Parasite Prevalence Predicts Authoritarianism

[pimpnamedraypeat]

So why are white people allowed to concede, to strike a deal, and keep their land? Not even the much‐dreaded Germans and Japanese were exterminated after World War II. I think the main reason was: besides looking differently, they were illiterate; they were simply treated as non‐people, or as savages.

They were needed at the time. The elites don't care for poor whites for anything other than their usefulness. I think in the coming decades we're going to see a large reduction in the human population from war, starvation, and natural disasters. I was researching global warming and stumbled onto the coming ice age. The sun is cooling down and we're going to see a long unending winter that will precipitate a full blown ice age. Human population will drop to approximately georgia guidestone level. Google adapt2030 or not by fire but by ice to learn more

Military men have historically manufactured tension where there'd been none, to increase the public's perception of their trade. Even to this day the public is fed inaccurate reasons for engagement, The Gulf of Tonkin and 9/11 being notable examples, but no doubt it's been occurring for centuries. I think you can be certain even back them, European military men would manufacture lies about the natives to increase the demand for war—and perhaps even staged 'false flag' events. You can also be nearly certain the industrialists also manufactured lies to justify the expropriation of land.

I think this happened a lot. For example scalping was started by the white man (for accounting reasons) but it's now accepted to be a native American tradition.

 

[x-ray peat]

The religious hullabaloo is bs crafted for the serfs to believe.

During the last century, US children were taught that US Manifest Destiny and Democracy was God ordained so that they would dutifully go off to war to spread "Western values" to the world. Now that the world has been so homogenized by a 100 years of war and is ready for one world government, the American Superpower is no longer needed and must be destroyed. What you may think is the truth is actually the latest in state sponsored propaganda designed to help bring about this end. It is what is taught in public schools today, and spouted by the vast majority of SJWs on campus who dutifully say "America was never great." You have only traded in the old BS hullabaloo for the new. The real truth lies in neither of those extremes but somewhere in the middle.

And the East India company was definitely involved maybe you should look into that.

I did, the only role they played in the colonies was through trade and most famously in starting the Boston tea party by changing the laws to favor their tea from China but that was about it.

 

[x-ray peat]

I'm positing this as the most developed argument in this thread:

fair and balanced

 

[x-ray peat]

So why are white people allowed to concede, to strike a deal, and keep their land? Not even the much‐dreaded Germans and Japanese were exterminated after World War II. I think the main reason was: besides looking differently, they were illiterate; they were simply treated as non‐people, or as savages.

Because there are different reasons for war. The wars of the previous centuries were about land and conquest, the wars of the last century were about changing societies. The chance to exterminate or at least greatly reduce the size of a few undesirable races was just a side benefit to TPTB.

 

[Travis]

I'm positing this as the most developed argument in this thread:

The term 'non‐people' is an Alan Watts term. He talks about this in great length, perhaps in this video—perhaps in another.

They were needed at the time. The elites don't care for poor whites for anything other than their usefulness. I think in the coming decades we're going to see a large reduction in the human population from war, starvation, and natural disasters.

I suppose we'll find out. I don't watch television so I really have no idea about the latest political shenanigans, but I've read enough about science to know whether their explanations are impossible or not. How people can still believe the Warren Commission's explanation, and NIST's explanation, is beyond me. But not really; the television merely presents an unflattering archetype of the people interested in non‐official—but more realistic and factual—explanations; most people are more than ready avoid those ideas for that reason. Disinformation is also a big issue, as anyone who just dabbles in certain areas can come out being completely nonplussed or believing in something totally absurd.

 

[DaveFoster]

fair and balanced

The term 'non‐people' is an Alan Watts term. He talks about this in great length, perhaps in this video—perhaps in another.
I suppose we'll find out. I don't watch television so I really have no idea about the latest political shenanigans, but I've read enough about science to know whether their explanations are impossible or not. How people can still believe the Warren Commission's explanation, and NIST's explanation, is beyond me. But not really; the television merely presents an unflattering archetype of the people interested in non‐official—but more realistic and factual—explanations; most people are more than ready avoid those ideas for that reason. Disinformation is also a big issue, as anyone who just dabbles in certain areas can come out being completely nonplussed or believing in something totally absurd.

Thanks for the link, I'll check it out.

 

[Travis]

Interferon-γ is released by T cells in response to foreign proteins, be they allergenic food proteins or those from an invading pathogen. This is likely the most powerful cytokine, on the same tier as interleukin-1 and TNF-α. Interferon-γ is responsible for the bald spots seen during certain parasitic infections, as it induces the transcription of phospholipase A₂ on target cells. Phospholipase goes on to cleave arachidonic acid from the cell membrane, where it is found, initiating the production of eicosanoids such as prostaglandin D₂. Gamma interferon also induces the enzyme inducible nitric oxide synthase.

But most important to the psychology of the immune response is the ability of interferon-γ to powerfully effect tryptophan metabolism. This is the only precursor for indole neurotransmitters such as serotonin and melatonin, so a reduction in this amino acid would be expected to produce psychological effects. Fernstrom has shown that brain serotonin synthesis is a direct function of the ratio of serum tryptophan over it's five competing amino acids (tyrosine, phenylalanine, leucine, isoleucine, and valine). Teleologically, it's effect on tryptophan metabolism serves to restrict this amino acid from the invading pathogen—but is entirely pathological in the case of food allergy, and serves no real beneficial function. The body does not seem capable of differentiating a seed storage protein fragment, such as wheat gluten or oat avenin, from a protein derived from an invading pathogen; the body releases interferon-γ as a response to many proteins, whether injected, inhaled, or ingested (or transdermal invasion in the case of some such parasites such as hookworm). Gamma interferon lowers tryptophan levels by inducing the enzyme indolamine diooxygenase:

'The IFN-γ-mediated IDO induction observed in vitro is consistent with the results from in vivo treatment. Plasma levels of tryptophan and urine levels of kynurenine were measured in individuals who had received iv. bolus injections of either IFN-α or IFN-γ. Plasma tryptophan levels were not altered in patients receiving IFN-α, but at 6 and 24 h after administration of IFN-γ, plasma levels were reduced and urinary kynurenine levels were elevated. In these studies it was not possible to correlate plasma tryptophan levels or urinary kynurenine levels with doses of IFN or neoplasia. Complete amino acid analysis of plasma from three patients showed that the catabolic effect was confined to tryptophan. Of the 22 amino acids examined, only tryptophan levels were significantly reduced (to 36.7% of pretreatment levels).' ―Taylor​

This is a significant reduction in tryptophan (63.3%), and would be expected to reduce brain serotonin synthesis. This would also serve to reduce new protein synthesis, perhaps explaining the thinness and weakness observed in those with with ongoing parasitic infections—an observation perhaps wrongly attributed to the insignificant 'nutrient theft' by the parasites themselves (parasites sometimes acquire the mythological ability to sequester all dietary minerals in places such as curezone.com). A reduction in any one amino acid of this magnitude would be expected to reduce new protein synthesis, and especially in the case of the relatively scarce tryptophan; serotonin is also responsible for releasing growth hormone from the pituitary. Eating enough protein—say about 100 grams per day—could be enough to overcome the reduced protein synthesis and slightly normalize the tryptophan ratio, but the induction of interferon-γ would still be a detriment. Eating more food does nothing about the prostaglandins produced; on the contrary, it would likely serve to increase them by introducing more linoleic acid.

Through interferon-γ you would expect people with severe food allergies to model those with parasitic infections. There are many parallels; parasitic infection, injection of peanut protein, and ingestion of gluten can cause hair loss. Below is a study demonstrating this, with peanut protein-sensitized mice exhibiting a type of hair loss reminiscent of mice genetically-manipulated to express interferon-γ on the skin and also canine leishmaniasis:

Li, Xui-Min. "Murine model of atopic dermatitis associated with food hypersensitivity." Journal of allergy and clinical immunology (2001)
Ciaramella, P. "A retrospective clinical study of canine leishmaniasis in 150 dogs naturally infected by Leishmania infantum." Veterinary record (1997)
Carroll, Joseph M. "Transgenic mice expressing IFN-γ in the epidermis have eczema, hair hypopigmentation, and hair loss." Journal of investigative dermatology (1997):​

And predictably: vaccination has been reported to cause hair loss.

'Within 1 day after her first dose of HBV, a 30-year-old female nurse developed mild hair loss, arthralgias, fatigue, and weakness, which lasted 1 week. One month later, her second dose was followed 1 day later by recurrent onset of hair loss and, about 2 weeks later, by recurrent arthralgias, fatigue, and weakness. Alopecia progressed for a few months until she estimated that half of her hair remained in a diffuse distribution with a thinned appearance. Her hair later regrew without treatment or workup.' ―Wise​

Nothing is associated more with hair loss than is prostaglandin D₂, an eicosanoid in which interferon-γ increases by inducing the transcription of phospolipase A₂. Of interest is the fact that the powerful hair growth drug cyclosporine A completely blocks interferon-γ production.

