reduced androgen synthesis and marked prostate cancer rates from its use. Because lycopene appears to be a mild and natural inhibitor of cholesterol synthesis, eating this should help in reducing all downstream steroids from pregnenolone to aldosterone.

 

[Travis]

Travi, is it possible that the adverse experience with vit D is due to having a lot more calcium than phosphorus?

How having a robust or weak metabolism affects phosphorus requirements? What are the effects of stimulants?
Niacin might increase its needs. What about creatine? Calcium carbonate? There are publications of a depletion induced by antiacids.

- Calcirol - Liquid Vitamin D3
- Dr. Hans Nieper, Has No One Heard About His Works?

There are books on nutrition that disconsider it altogether. Fortunately the LPI doesn't:
- Phosphorus

Given that many nutrients in their active form are bound to phosphorus, various supplements can provide some: choline, thiamine, riboflavin, pyridoxine, and so on.

I think I can feel 5,000 IU largely because I have low body fat, and that the same could happen in others using a comparable dose adjusted for BMI. Calcium channels have been highly implicated in joint pain, where a role for Ca²⁺ would seem intuitive because it could signal-for joint attrition. Oral cholecalciferol could tend towards hypercalcemia by increasing intestinal Ca²⁺ absorption, yet hypercalcemia and joint pain has also been induced by retinol. In the latter case, hypercalcemia results from the demineralization of the bones and not 'their remineralization:'

Frame, Boy. "Hypercalcemia and skeletal effects in chronic hypervitaminosis A." Annals of internal medicine (1974)

'The clinical features of vitamin A toxicity in a 7-year-old boy, a 16-year-old boy, and a 46-year-old man included vague skeletal pains and hypercalcemia. Experimental and clinical evidence indicates that hypervitaminosis A can cause bony resorption as well as periosteal calcification. Ingestion of excessive amounts of vitamin A should be considered in the differential diagnosis of hypercalcemia.' ―Frame​

'A 7-year-old boy was admitted with generalized muscular and skeletal discomfort of 6 weeks' duration. For 5 days he had been unable to walk or straighten his legs. He cried readily, complained of a headache, was irritable, and had a poor appetite. Examination showed a thin, pale child who was unable to stand or straighten his flexed legs because of pain. Tenderness was noted along both tibiae. Hemoglobin was 12.7 g/100 ml, and the leukocyte count, 7500/mm³ . Urinalysis was normal. [...] The presence of hypercalcemia prompted an inquiry of medications taken by the patient, which revealed a daily intake of 85,000 units of vitamin A for 2 years, with less than 1,500 units of vitamin D per day. Because of the patient's poor appetite, his parents increased the vitamin A to 160,000 units daily on the advice of a salesman in a health food store several months before admission. Skeletal roentgenograms were normal. The vitamin A level in the serum was 403 IU/100 ml. The excessive ingestion of vitamin A was discontinued, and fluids were forced. He improved rapidly. After 3 weeks the serum calcium had decreased to 10.1 mg/100 ml, and the skeletal discomfort had disappeared.' ―Frame​

'A 16-year-old boy had had generalized myalgia and arthralgias for 3 months. He showed emotional lability and had lost 10 lb because of loss of appetite. Examination showed weakness of hand grip caused by pain and tenderness over the small bones of the hands and distal forearms. Serum calcium was elevated, ranging from 12.0 to 14.0 mg/100 ml. The alkaline phosphatase was 10 Bodansky units. Evidence for the correct diagnosis was observed on the skeletal roentgenograms (Figures 1 to 3). Multiple sites of periosteal calcification were noted along the shafts of several of the metacarpals and proximal phalanges. The periosteal calcifications suggested vitamin A intoxication. [...] The demineralization of the sella was so pronounced that the possibility of an intrasellar mass was strongly considered. The patient initially denied ingestion of vitamin supplements. After the roentgenologic changes were noted, the patient was again questioned about vitamin ingestion. A pertinent history was then obtained. The patient wanted to become an aircraft pilot, and, hoping to improve his night vision, he had ingested variable and excessive amounts of vitamin A for several years.' ―Frame​