Ercan, A. R. "Interferon‐gamma in alopecia areata." European Journal of Dermatology (2004)
Larson, Allison R. "A prostaglandin d‐synthase‐positive mast cell gradient characterizes scalp patterning." Journal of cutaneous pathology (2014)
Garza, Luis A. "Prostaglandin D₂ inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia." Science translational medicine (2012)​

The clinical presentation of celiac disease, also characterized by very high interferon-γ levels, involves weight loss:

'This form is characterized by gastrointestinal manifestations starting between 6 and 24 months of age, after the introduction of gluten in the diet. Infants and young children typically present with impaired growth, chronic diarrhea, abdominal distention, muscle wasting and hypotonia, poor appetite, and unhappy behavior. Within weeks to months of starting to ingest gluten, weight gain velocity decreases and, finally, weight loss can be observed.' ―Fasano​

But since this involves a prominent reduction of the intestinal villi, and likely reduced absorption of certain things, this is not conclusive. However, alopecia is also observed in celiac disease—a condition dominated by interferon-γ.

Corazza, Gino R. "Celiac disease and alopecia areata: report of a new association." Gastroenterology (1995)
Fasano, Alessio. "Clinical presentation of celiac disease in the pediatric population." Gastroenterology (2005)
Nilsen, Ellen M. "Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease." Gastroenterology (1998)​

Celiac disease isn't the best model since gluten also has exorphins—small peptides about five amino acids in length—which act through the δ-opioid receptor; this raises prolactin and perhaps causes psycho-opiate effects.

This may seem speculative to those who haven't read many of these studies, but it's not really. I found one person who thinks along these lines, will confirm many things I had written, and has conducted an interesting study on this topic:

Maes, Michael. "Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response." Psychiatry research (1994)​

(Neopterin is a product of GTP, usually found increased in proportion with interferon-γ.)

'However, immune responses may be accompanied by signs of immune activation (e.g., hypersecretion of cytokines and prostaglandins, T-cell activation) as well as immunosuppression.' ―Maes

'Recently, it was suggested that lower plasma L-tryptophan (L-TRP) levels, which frequently occur in major depression, may be related to the immune response. Indeed, our laboratory found significant inverse relationships between various immune or inflammatory markers and plasma L-TRP concentrations or the L-TRP/competing amino acid (CAA) ratio [The Fernstrom Ratio]. Activation of cell-mediated immunity is known to accelerate L-TRP catabolism through induction of indoleamine 2,3-dioxygenase, with subsequent depletion of plasma L-TRP. This phenomenon could compromise central serotonergic turnover, since L-TRP plasma concentration or the L-TRP/CAA ratio provides an index of the availability of L-TRP to the brain (Fernstrom et al., 1973; Fernstrom, 1984; Moller et al., 1986), which, in part, determines central serotonin synthesis (Moir and Eccleston, 1968; Fernstrom and Faller, 1977). '―Maes

'Procedures. In study group I, fasting blood samples were collected at 8 a.m. for determination of plasma neopterin, L-TRP, valine, leucine, isoleucine, tyrosine, and phenylalanine.' ―Maes

'Table 2 shows that the L-TRP/CAA ratio was significantly lower in depressed subjects than in normal control subjects. The lowest L-TRP/CAA values were observed in subjects with simple major depression and melancholia. The number of subjects with lower L-TRP/ CAA values differed significantly among the four study groups. Up to 77.4% of the major depressed subjects showed lower L-TRP/CAA values with a specificity of 96.7% and a PV of 95.9%; the area under the ROC plot was 92.6%. Table 3 shows that up to 43.0% of the variance in the L-TRP/ CAA ratio was explained by diagnostic classification.' ―Maes

'IFNy and Major Depression. IFNy secretion was significantly higher in major depressed subjects (mean = 710 IU/ml, SD = 775) than in normal control subjects (mean = 206 IU/ml, SD = 244). These differences remained significant after covariation for age.' ―Maes

'IFNy and Depression. The second major finding of this study is the significantly increased IFNγ secretion in culture supernatant of mitogen-stimulated PBMC of major depressed subjects compared with normal control subjects. It has been suggested that disturbances in cytokine synthesis or secretion (e.g., IFNγ) can best be studied under dynamic conditions by stimulating immunocompetent cells with polyclonal activators and that the pattern of cytokine production offers an index of in vivo cytokine secretion. Since it is known that IFNγ is released from activated immune T cells, the present results corroborate our previous findings that major depression is characterized by T-cell activation.' ―Maes

'L-TRP Availability and Depression. This study replicates previous findings on lower total L-TRP availability in major depressed patients compared with normal control subjects. In the present study group, lower L-TRP/CAA values were highly sensitive and specific for major depression: up to 77% (sensitivity) of major depressed patients exhibited lower L-TRP/CAA values with a specificity and predictive value of 97% and 96%, respectively.' ―Maes

'This may be explained by the fact that the major depression-related hypersecretion of IFNγ is the common denominator of both phenomena. However, the putative relationship between activation of cell-mediated immunity and lower L-TRP availability in depression may not only be explained by increased IFNγ secretion, but also by IL-l and IL-6-related mechanisms. These cytokines may induce muscle proteolysis and increased uptake of amino acids into hepatocytes for the synthesis of APPs and secretory proteins.' ―Maes​

 

[pimpnamedraypeat]

During the last century, US children were taught that US Manifest Destiny and Democracy was God ordained so that they would dutifully go off to war to spread "Western values" to the world. Now that the world has been so homogenized by a 100 years of war and is ready for one world government, the American Superpower is no longer needed and must be destroyed. What you may think is the truth is actually the latest in state sponsored propaganda designed to help bring about this end. It is what is taught in public schools today, and spouted by the vast majority of SJWs on campus who dutifully say "America was never great." You have only traded in the old BS hullabaloo for the new. The real truth lies in neither of those extremes but somewhere in the middle.

I did, the only role they played in the colonies was through trade and most famously in starting the Boston tea party by changing the laws to favor their tea from China but that was about it.

You're getting defensive about the US like it's part of your identity. Perhaps it is. If so congrats for drinking the kool aid. Don't get into the cognitive dissonance of defending America because you think its under atack from nefarious sources. America is itself nefarious. It's a ***t country and the actions it engages in overtly and covertly are unforgivable.

The original colonies were land holding colonization companies based off the east india company. Nothing to with what you were taught in school.

I suppose we'll find out. I don't watch television so I really have no idea about the latest political shenanigans, but I've read enough about science to know whether their explanations are impossible or not. How people can still believe the Warren Commission's explanation, and NIST's explanation, is beyond me. But not really; the television merely presents an unflattering archetype of the people interested in non‐official—but more realistic and factual—explanations; most people are more than ready avoid those ideas for that reason. Disinformation is also a big issue, as anyone who just dabbles in certain areas can come out being completely nonplussed or believing in something totally absurd.

I was referring more to the end of the holocene and the coming of a new ice age. It's something I wanted to get your hot take on. It's not your field of expertise but I figured your high g would carry over well.

The basic gist is that global warming is a hoax (which we all know) but it's a hoax made to cover up what's actually happening, which is the end of the holocene and a new ice age.

The temperature is controlled by the sun and it seems like we're headed towards another solar minimum, which is a period of reduced solar activity and output as measure by the number of sunspots.

The last solar minimum was the maunder minimum in the 1600s. Millions died from freezing and starvation.

Supposedly these ice ages are preceded by natural disasters. Earthquakes, hurricanes, and volcanic explosions. Yellowstone is due to blow and the san Andreas fault is due to shift. Both volcanic eruptions and earthquakes are electrical and can be triggered by the sun. When this thing kicks off I reckon we'll be seeing a worldwide flurry of natural disasters and this time America will not be untouched. The people who I've been following on this say we have about 10 years.

Interferon-γ is released by T cells in response to foreign proteins, be they allergenic food proteins or those from an invading pathogen. This is likely the most powerful cytokine, on the same tier as interleukin-1 and TNF-α. Interferon-γ is responsible for the bald spots seen during certain parasitic infections, as it induces the transcription of phospholipase A₂ on target cells. Phospholipase goes on to cleave arachidonic acid from the cell membrane, where it is found, initiating the production of eicosanoids such as prostaglandin D₂. Gamma interferon also induces the enzyme inducible nitric oxide synthase.

But most important to the psychology of the immune response is the ability of interferon-γ to powerfully effect tryptophan metabolism. This is the only precursor for indole neurotransmitters such as serotonin and melatonin, so a reduction in this amino acid would be expected to produce psychological effects. Fernstrom has shown that brain serotonin synthesis is a direct function of the ratio of serum tryptophan over it's five competing amino acids (tyrosine, phenylalanine, leucine, isoleucine, and valine). Teleologically, it's effect on tryptophan metabolism serves to restrict this amino acid from the invading pathogen—but is entirely pathological in the case of food allergy, and serves no real beneficial function. The body does not seem capable of differentiating a seed storage protein fragment, such as wheat gluten or oat avenin, from a protein derived from an invading pathogen; the body releases interferon-γ as a response to many proteins, whether injected, inhaled, or ingested (or transdermal invasion in the case of some such parasites such as hookworm). Gamma interferon lowers tryptophan levels by inducing the enzyme indolamine diooxygenase:

'The IFN-γ-mediated IDO induction observed in vitro is consistent with the results from in vivo treatment. Plasma levels of tryptophan and urine levels of kynurenine were measured in individuals who had received iv. bolus injections of either IFN-α or IFN-γ. Plasma tryptophan levels were not altered in patients receiving IFN-α, but at 6 and 24 h after administration of IFN-γ, plasma levels were reduced and urinary kynurenine levels were elevated. In these studies it was not possible to correlate plasma tryptophan levels or urinary kynurenine levels with doses of IFN or neoplasia. Complete amino acid analysis of plasma from three patients showed that the catabolic effect was confined to tryptophan. Of the 22 amino acids examined, only tryptophan levels were significantly reduced (to 36.7% of pretreatment levels).' ―Taylor​

This is a significant reduction in tryptophan (63.3%), and would be expected to reduce brain serotonin synthesis. This would also serve to reduce new protein synthesis, perhaps explaining the thinness and weakness observed in those with with ongoing parasitic infections—an observation perhaps wrongly attributed to the insignificant 'nutrient theft' by the parasites themselves (parasites sometimes acquire the mythological ability to sequester all dietary minerals in places such as curezone.com). A reduction in any one amino acid of this magnitude would be expected to reduce new protein synthesis, and especially in the case of the relatively scarce tryptophan; serotonin is also responsible for releasing growth hormone from the pituitary. Eating enough protein—say about 100 grams per day—could be enough to overcome the reduced protein synthesis and slightly normalize the tryptophan ratio, but the induction of interferon-γ would still be a detriment. Eating more food does nothing about the prostaglandins produced; on the contrary, it would likely serve to increase them by introducing more linoleic acid.

Through interferon-γ you would expect people with severe food allergies to model those with parasitic infections. There are many parallels; parasitic infection, injection of peanut protein, and ingestion of gluten can cause hair loss. Below is a study demonstrating this, with peanut protein-sensitized mice exhibiting a type of hair loss reminiscent of mice genetically-manipulated to express interferon-γ on the skin and also canine leishmaniasis:

Li, Xui-Min. "Murine model of atopic dermatitis associated with food hypersensitivity." Journal of allergy and clinical immunology (2001)
Ciaramella, P. "A retrospective clinical study of canine leishmaniasis in 150 dogs naturally infected by Leishmania infantum." Veterinary record (1997)
Carroll, Joseph M. "Transgenic mice expressing IFN-γ in the epidermis have eczema, hair hypopigmentation, and hair loss." Journal of investigative dermatology (1997):​

And predictably: vaccination has been reported to cause hair loss.

'Within 1 day after her first dose of HBV, a 30-year-old female nurse developed mild hair loss, arthralgias, fatigue, and weakness, which lasted 1 week. One month later, her second dose was followed 1 day later by recurrent onset of hair loss and, about 2 weeks later, by recurrent arthralgias, fatigue, and weakness. Alopecia progressed for a few months until she estimated that half of her hair remained in a diffuse distribution with a thinned appearance. Her hair later regrew without treatment or workup.' ―Wise​

Nothing is associated more with hair loss than is prostaglandin D₂, an eicosanoid in which interferon-γ increases by inducing the transcription of phospolipase A₂. Of interest is the fact that the powerful hair growth drug cyclosporine A completely blocks interferon-γ production.

Ercan, A. R. "Interferon‐gamma in alopecia areata." European Journal of Dermatology (2004)
Larson, Allison R. "A prostaglandin d‐synthase‐positive mast cell gradient characterizes scalp patterning." Journal of cutaneous pathology (2014)
Garza, Luis A. "Prostaglandin D₂ inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia." Science translational medicine (2012)​

The clinical presentation of celiac disease, also characterized by very high interferon-γ levels, involves weight loss:

'This form is characterized by gastrointestinal manifestations starting between 6 and 24 months of age, after the introduction of gluten in the diet. Infants and young children typically present with impaired growth, chronic diarrhea, abdominal distention, muscle wasting and hypotonia, poor appetite, and unhappy behavior. Within weeks to months of starting to ingest gluten, weight gain velocity decreases and, finally, weight loss can be observed.' ―Fasano​

But since this involves a prominent reduction of the intestinal villi, and likely reduced absorption of certain things, this is not conclusive. However, alopecia is also observed in celiac disease—a condition dominated by interferon-γ.

Corazza, Gino R. "Celiac disease and alopecia areata: report of a new association." Gastroenterology (1995)
Fasano, Alessio. "Clinical presentation of celiac disease in the pediatric population." Gastroenterology (2005)
Nilsen, Ellen M. "Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease." Gastroenterology (1998)​

Celiac disease isn't the best model since gluten also has exorphins—small peptides about five amino acids in length—which act through the δ-opioid receptor; this raises prolactin and perhaps causes psycho-opiate effects.

This may seem speculative to those who haven't read many of these studies, but it's not really. I found one person who thinks along these lines, will confirm many things I had written, and has conducted an interesting study on this topic:

Maes, Michael. "Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response." Psychiatry research (1994)​

(Neopterin is a product of GTP, usually found increased in proportion with interferon-γ.)

'However, immune responses may be accompanied by signs of immune activation (e.g., hypersecretion of cytokines and prostaglandins, T-cell activation) as well as immunosuppression.' ―Maes

'Recently, it was suggested that lower plasma L-tryptophan (L-TRP) levels, which frequently occur in major depression, may be related to the immune response. Indeed, our laboratory found significant inverse relationships between various immune or inflammatory markers and plasma L-TRP concentrations or the L-TRP/competing amino acid (CAA) ratio [The Fernstrom Ratio]. Activation of cell-mediated immunity is known to accelerate L-TRP catabolism through induction of indoleamine 2,3-dioxygenase, with subsequent depletion of plasma L-TRP. This phenomenon could compromise central serotonergic turnover, since L-TRP plasma concentration or the L-TRP/CAA ratio provides an index of the availability of L-TRP to the brain (Fernstrom et al., 1973; Fernstrom, 1984; Moller et al., 1986), which, in part, determines central serotonin synthesis (Moir and Eccleston, 1968; Fernstrom and Faller, 1977). '―Maes

'Procedures. In study group I, fasting blood samples were collected at 8 a.m. for determination of plasma neopterin, L-TRP, valine, leucine, isoleucine, tyrosine, and phenylalanine.' ―Maes

'Table 2 shows that the L-TRP/CAA ratio was significantly lower in depressed subjects than in normal control subjects. The lowest L-TRP/CAA values were observed in subjects with simple major depression and melancholia. The number of subjects with lower L-TRP/ CAA values differed significantly among the four study groups. Up to 77.4% of the major depressed subjects showed lower L-TRP/CAA values with a specificity of 96.7% and a PV of 95.9%; the area under the ROC plot was 92.6%. Table 3 shows that up to 43.0% of the variance in the L-TRP/ CAA ratio was explained by diagnostic classification.' ―Maes

'IFNy and Major Depression. IFNy secretion was significantly higher in major depressed subjects (mean = 710 IU/ml, SD = 775) than in normal control subjects (mean = 206 IU/ml, SD = 244). These differences remained significant after covariation for age.' ―Maes

'IFNy and Depression. The second major finding of this study is the significantly increased IFNγ secretion in culture supernatant of mitogen-stimulated PBMC of major depressed subjects compared with normal control subjects. It has been suggested that disturbances in cytokine synthesis or secretion (e.g., IFNγ) can best be studied under dynamic conditions by stimulating immunocompetent cells with polyclonal activators and that the pattern of cytokine production offers an index of in vivo cytokine secretion. Since it is known that IFNγ is released from activated immune T cells, the present results corroborate our previous findings that major depression is characterized by T-cell activation.' ―Maes

'L-TRP Availability and Depression. This study replicates previous findings on lower total L-TRP availability in major depressed patients compared with normal control subjects. In the present study group, lower L-TRP/CAA values were highly sensitive and specific for major depression: up to 77% (sensitivity) of major depressed patients exhibited lower L-TRP/CAA values with a specificity and predictive value of 97% and 96%, respectively.' ―Maes

'This may be explained by the fact that the major depression-related hypersecretion of IFNγ is the common denominator of both phenomena. However, the putative relationship between activation of cell-mediated immunity and lower L-TRP availability in depression may not only be explained by increased IFNγ secretion, but also by IL-l and IL-6-related mechanisms. These cytokines may induce muscle proteolysis and increased uptake of amino acids into hepatocytes for the synthesis of APPs and secretory proteins.' ―Maes​

It doesn't sound speculative at all. It's something I feel intuitively from having had gluten allergy and chronic infections. They feel the same and function the same. When i eat something with gluten i get strong inflammation on my hairline the next day. Joints hurt, feel tired and groggy, can't think well. Liable to have overemotional reaction and ruminate over bad thoughts. When I get sick and my infections flare up my hairline also suffers and I get many of the same symptoms. Same with hangovers.

It makes sense that the body would have a main route that it takes when dealing with these stressors to the body and it seems like interferon y and the serotonin reaction is that main route.