'A 46-year-old man complained of fatigue, vague chest pains, headaches, and general skeletal discomfort of 6 years' duration. His family physician found elevated serum and urinary calcium concentrations and evidence of renal insufficiency. Nephrocalcinosis was demonstrated on an intravenous pyelogram. He passed several small renal calculi. The patient was seen in a large midwestern clinic where hypercalcemia, averaging 12.6 mg/100 ml was confirmed. [...] In October 1972 the patient was further questioned regarding vitamin ingestion. He admitted to taking up to 50 000 units of vitamin A in a multivitamin preparation daily, at least during 1972, but denied taking vitamin supplements before this time when the hypercalcemia had initially been detected. Some residual frozen serum taken at the time of the parathyroid exploration was located. In this sample the carotene level was 286 μg/100 ml, and the vitamin A level was 625 IU/100 ml (normal, less than 125 IU/100 ml). On the basis of this information, the patient was questioned further about vitamin intake. It was discovered that he was a part-time, door-to-door vitamin salesman. One of the products he sold was a multivitamin preparation containing vitamin A. He admitted taking an average of three capsules per day containing a total of 25,000 units of vitamin A and 1,250 units of vitamin D for 6 to 7 years, the duration of his illness. Periodically, he had increased the dose, thinking that his symptoms indicated a need for larger amounts of these nutritional supplements.' ―Frame​

It appears that salesmen not only prefer to imagine their drugs are completely safe, and any practical dose, but that their side-effects are actually an indication for taking more. I feel this is unrealistic, yet with the sole exception of the 'die-off' reaction: In this situation, increasing the dose may lead to a quicker resolution at the expense of accentuated acute symptoms.

From the known effects of calcitriol and retinoic acid: it would imagine Vitamin D-induced joint pain could more strictly be considered hypercalcemia-related joint pain, perhaps the result of a high Ca²⁺/Mg²⁺ ratio. Perhaps I will try taking a few grams of calcium soon to see if I can feel anything from that. I feel it bears repeating that even a dose of 5,000 IU of vitamin D orally—i.e. directed at the Ca²⁺-responsive intestines—is completely unnatural, unless of course you consider fish liver oil a 'natural food.'

 

[Travis]

More productive than avoidance is trying to find out how some people manage to not have problems with those at all.

Are you implying it's better to actually eat the food most correlated with acne—when trying to eliminate acne—than to avoid it?

Sequeira, Jeffrey. "The diagnostic utility of folate receptor autoantibodies in blood." Clinical chemistry and laboratory medicine (2013)

'As we age, the immune system also changes, leading to immunosenescence, and therefore, AuAbs to many antigens are prevalent in the elderly population [ 30 , 31 ]. This trend is also seen for blocking FRα AuAbs, whose prevalence increases from < 2% in those younger-than-16-years age group to approximately 10% in the 18-to-35-years age group, and with approximately 25% of the older-than-65-years age group testing positive for the antibody ( Figure 6 ).' ―Sequeira​

[The above quote is only considering the relatively easy-to-measure blocking FRα autoantibody, yet in general there exists a like amount of those that bind yet do not block. This would make for a 50% prevalence in those over 65 years of age when considering both, which is approaching the very prevalence of the homogenized milk use. Autoantibodies that bind and do not block folate receptor α can still indirectly reduce brain folate uptake, and this could happens by serving as beacon for neutrophils—an immune cell that will damage any anything having a bound antibody using hypochlorite (ClO⁻). For confirmation of the latter statement, one only needs to read a few decent articles on the islet β-cells involved in diabetes mellitus.]