 

[Travis]

Perhaps, but I looked a bit more into histamine. This is another, small molecule neurotransmitter involved in the immune response. Under an allergenic challenge, you'd expect high histamine along with low serotonin. Here are some quotes from a review article (it would be interesting to read the individual studies):

'Aggressive behaviour: Strong evidence from studies with animals suggests that drugs which modify brain histamine activity also alter aggressive behaviour. Furthermore, there is some evidence for distinct H₁ and H₂ receptor mechanisms. Several types of aggressive behaviour have been studied. One is fighting behaviour in mice. This can be induced by putting two previously isolated male mice into the same cage. Alternatively, pairs of mice or rats are given electric shocks to their feet, eliciting aggressive interactions between them. A third method is to lesion the septum of rats. The other main type of aggressive behaviour studied involves inter-species interactions. Rats which spontaneously kill mice introduced into their cages are selected and used for study. Three main studies have examined the effects of compounds altering histaminergic function on shock-induced fighting. The results are not entirely consistent. Ray showed that intracerebroventricularly‐administered histamine decreased aggressive behaviour, while Nath showed that this behaviour increased as a result of histamine administration. The difference may be in the species: rats were used in the former study and mice in the latter. However, Costentin showed that a dose of the precursor histidine which was sufficient to increase brain histamine levels by 80–120% depressed shock-induced fighting in mice—a result consistent with the findings of Ray. It should also be noted that Nath used a relatively high dose: 25–100 μg compared with 5 μg used by Ray. (1981). Ray further showed that the H₁ agonist 2‐pyridylethylamine decreased aggressive behaviour and the H₂ agonist 4‐methylhistamine increased it. These effects were blocked by the respective antagonists, mepyramine and cimetidine. While these authors found no effect when the antagonists were administered by themselves, Nath reported an increase in aggressive behaviour following mepyramine administration and a decrease following metiamide. Both groups report an enhancement after combinations of histamine and mepyramine; combinations of histamine and an H₂ antagonist resulted in a decrease or no change. While there are some contradictions (which may be a result of differences in species, dose or the conditions used to elicit the behaviour), the results are fairly convincing demonstrations of the role of histaminergic systems in footshock aggression. The data suggest that activation of H₁ receptors is inhibitory and activation of the H₂ receptors facilitatory for this type of aggressive behaviour. It is interesting to observe the opposite role for H₁ and H₂ receptors, just as in so many peripheral functions. The results are somewhat different when other types of aggression are considered. H₁ antagonists have been found to suppress isolation-induced fighting in mice. The effect occurs at doses which are not producing a general suppression of motor activity. However, anticholinergics are also effective inhibitors of isolation-induced fighting and the order of potency of antihistamines in the test suggests that their anticholinergic activity may be more important than their antihistaminic activity. The only other study to examine within-species aggressive behaviour used septal‐lesioned rats and found no effect on their hyperirritabilty and aggressiveness. The results of two studies examining muricide in rats show that H₂ antagonists can decrease this behaviour. One author noted the effect only with chlorpheniramine and not with other antihistamines studied; the other group observed the same change with diphenhydramine and promethazine, but not with astemizole. Histamine itself and histamine synthesis inhibitors both suppressed muricide. To date there has been some effort to characterize the role of histaminergic mechanisms with foot-shock induced aggression only. Further research is needed to determine the roles of H₁ and H₂ receptors in other types of aggressive behaviour. Case reports from humans taking H₂ antagonists suggest that aggressive behaviour may be one adverse symptom associated with cimetidine use. Finally, several studies should be mentioned in which behaviour resembling aggression was induced by administration of histidine. Pairs of animals were observed to rear and face each other and rhythmically beat each other with their forepaws. Other characteristic patterns of rat aggressive behaviour were not present. The relationship between this" bizarre" behaviour and norreal aggression is not clear.' ―White​

The two histamine receptors antagonize each other, and biphasic effects are often noted: first an increase or a decrease in a response, followed by its opposite. These two histamine receptors are found on T cells, where the H₁ receptor acts to release interferon‐γ. Mice genetically‐manipulated to lack the H₁ receptor have essentially negligible interferon‐γ levels. Histamine directly controls interferon‐γ, and not the other way around. This sets the mast cells and the basophils on a higher regulatory level than the helper T cells which produce most relevant cytokines, so the protein–immune response likely starts here.

In a mouse model of autism, a histamine three receptor (H₃) antagonist was able to completely reverse all symptoms tested including exploratory behavior and social interaction. The Fernstrom Ratio is found lower in autism, implicating interferon‐γ and immune response. This vindicates the observational associations between autism, vaccines, and cow's milk allergy, and biopterins in the urine have been found threefold increased (another biomarker of interferon‐γ). A lower Fernstrom Ratio coupled with increased biopterins would indicate the activity of interferon‐γ, and hence the increase in histamine. The immunogenic neurotransmitter profile would then most likely be characterized by both a relative decrease in serotonin and an increase in histamine. The biopterins themselves could also be a factor.

This could explain the consistent beneficial findings of niacin in autism. Molecularly similar to histamine, this small molecule vitamin creates a flush and releases prostaglandin D₂—histamine does the exact same thing. Large doses of niacin of this type are not exerting their effects by becoming NADH, and nobody is claiming a metabolic theory of schizophrenia or autism. What niacin does, ostensibly, is serve either as a ligand of one of the histamin receptors (H₁, H₂, or H₃). Niacin also removes methyl groups from the body, an unambiguous experimental finding which could have relevance.

I think Hoffer's mechanism for niacin's effects was exceedingly drawn‐out, prolix, and indirect. It would be a great simplification if niacin were proven to bind a histamine receptor directly (or the so‐called 'niacin receptor' was also a histamine receptor).

'HISTAMINE: Current research indicates that the neurotransmitter histamine also plays an important role in the formation of schizophrenia. Although only recently acknowledged, there actually appears to be much more evidence for the etiological role of histamine rather than dopamine.' ―Heleniak

'Research in this area was done as early as 1938. Researchers at this time found that subcutaneous injections of histamine produced favorable therapeutic responses in schizophrenic patients.' ―Heleniak

'Histaminase metabolized histamine and it has been frequently noted that schizophrenics show a significantly lower incidence of colds and allergic reactions such as eczema, asthma and hayfever, when compared to the general population. They also show a reduced sensitivity to both cold and pain. In addition, schizophrenics have small wheal and flare reactions to intradermal injections of histamine. This indicates that low levels of histamine are involved. It has also been shown that a schizophrenic-like psychosis may be induced in a normal population by administering a high amount of anti-histamines, particularly the H₂ blockers.' ―Heleniak

'Direct evidence for histamine being a primary causative factor in schizophrenia, as opposed to dopmine, comes from recent work by Nakai. They found that there was a down-regulation of the H₁ receptor in the frontal cortex and suggested that this may be etiologically significant in schizophrenia. Frontal lobe H₁ receptors are involved in sleep/wakefulness, feeding/drinking, locomotor/catalepsy, and neuroendocrine regulation. Schizophrenic patients may exhibit dysfunction in any or all of these areas. Related evidence for the primacy of histamine in schizophrenia comes from the fact that schizophrenics show a scarcity of mast cells in the skin, and Stellato demonstrated how anaesthetics induce histamine release selectively from human mast cells. Taking this one step further, a lack of mast cells would lead to a histamine deficiency in these individuals.' ―Heleniak​

Heleniak, E. "Histamine and prostaglandins in schizophrenia: revisited." Medical hypotheses (1999)
Naushad, Shaik Mohammad. "Autistic children exhibit distinct plasma amino acid profile." (2013).
Messahel, S. "Urinary levels of neopterin and biopterin in autism." Neuroscience letters (1998)
White, Jason M. "Behavioural effects of histamine and its antagonists: a review." Psychopharmacology
Jutel, Marek. "Histamine regulates T-cell and antibody responses by differential expression of H₁ and H₂ receptors." Nature (2001)
Baronio, Diego. "Effects of an H₃R antagonist on the animal model of autism induced by prenatal exposure to valproic acid." PLoS One (2015)
D'Eufemia, P. "Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism." Biomedicine & pharmacotherapy (1995)

 

[Koveras]

Interferon-γ is released by T cells in response to foreign proteins, be they allergenic food proteins or those from an invading pathogen. This is likely the most powerful cytokine, on the same tier as interleukin-1 and TNF-α. Interferon-γ is responsible for the bald spots seen during certain parasitic infections, as it induces the transcription of phospholipase A₂ on target cells. Phospholipase goes on to cleave arachidonic acid from the cell membrane, where it is found, initiating the production of eicosanoids such as prostaglandin D₂. Gamma interferon also induces the enzyme inducible nitric oxide synthase.

But most important to the psychology of the immune response is the ability of interferon-γ to powerfully effect tryptophan metabolism. This is the only precursor for indole neurotransmitters such as serotonin and melatonin, so a reduction in this amino acid would be expected to produce psychological effects. Fernstrom has shown that brain serotonin synthesis is a direct function of the ratio of serum tryptophan over it's five competing amino acids (tyrosine, phenylalanine, leucine, isoleucine, and valine). Teleologically, it's effect on tryptophan metabolism serves to restrict this amino acid from the invading pathogen—but is entirely pathological in the case of food allergy, and serves no real beneficial function. The body does not seem capable of differentiating a seed storage protein fragment, such as wheat gluten or oat avenin, from a protein derived from an invading pathogen; the body releases interferon-γ as a response to many proteins, whether injected, inhaled, or ingested (or transdermal invasion in the case of some such parasites such as hookworm). Gamma interferon lowers tryptophan levels by inducing the enzyme indolamine diooxygenase:

'The IFN-γ-mediated IDO induction observed in vitro is consistent with the results from in vivo treatment. Plasma levels of tryptophan and urine levels of kynurenine were measured in individuals who had received iv. bolus injections of either IFN-α or IFN-γ. Plasma tryptophan levels were not altered in patients receiving IFN-α, but at 6 and 24 h after administration of IFN-γ, plasma levels were reduced and urinary kynurenine levels were elevated. In these studies it was not possible to correlate plasma tryptophan levels or urinary kynurenine levels with doses of IFN or neoplasia. Complete amino acid analysis of plasma from three patients showed that the catabolic effect was confined to tryptophan. Of the 22 amino acids examined, only tryptophan levels were significantly reduced (to 36.7% of pretreatment levels).' ―Taylor​

This is a significant reduction in tryptophan (63.3%), and would be expected to reduce brain serotonin synthesis. This would also serve to reduce new protein synthesis, perhaps explaining the thinness and weakness observed in those with with ongoing parasitic infections—an observation perhaps wrongly attributed to the insignificant 'nutrient theft' by the parasites themselves (parasites sometimes acquire the mythological ability to sequester all dietary minerals in places such as curezone.com). A reduction in any one amino acid of this magnitude would be expected to reduce new protein synthesis, and especially in the case of the relatively scarce tryptophan; serotonin is also responsible for releasing growth hormone from the pituitary. Eating enough protein—say about 100 grams per day—could be enough to overcome the reduced protein synthesis and slightly normalize the tryptophan ratio, but the induction of interferon-γ would still be a detriment. Eating more food does nothing about the prostaglandins produced; on the contrary, it would likely serve to increase them by introducing more linoleic acid.

Through interferon-γ you would expect people with severe food allergies to model those with parasitic infections. There are many parallels; parasitic infection, injection of peanut protein, and ingestion of gluten can cause hair loss. Below is a study demonstrating this, with peanut protein-sensitized mice exhibiting a type of hair loss reminiscent of mice genetically-manipulated to express interferon-γ on the skin and also canine leishmaniasis:

Li, Xui-Min. "Murine model of atopic dermatitis associated with food hypersensitivity." Journal of allergy and clinical immunology (2001)
Ciaramella, P. "A retrospective clinical study of canine leishmaniasis in 150 dogs naturally infected by Leishmania infantum." Veterinary record (1997)
Carroll, Joseph M. "Transgenic mice expressing IFN-γ in the epidermis have eczema, hair hypopigmentation, and hair loss." Journal of investigative dermatology (1997):​

And predictably: vaccination has been reported to cause hair loss.

'Within 1 day after her first dose of HBV, a 30-year-old female nurse developed mild hair loss, arthralgias, fatigue, and weakness, which lasted 1 week. One month later, her second dose was followed 1 day later by recurrent onset of hair loss and, about 2 weeks later, by recurrent arthralgias, fatigue, and weakness. Alopecia progressed for a few months until she estimated that half of her hair remained in a diffuse distribution with a thinned appearance. Her hair later regrew without treatment or workup.' ―Wise​

Nothing is associated more with hair loss than is prostaglandin D₂, an eicosanoid in which interferon-γ increases by inducing the transcription of phospolipase A₂. Of interest is the fact that the powerful hair growth drug cyclosporine A completely blocks interferon-γ production.

Ercan, A. R. "Interferon‐gamma in alopecia areata." European Journal of Dermatology (2004)
Larson, Allison R. "A prostaglandin d‐synthase‐positive mast cell gradient characterizes scalp patterning." Journal of cutaneous pathology (2014)
Garza, Luis A. "Prostaglandin D₂ inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia." Science translational medicine (2012)​

The clinical presentation of celiac disease, also characterized by very high interferon-γ levels, involves weight loss:

'This form is characterized by gastrointestinal manifestations starting between 6 and 24 months of age, after the introduction of gluten in the diet. Infants and young children typically present with impaired growth, chronic diarrhea, abdominal distention, muscle wasting and hypotonia, poor appetite, and unhappy behavior. Within weeks to months of starting to ingest gluten, weight gain velocity decreases and, finally, weight loss can be observed.' ―Fasano​

But since this involves a prominent reduction of the intestinal villi, and likely reduced absorption of certain things, this is not conclusive. However, alopecia is also observed in celiac disease—a condition dominated by interferon-γ.

Corazza, Gino R. "Celiac disease and alopecia areata: report of a new association." Gastroenterology (1995)
Fasano, Alessio. "Clinical presentation of celiac disease in the pediatric population." Gastroenterology (2005)
Nilsen, Ellen M. "Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease." Gastroenterology (1998)​

Celiac disease isn't the best model since gluten also has exorphins—small peptides about five amino acids in length—which act through the δ-opioid receptor; this raises prolactin and perhaps causes psycho-opiate effects.

This may seem speculative to those who haven't read many of these studies, but it's not really. I found one person who thinks along these lines, will confirm many things I had written, and has conducted an interesting study on this topic:

Maes, Michael. "Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response." Psychiatry research (1994)​

(Neopterin is a product of GTP, usually found increased in proportion with interferon-γ.)

'However, immune responses may be accompanied by signs of immune activation (e.g., hypersecretion of cytokines and prostaglandins, T-cell activation) as well as immunosuppression.' ―Maes

'Recently, it was suggested that lower plasma L-tryptophan (L-TRP) levels, which frequently occur in major depression, may be related to the immune response. Indeed, our laboratory found significant inverse relationships between various immune or inflammatory markers and plasma L-TRP concentrations or the L-TRP/competing amino acid (CAA) ratio [The Fernstrom Ratio]. Activation of cell-mediated immunity is known to accelerate L-TRP catabolism through induction of indoleamine 2,3-dioxygenase, with subsequent depletion of plasma L-TRP. This phenomenon could compromise central serotonergic turnover, since L-TRP plasma concentration or the L-TRP/CAA ratio provides an index of the availability of L-TRP to the brain (Fernstrom et al., 1973; Fernstrom, 1984; Moller et al., 1986), which, in part, determines central serotonin synthesis (Moir and Eccleston, 1968; Fernstrom and Faller, 1977). '―Maes

'Procedures. In study group I, fasting blood samples were collected at 8 a.m. for determination of plasma neopterin, L-TRP, valine, leucine, isoleucine, tyrosine, and phenylalanine.' ―Maes

'Table 2 shows that the L-TRP/CAA ratio was significantly lower in depressed subjects than in normal control subjects. The lowest L-TRP/CAA values were observed in subjects with simple major depression and melancholia. The number of subjects with lower L-TRP/ CAA values differed significantly among the four study groups. Up to 77.4% of the major depressed subjects showed lower L-TRP/CAA values with a specificity of 96.7% and a PV of 95.9%; the area under the ROC plot was 92.6%. Table 3 shows that up to 43.0% of the variance in the L-TRP/ CAA ratio was explained by diagnostic classification.' ―Maes

'IFNy and Major Depression. IFNy secretion was significantly higher in major depressed subjects (mean = 710 IU/ml, SD = 775) than in normal control subjects (mean = 206 IU/ml, SD = 244). These differences remained significant after covariation for age.' ―Maes

'IFNy and Depression. The second major finding of this study is the significantly increased IFNγ secretion in culture supernatant of mitogen-stimulated PBMC of major depressed subjects compared with normal control subjects. It has been suggested that disturbances in cytokine synthesis or secretion (e.g., IFNγ) can best be studied under dynamic conditions by stimulating immunocompetent cells with polyclonal activators and that the pattern of cytokine production offers an index of in vivo cytokine secretion. Since it is known that IFNγ is released from activated immune T cells, the present results corroborate our previous findings that major depression is characterized by T-cell activation.' ―Maes

'L-TRP Availability and Depression. This study replicates previous findings on lower total L-TRP availability in major depressed patients compared with normal control subjects. In the present study group, lower L-TRP/CAA values were highly sensitive and specific for major depression: up to 77% (sensitivity) of major depressed patients exhibited lower L-TRP/CAA values with a specificity and predictive value of 97% and 96%, respectively.' ―Maes

'This may be explained by the fact that the major depression-related hypersecretion of IFNγ is the common denominator of both phenomena. However, the putative relationship between activation of cell-mediated immunity and lower L-TRP availability in depression may not only be explained by increased IFNγ secretion, but also by IL-l and IL-6-related mechanisms. These cytokines may induce muscle proteolysis and increased uptake of amino acids into hepatocytes for the synthesis of APPs and secretory proteins.' ―Maes​

I've seen similar research in regards to gastrointestinal research - and although the researchers suggest that a 'tryptophan deficiency' could be contributing to the pathology - I'm not convinced that it wouldn't just continue to serve as substrate for additional serotonin, quinolinic acid, et al in the presence of whatever stressor is there.

Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases.
Nikolaus S1, Schulte B1, Al-Massad N1, Thieme F2, Schulte DM1, Bethge J1, Rehman A3, Tran F4, Aden K4, Häsler R3, Moll N5, Schütze G5, Schwarz MJ5, Waetzig GH6, Rosenstiel P3, Krawczak M7, Szymczak S7, Schreiber S8.
BACKGROUND & AIMS:
Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features.
METHODS:
We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits.
RESULTS:
Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10-6) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10-10) than UC (vs control; P = 2.8 × 10-3). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan.
CONCLUSIONS:
In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-especially of quinolinic acid-indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.​

 

[lollipop]

Excuse me, I haven’t followed the thread so forgive me if this has already been discussed and/or posted. They found parasites in Ancient Greece:

https://www.sciencedaily.com/releases/2017/12/171215094521.htm

 

[Koveras]

I've seen similar research in regards to gastrointestinal research - and although the researchers suggest that a 'tryptophan deficiency' could be contributing to the pathology - I'm not convinced that it wouldn't just continue to serve as substrate for additional serotonin, quinolinic acid, et al in the presence of whatever stressor is there.

Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases.
Nikolaus S1, Schulte B1, Al-Massad N1, Thieme F2, Schulte DM1, Bethge J1, Rehman A3, Tran F4, Aden K4, Häsler R3, Moll N5, Schütze G5, Schwarz MJ5, Waetzig GH6, Rosenstiel P3, Krawczak M7, Szymczak S7, Schreiber S8.
BACKGROUND & AIMS:
Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features.
METHODS:
We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits.
RESULTS:
Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10-6) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10-10) than UC (vs control; P = 2.8 × 10-3). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan.
CONCLUSIONS:
In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-especially of quinolinic acid-indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.​

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@Travis

You might also be interested in this one

Excretion of tryptophan metabolites in different forms of haemoblastosis

They looked at some of the tryptophan pathway metabolites as well as the effect of tryptophan loading, and vitamin B6

"The response of 10 patients with Hodgkin’s disease, whose kynurenine excretion was not influenced by previous treatments, to the administration of vitamin
B6, either as pyridoxine hydrochloride or as pyridoxal-5-phosphate, seemed to be consistent. Vitamin B6, always caused a quantitative decrease of kynurenine and 3-
hydroxykynurenine and very often normalised the excretion of these derivatives. It was possible to follow such an effect by observing the increase of 3-hydroxyanthranilic acid above normal levels."

"The execution of a contemporaneous determination of several products of the tryptophan degradation pathway allowed us to investigate also the fate of tryptophan when administered in large doses, and to obtain a more complete picture of its metabolism in Hodgkin’s disease patients. It is evident from the analysis of our data that all Hodgkin’s patients showed a peculiar behaviour in regard to tryptophan metabolism, either through spontaneous excretion of its products or after a loading test. At this point, another observation should be made. The spontaneous excretion of abnormal levels of metabolites was corrected by large doses of vitamin B6, in a relatively short time, whereas contemporaneous loads of pyridoxine and tryptophan caused only a slight decrease in the percent of urinary metabolites. The effect of vitamin B6, administration, in this case, was especially to normalize the N-a-acetylkynurenine and 3-hydroxykynurenine excretion, to decrease that of kynurenine, kynurenic and xanthurenic acids, and consistently to increase the urinary 3-hydroxyanthranilic acid. "

"From the results presented here, it appears that tryptophan disorders in haemoblastosis are only partially related to a vitamin B6 deficiency. Very likely, other enzymatic disturbances, closely related to the diseases, could contribute to producing abnormal amounts of tryptophan metabolites excreted by many of these patients. "

I wonder if the other enzymatic disturbances they are speculating about relate to the activation of IDO by interferon gamma and/or by interleukin-6.

I also wonder if a portion of Vitamin B6's therapeutic action could be ascribed to its ability to lower prolactin.

 

[x-ray peat]

You're getting defensive about the US like it's part of your identity. Perhaps it is. If so congrats for drinking the kool aid. Don't get into the cognitive dissonance of defending America because you think its under atack from nefarious sources. America is itself nefarious. It's a ***t country and the actions it engages in overtly and covertly are unforgivable.

'Insults are the last resort of insecure people trying to appear confident in their weak position.'

The original colonies were land holding colonization companies based off the east india company. Nothing to with what you were taught in school.

still not right, care to walk this back a third time?

 

[Koveras]

Interferon-γ is released by T cells in response to foreign proteins, be they allergenic food proteins or those from an invading pathogen. This is likely the most powerful cytokine, on the same tier as interleukin-1 and TNF-α. Interferon-γ is responsible for the bald spots seen during certain parasitic infections, as it induces the transcription of phospholipase A₂ on target cells. Phospholipase goes on to cleave arachidonic acid from the cell membrane, where it is found, initiating the production of eicosanoids such as prostaglandin D₂. Gamma interferon also induces the enzyme inducible nitric oxide synthase.

But most important to the psychology of the immune response is the ability of interferon-γ to powerfully effect tryptophan metabolism. This is the only precursor for indole neurotransmitters such as serotonin and melatonin, so a reduction in this amino acid would be expected to produce psychological effects. Fernstrom has shown that brain serotonin synthesis is a direct function of the ratio of serum tryptophan over it's five competing amino acids (tyrosine, phenylalanine, leucine, isoleucine, and valine). Teleologically, it's effect on tryptophan metabolism serves to restrict this amino acid from the invading pathogen—but is entirely pathological in the case of food allergy, and serves no real beneficial function. The body does not seem capable of differentiating a seed storage protein fragment, such as wheat gluten or oat avenin, from a protein derived from an invading pathogen; the body releases interferon-γ as a response to many proteins, whether injected, inhaled, or ingested (or transdermal invasion in the case of some such parasites such as hookworm). Gamma interferon lowers tryptophan levels by inducing the enzyme indolamine diooxygenase:

'The IFN-γ-mediated IDO induction observed in vitro is consistent with the results from in vivo treatment. Plasma levels of tryptophan and urine levels of kynurenine were measured in individuals who had received iv. bolus injections of either IFN-α or IFN-γ. Plasma tryptophan levels were not altered in patients receiving IFN-α, but at 6 and 24 h after administration of IFN-γ, plasma levels were reduced and urinary kynurenine levels were elevated. In these studies it was not possible to correlate plasma tryptophan levels or urinary kynurenine levels with doses of IFN or neoplasia. Complete amino acid analysis of plasma from three patients showed that the catabolic effect was confined to tryptophan. Of the 22 amino acids examined, only tryptophan levels were significantly reduced (to 36.7% of pretreatment levels).' ―Taylor​

This is a significant reduction in tryptophan (63.3%), and would be expected to reduce brain serotonin synthesis. This would also serve to reduce new protein synthesis, perhaps explaining the thinness and weakness observed in those with with ongoing parasitic infections—an observation perhaps wrongly attributed to the insignificant 'nutrient theft' by the parasites themselves (parasites sometimes acquire the mythological ability to sequester all dietary minerals in places such as curezone.com). A reduction in any one amino acid of this magnitude would be expected to reduce new protein synthesis, and especially in the case of the relatively scarce tryptophan; serotonin is also responsible for releasing growth hormone from the pituitary. Eating enough protein—say about 100 grams per day—could be enough to overcome the reduced protein synthesis and slightly normalize the tryptophan ratio, but the induction of interferon-γ would still be a detriment. Eating more food does nothing about the prostaglandins produced; on the contrary, it would likely serve to increase them by introducing more linoleic acid.

Through interferon-γ you would expect people with severe food allergies to model those with parasitic infections. There are many parallels; parasitic infection, injection of peanut protein, and ingestion of gluten can cause hair loss. Below is a study demonstrating this, with peanut protein-sensitized mice exhibiting a type of hair loss reminiscent of mice genetically-manipulated to express interferon-γ on the skin and also canine leishmaniasis:

Li, Xui-Min. "Murine model of atopic dermatitis associated with food hypersensitivity." Journal of allergy and clinical immunology (2001)
Ciaramella, P. "A retrospective clinical study of canine leishmaniasis in 150 dogs naturally infected by Leishmania infantum." Veterinary record (1997)
Carroll, Joseph M. "Transgenic mice expressing IFN-γ in the epidermis have eczema, hair hypopigmentation, and hair loss." Journal of investigative dermatology (1997):​

And predictably: vaccination has been reported to cause hair loss.

'Within 1 day after her first dose of HBV, a 30-year-old female nurse developed mild hair loss, arthralgias, fatigue, and weakness, which lasted 1 week. One month later, her second dose was followed 1 day later by recurrent onset of hair loss and, about 2 weeks later, by recurrent arthralgias, fatigue, and weakness. Alopecia progressed for a few months until she estimated that half of her hair remained in a diffuse distribution with a thinned appearance. Her hair later regrew without treatment or workup.' ―Wise​

Nothing is associated more with hair loss than is prostaglandin D₂, an eicosanoid in which interferon-γ increases by inducing the transcription of phospolipase A₂. Of interest is the fact that the powerful hair growth drug cyclosporine A completely blocks interferon-γ production.