 

[Travis]

Where I am, aspiring tablets come in
- little daily 'heart health' size of 100mg or less
- ~300mg regular (adult dose is 2 x 300 mg)
~500mg extra strength (adult dose is 2 x 500mg)

Acetaminophen tablets only come in 200mg tablets, adult dose is 2 x 200mg = 400mg.
Also syrups for children a couple of different strengths for different age ranges.

Where I live, and most outlets online, the average dose of the most popular brand appears to be 325 milligrams.

I don't know anyone who sounds like they are reckless about acetaminophen dosing [...]

Me neither, but that's not what I said or had even implied.

[...] but I've heard it's one of the most common causes of poisoning in children.

Isbister, Geoff. "Pediatric acetaminophen poisoning." Archives of pediatrics & adolescent medicine (2001)

'There is more recent evidence to indicate that children younger than 6 years are much less susceptible to acute acitominophen poisoning. There has never been a confirmed death in a child following actute acetominophen poisoning, and the toxic dose seems to be much higher than 150 mg/kg. The reduced toxicity in children is thought to be due to either slower oxidative metabolism and/or increased glutathione synthesis.' ―Isbister​

 

[Travis]

there's an earlier study by this guy on the Cell Danger Response. he says some things that seem to accord with peat and I liek that he's a deep systematic thinker , but there are things that don't really jive with peat, like talking about PUFAs being replaced by SFAs in cell membranes ! due to stress.

But then in this CDR thing, he calls mitochondria an "electron sink" which very much sounds like Ling's language of cardinal adsorbents . https://www.sciencedirect.com/science/article/pii/S1567724913002390



If you're looking at this whole area, there's this paper: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome that indicates impaired pyruvate dehydrogenase function in CFS.

What do you think can be done treatment-wise with any of these findings? Of course they don't really offer any conclusions, but I have had some thoughts, around high dose thiamine, niacinamide, etc...

I can't think of anything besides thiamine, unless of course you'd find a way to increase the expression of the enzyme. Yet there could be a way to do this: Since pyruvate dehydrogenase is under negative regulation by hypoxia inducible factor-1—via transcribing-for pyruvate dehydrogenase kinase—then taking baicalein and/or lapachol should ultimately act to increase it. These phytochemicals are the two most powerful natural glyoxalase-1 inhibitors (Kᵢ ≈ 5–7 μM), acting to increase methylglyoxal by inhibiting its degradation to lactate. Methylglyoxal is very powerful because it selectively reacts with exposed arginyl side-chains on proteins, irreversibly converting them into hydroimidazolone rings. By reacting with 'hot spot' arginine residues is how methylglyoxal been shown to regulate transcription (Yao, 2007), and the transcription factor HIF-1 is also inactivated in this manner (Bento, 2010). Taking a glyoxalase inhibitor such as baicalein could be expected to: increase intracellular methylglyoxal, decrease intracellular lactate, inhibit 15-lipoxygenase (Deschamps, 2006), inactivate hypoxia inducible factor-1α (Bento, 2010) thereby increasing pyruvate dehydrogenase expression. Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs. Methylglyoxal also forms inside the cell mainly from carbohydrates, and appears to be the biochemical signal for their metabolic rate. Intracellular methylglyoxal has also acquired reputation for powerfully inhibiting cancer, and very likely the reason why baicalein and lapachol have been so successful at treating it.

Kim, Jung-Whan. "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Cell metabolism (2006)

'Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1a null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.' ―Jung-Whan​

Bento, C. F. "The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal." PloS one (2010)

'Methylglyoxal has recently been shown to modify HIF-1α on arginine residues [22], probably leading to changes in protein conformation. Indeed, immunoprecipitation experiments showed that methylgloxal-modified lysine and arginine residues of HIF-1α, increasing its immunoreactivity against N-carboxymethyl-lysine and Nα-acetyl-Nδ(5-hydro-5-methyl)-4-imidazolone (MG-H1) antibodies, respectively. Thus, we hypothesized that modification by methylgloxal might stimulate proteasome-dependent degradation of HIF-1α, as a result of post-translational modifications.' ―Bento​

Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)

'Our studies demonstrate for the first time that methylglyoxal causes post-translational modification of a coregulator protein and that this modification affects gene expression. The extent of this modification reflects the net effect of a variety of intracellular processes, including metabolic flux and reactive oxygen formation, and may thus function as a new integrating signal to coordinately regulate distinct patterns of gene expression.' ―Yao​

 

[energyandstruct]

I can't think of anything besides thiamine, unless of course you'd find a way to increase the expression of the enzyme. Yet there could be a way to do this: Since pyruvate dehydrogenase is under negative regulation by hypoxia inducible factor-1—via transcribing-for pyruvate dehydrogenase kinase—then taking baicalein and/or lapachol should ultimately act to increase it. These phytochemicals are the two most powerful natural glyoxalase-1 inhibitors (Kᵢ ≈ 5–7 μM), acting to increase methylglyoxal by inhibiting its degradation to lactate. Methylglyoxal is very powerful because it selectively reacts with exposed arginyl side-chains on proteins, irreversibly converting them into hydroimidazolone rings. By reacting with 'hot spot' arginine residues is how methylglyoxal been shown to regulate transcription (Yao, 2007), and the transcription factor HIF-1 is also inactivated in this manner (Bento, 2010). Taking a glyoxalase inhibitor such as baicalein could be expected to: increase intracellular methylglyoxal, decrease intracellular lactate, inhibit 15-lipoxygenase (Deschamps, 2006), inactivate hypoxia inducible factor-1α (Bento, 2010) thereby increasing pyruvate dehydrogenase expression. Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs. Methylglyoxal also forms inside the cell mainly from carbohydrates, and appears to be the biochemical signal for their metabolic rate. Intracellular methylglyoxal has also acquired reputation for powerfully inhibiting cancer, and very likely the reason why baicalein and lapachol have been so successful at treating it.

Kim, Jung-Whan. "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Cell metabolism (2006)

'Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1a null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.' ―Jung-Whan​

Bento, C. F. "The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal." PloS one (2010)

'Methylglyoxal has recently been shown to modify HIF-1α on arginine residues [22], probably leading to changes in protein conformation. Indeed, immunoprecipitation experiments showed that methylgloxal-modified lysine and arginine residues of HIF-1α, increasing its immunoreactivity against N-carboxymethyl-lysine and Nα-acetyl-Nδ(5-hydro-5-methyl)-4-imidazolone (MG-H1) antibodies, respectively. Thus, we hypothesized that modification by methylgloxal might stimulate proteasome-dependent degradation of HIF-1α, as a result of post-translational modifications.' ―Bento​

Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)

'Our studies demonstrate for the first time that methylglyoxal causes post-translational modification of a coregulator protein and that this modification affects gene expression. The extent of this modification reflects the net effect of a variety of intracellular processes, including metabolic flux and reactive oxygen formation, and may thus function as a new integrating signal to coordinately regulate distinct patterns of gene expression.' ―Yao​

Thanks travis, this is a lot to chew on and I've copied all of it down. I've tried some of the standard Peat suggestions without a ton of success. Often temporary relief from something like progestE or thyroid doses but seemingly diminishing returns for some reason.

I read Szent-gyorgyi's "cancer and the living state" which is pretty much the only serious biology I've read, besides Ray's articles, and I remember him talking about methylgloxal in the context of life formation on Earth, so I'm excited to hear some less speculative stuff about its specific biological role.

I also got intriguing results from ultra high dose thiamine--2000 mg a few times, which I used because an italian study on fibro got very good results only when they pushed the dose this high. It was a small study and fibro is different from CFS but I figured worth a try. I did get some insomnia and heart palps from it though.

I have skullcap in my garden actually, not much. I may try digging up the roots and doing an extract, but I'll also just go ahead and get some baicalein. Would you think that beta-lapachone would have a similar effect to lapachol? I ask because I already have some lapodin lying around.




​