Ercan, A. R. "Interferon‐gamma in alopecia areata." European Journal of Dermatology (2004)
Larson, Allison R. "A prostaglandin d‐synthase‐positive mast cell gradient characterizes scalp patterning." Journal of cutaneous pathology (2014)
Garza, Luis A. "Prostaglandin D₂ inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia." Science translational medicine (2012)​

The clinical presentation of celiac disease, also characterized by very high interferon-γ levels, involves weight loss:

'This form is characterized by gastrointestinal manifestations starting between 6 and 24 months of age, after the introduction of gluten in the diet. Infants and young children typically present with impaired growth, chronic diarrhea, abdominal distention, muscle wasting and hypotonia, poor appetite, and unhappy behavior. Within weeks to months of starting to ingest gluten, weight gain velocity decreases and, finally, weight loss can be observed.' ―Fasano​

But since this involves a prominent reduction of the intestinal villi, and likely reduced absorption of certain things, this is not conclusive. However, alopecia is also observed in celiac disease—a condition dominated by interferon-γ.

Corazza, Gino R. "Celiac disease and alopecia areata: report of a new association." Gastroenterology (1995)
Fasano, Alessio. "Clinical presentation of celiac disease in the pediatric population." Gastroenterology (2005)
Nilsen, Ellen M. "Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease." Gastroenterology (1998)​

Celiac disease isn't the best model since gluten also has exorphins—small peptides about five amino acids in length—which act through the δ-opioid receptor; this raises prolactin and perhaps causes psycho-opiate effects.

This may seem speculative to those who haven't read many of these studies, but it's not really. I found one person who thinks along these lines, will confirm many things I had written, and has conducted an interesting study on this topic:

Maes, Michael. "Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response." Psychiatry research (1994)​

(Neopterin is a product of GTP, usually found increased in proportion with interferon-γ.)

'However, immune responses may be accompanied by signs of immune activation (e.g., hypersecretion of cytokines and prostaglandins, T-cell activation) as well as immunosuppression.' ―Maes

'Recently, it was suggested that lower plasma L-tryptophan (L-TRP) levels, which frequently occur in major depression, may be related to the immune response. Indeed, our laboratory found significant inverse relationships between various immune or inflammatory markers and plasma L-TRP concentrations or the L-TRP/competing amino acid (CAA) ratio [The Fernstrom Ratio]. Activation of cell-mediated immunity is known to accelerate L-TRP catabolism through induction of indoleamine 2,3-dioxygenase, with subsequent depletion of plasma L-TRP. This phenomenon could compromise central serotonergic turnover, since L-TRP plasma concentration or the L-TRP/CAA ratio provides an index of the availability of L-TRP to the brain (Fernstrom et al., 1973; Fernstrom, 1984; Moller et al., 1986), which, in part, determines central serotonin synthesis (Moir and Eccleston, 1968; Fernstrom and Faller, 1977). '―Maes

'Procedures. In study group I, fasting blood samples were collected at 8 a.m. for determination of plasma neopterin, L-TRP, valine, leucine, isoleucine, tyrosine, and phenylalanine.' ―Maes

'Table 2 shows that the L-TRP/CAA ratio was significantly lower in depressed subjects than in normal control subjects. The lowest L-TRP/CAA values were observed in subjects with simple major depression and melancholia. The number of subjects with lower L-TRP/ CAA values differed significantly among the four study groups. Up to 77.4% of the major depressed subjects showed lower L-TRP/CAA values with a specificity of 96.7% and a PV of 95.9%; the area under the ROC plot was 92.6%. Table 3 shows that up to 43.0% of the variance in the L-TRP/ CAA ratio was explained by diagnostic classification.' ―Maes

'IFNy and Major Depression. IFNy secretion was significantly higher in major depressed subjects (mean = 710 IU/ml, SD = 775) than in normal control subjects (mean = 206 IU/ml, SD = 244). These differences remained significant after covariation for age.' ―Maes

'IFNy and Depression. The second major finding of this study is the significantly increased IFNγ secretion in culture supernatant of mitogen-stimulated PBMC of major depressed subjects compared with normal control subjects. It has been suggested that disturbances in cytokine synthesis or secretion (e.g., IFNγ) can best be studied under dynamic conditions by stimulating immunocompetent cells with polyclonal activators and that the pattern of cytokine production offers an index of in vivo cytokine secretion. Since it is known that IFNγ is released from activated immune T cells, the present results corroborate our previous findings that major depression is characterized by T-cell activation.' ―Maes

'L-TRP Availability and Depression. This study replicates previous findings on lower total L-TRP availability in major depressed patients compared with normal control subjects. In the present study group, lower L-TRP/CAA values were highly sensitive and specific for major depression: up to 77% (sensitivity) of major depressed patients exhibited lower L-TRP/CAA values with a specificity and predictive value of 97% and 96%, respectively.' ―Maes

'This may be explained by the fact that the major depression-related hypersecretion of IFNγ is the common denominator of both phenomena. However, the putative relationship between activation of cell-mediated immunity and lower L-TRP availability in depression may not only be explained by increased IFNγ secretion, but also by IL-l and IL-6-related mechanisms. These cytokines may induce muscle proteolysis and increased uptake of amino acids into hepatocytes for the synthesis of APPs and secretory proteins.' ―Maes​

Int J Tryptophan Res. 2016 Dec 7;9:89-93. eCollection 2016.
Progesterone Alters Kynurenine Pathway Activation in IFN-γ-Activated Macrophages - Relevance for Neuroinflammatory Diseases.
de Bie J1, Lim CK1, Guillemin GJ1.
We have previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in many inflammatory disorders that are often associated with sexual dimorphisms. We aimed to identify a potential functional interaction between the KP and gonadal hormones. We have treated primary human macrophages with progesterone in the presence and absence of inflammatory cytokine interferon-gamma (interferon-γ) that is known to be a potent inducer of regulating the KP enzyme. We found that progesterone attenuates interferon-γ-induced KP activity, decreases the levels of the excitotoxin quinolinic acid, and increases the neuroprotective kynurenic acid levels. We also showed that progesterone was able to reduce the inflammatory marker neopterin. These results may shed light on the gender disparity in response to inflammation.

 

[Travis]

I've seen similar research in regards to gastrointestinal research - and although the researchers suggest that a 'tryptophan deficiency' could be contributing to the pathology - I'm not convinced that it wouldn't just continue to serve as substrate for additional serotonin, quinolinic acid, et al in the presence of whatever stressor is there.

I'm starting to think that histamine is more important in the brains of people dominated by interferon‐γ. Of course the kyneurenine metabolites and biopterins are increased as well, but histamine is a neurotransmitter with its own receptors and powerful effects. Most all studies which measure low tryptophan during infection don't measure histamine, but I think you can assume it to present in amounts proportional to interferon‐γ. Histamine released by mast cells appears to be requisite for interferon‐γ formation.

Histamine is an imidazole, and has an aminoethane tail. As as endogenous neurotransmitter that does not change form—a neuromodulator—I would place it in the same category as serotonin and melatonin. The excitatory neurotransmitters acetylcholine and glutamate aren't fluorescent, nor are they psychedelic, so I view these as belonging to separate category: the apathetic neurotransmitters. The catecholamines don't appear psychedelic either, but seem to act primarily to donate electrons. Only after donating four electrons does dopamine become psychedelic when it becomes the indole aminochrome. Epinephrine behaves similarly, and becomes the psychedelic adrenochrome upon oxidation.

Most neurotransmitters appear simply to control nerve speed, or thought velocity, and perhaps can be eliminated from consideration in the etiology of sympathetic conditions such as autism (though, these are the natural suspects behind conditions such as ADD). It is interesting to note that the brain has its own histamine, and this is highly variable. It would appear that histamine is the most variable neurotransmitter between members of the normal population; that is to say, it appears to have the greatest range:

From: Persinger, Michael A. "Mast cells in the brain: possibilities for physiological psychology." Physiological Psychology (1977)

'Dropp reported between 0 and 1,500 total mast cell numbers within the brains of squirrel monkeys, but found no brain mast cells within five mulatta monkeys; three chimpanzees displayed 8,600, 15,470 and 69,570 total brain mast cells. Thirteen cat brains analyzed by Dropp displayed total mast cells ranging from 144 to 203,226. The median value for seven meadow voles was 180 total brain mast cells.' ―Persinger

'The laboratory rat demonstrates a similar marked intraspecies variation. Total brain mast cells (MCs) ranged between 333 and 4,358 in 10 hooded rats and between 632 and 1,205 in 3 albino rats. Unpublished data from my laboratory indicates that some albino rat brains may show even greater MC concentrations. Twelve 100-day-old Wistar-strain male and female rats whose brains had been fixed in E.F.A. and stained with the Thionin method showed total MC (as identified by morphology and metachromasia) numbers ranging from 5,230 to 10,144 within the diencephalon alone. Total thalamic MCs from four 240-day-old normal male Wistar rats ranged from 3,328 to 4,050.' ―Persinger

'In rat brain, the age-related peak and decline in MC numbers are reflected in whole brain histamine concentrations which achieve maxima in the 2- to 6-day-old rat brain but rapidly decrease after Postnatal Day 10.' ―Persinger
​

For Hans Selye fans—such as @DaveFoster—the author is familiar with Hans Selye's 1965 book entitled "The Mast Cells" and chronically cites it:

'Simple calculations indicate that MCs could contain significant proportions of whole brain histamine in the rat. Assumptions are usually made that a brain MC contains histamine concentrations similar to that of a nonneural MC, e.g., peritoneal MC, which can contain between 7 pg/cell and 32 pg/cell (Selye, 1965) of this.substance; to this experimenter's knowledge, no direct measurements of histamine concentrations within CNS MCs have been reported. If each brain MC did contain 10 pg of histamine, then a 100-day-old rat containing 2,000 MCs would sequester 20 ng of brain histamine; a rat containing 7,000 MCs could involve 70 ng of brain histamine. Whole-brain total concentrations of histamine range from 50 ng to 250 ng, depending upon assay technique. Assuming total adult rat brain histamine values of 70 ng made by Green and Erikson (1964), as an example, then brain MCs could account for a significant, if not a major, portion of total brain histamine. Similarly, in the 1-week-old rat brain , which contains about 300 ng of histamine and averages 38,037 MCs, MCs could contain almost all brain histamine. Similar calculations have been made by Dropp and Kruger.' ―Persinger

'The contribution of histamine-related processes to behavioral pathology has been suspected since the time that: (1) allergic reactions were infrequently found in psychotics, and (2) it was noted that some patients alternated between allergies and psychosis. Indeed, elevations of blood histamine levels are known to occur in schizophrenics, especially acute cases, and more recently, Heath (1971) reported marked similarities between electroencephalographic changes induced by known "psychosis-inducing" immunoglobulins and histamine when these compounds were injected directly into the brains of primates. These observations superficially support a MC involvement, since chlorpromazine, a major tranquilizer, displays antihistamine properties and has deleterious effects upon nonneural MC function.' ―Persinger

​

So we have a fivefold range of histidine in the rat brain. Could this neurotransmitter do even half of what they say it can do, this interpersonal range would likely be of greater significance than the 66% reduction in plasma tryptophan seen during chronic interferon-γ-dominated immune response. I think histamine can describe autism, at least, the best. It shows why both vaccines, gluten, and casein have been strongly implicated: these lead to histamine, a neurotransmitter with great interpersonal variation shown to cause similar behavioural symptoms in rats.

@TravisI wonder if the other enzymatic disturbances they are speculating about relate to the activation of IDO by interferon gamma and/or by interleukin-6.

Don't forget about interleukin‐7, which also removes tryptophan from the blood during infection and sends it down the serotonin pathway. I think allergenic (protein) immune stimulation involves a net loss in brain serotonin, since plasma serotonin cannot reach the brain in any considerable extent (bound to platelets). Tryptophan bound to serum albumin appears to be the only indole capable of crossing the blood brain barrier.

Is there anything else which powerfully controls the kyneurenine pathway besides interferons, interleukins, and niacin (negative feedback)? I don't think that biochemists knew anything about inducible indolamine diooxygenase during the kyneurenine, tryptophan, pellagra discovery period. Back then, control of this pathway was mostly seen as under nutritional control exclusively. Control of this pathway makes perfects sense, and lowering trypophan is a great way to starve an invading pathogen. Out adaptive immune system creates antibodies against invading proteins while limiting tryptophan—to prevent them from growing—

The temperature is controlled by the sun and it seems like we're headed towards another solar minimum, which is a period of reduced solar activity and output as measure by the number of sunspots.

The last solar minimum was the maunder minimum in the 1600s. Millions died from freezing and starvation.

Supposedly these ice ages are preceded by natural disasters. Earthquakes, hurricanes, and volcanic explosions. Yellowstone is due to blow and the san Andreas fault is due to shift. Both volcanic eruptions and earthquakes are electrical and can be triggered by the sun. When this thing kicks off I reckon we'll be seeing a worldwide flurry of natural disasters and this time America will not be untouched. The people who I've been following on this say we have about 10 years.

Solar radiation is interesting, and George Lakhovsky has some things to say about that.

I'm getting the impression that the global warming myth, itself, is a myth. Global warming can be seen as exaggerated by some organizations—like the International Panel of Climate Change—for socio‐political reasons, but increased carbon dioxide must cause increased infrared absorption and increased temperature. Everyone wants more trees, but nobody will sacrifice their land; everyone want less carbon dioxide, but nobody will stop driving. The use of gasoline could be greatly reduced by the creation of Brown's gas without sacrificing drive‐ability, but the oil companies cannot stand to see this. Atmospheric chemistry and physics is so complicated that the actual rise in temperature can only be roughly estimated, and one could argue for years about the expected temperature increase per increment. You could even argue for some time about the best way to estimate this temperature rise. I think the best way would be to use two or three radically different approaches and see if they tend towards the same answer. The physicists use the Plank Equations, and the atmospheric chemists use Beer's Law.

It would be interesting to have some other forms of energy, to be totally independent an off the grid. The Brown's gas generators are easy to implement, but most people are concerned with things like 'violating their warranty.' I think magnetic motors have potential, and would like to do some of that. Perhaps someday I will buy magnets and see if I can get one to work. That sounds like a fun activity.

The future of our planet seems under the control of carbon dioxide, sunspots, comets, and perhaps even HARP (I need to look more into this).

 

[Koveras]

Histamine released by mast cells appears to be requisite for interferon‐γ formation.

Does this circle back to the role of hypoxia, pseudohypoxia, and the warburg effect in cancer and disorder? Since hypoxia, lactate, et al seem to have destabilizing effects on mast cells, and conversely CO2 a stabilizing one. Mast cell degranulation then releasing histamine and serotonin, serotonin further contributing to (pseudo)hypoxia through it's interference with energy metabolism, and both having various other downstream effectors.

 

[pimpnamedraypeat]

'Insults are the last resort of insecure people trying to appear confident in their weak position.'

still not right, care to walk this back a third time?

Although its Charter only gave the East India Company a monopoly on trade to the east of the Cape of Good Hope, the sheer scale of its enterprise meant that the Company had a significant influence on the newly emerging American colonies. Indeed the American historian Henry Newton Stevens maintained that the Mayflower which participated in the third voyage of the Company was the same ship that later was to take the Pilgrim Fathers on their voyage from Plymouth.

Muh mayflower!

In the early days of the seventeenth century the small circle of influential merchants in the City of London who formed the East India Company in 1600 had their fingers in a number of other trading pies. The Governor of the East India Company in its first decade, Sir Thomas Smyth, was also the first Governor of the Virginia Company founded in 1606, and the two Companies shared their headquarters in Smyth's house, along with that of the Levant Company. The Virginia Company was the first British colonial enterprise in North America, following on the naming of that state after the Virgin Queen, Elizabeth I. The Virginia Company founded the colonial port of Jamestown on Chesapeake Bay, now a Colonial Heritage site.

Muh religious purr say queue chon

The story of the origin of the Stars and Stripes, the American flag, forms an essential part of every schoolchild's education in the United States, but it is not commonly known that the inspiration for Betsy Rose's gift to Washington was the flag of the East India Company, which consisted of a Union Jack and stripes. Even now, the state flag of Hawaii is the same as the East India Company's flag — a memorial to the Company's involvement in the voyages of Captain Cook, who was to die there.

Muh muh red white and blue

 

[x-ray peat]

Muh mayflower!

Muh religious purr say queue chon

Muh muh red white and blue

All that shows is that some of the same rich people who were involved with the East India Company were also involved with the Virginia Company, which lasted less than 20 years, being dissolved in the 1620s. So much for "muh East India Company."

also next time don't waste our time with quotes from a novel or its web page. Thomas Pynchon is not an historian but a writer of fiction.

 

[Terma]

This is interesting. There is that well‐known relationship between toxoplasmosis and rage:

Coccaro, Emil F. "Toxoplasma gondii infection: relationship with aggression in psychiatric subjects." The Journal of clinical psychiatry (2016)​

But even more interesting is this, which provides a solid chemical mechanism for these observations. This study demonstrates the relationship between Toxoplasma gondii infection and kyneurenine pathway metabolites.

Fujigaki, Suwako. "L-tryptophan-L-kynurenine pathway metabolism accelerated by Toxoplasma gondii infection is abolished in gamma interferon-gene-deficient mice: cross-regulation between inducible nitric oxide synthase and indoleamine-2, 3-dioxygenase." Infection and immunity (2002)​

Apparently during infection, interferon‐γ actually either induces transcription of the enzyme indoleamine 2,3‐dioxygenase directly or through prostaglandin E₂. It's has been proven multiple times that interferon‐γ induces transcription of phospholipase A₂, the first step in prostaglandin synthesis. The author of this article didn't give his opinion as to how this happens, but it happens nonetheless. This enzyme was increased nearly two‐hundred‐fold in the brain as a result of Toxoplasma gondii infection:

'Brain IDO activity was also increased (198-fold) on day 14 (from 25.5 ± 5.1 to 5,049 ± 1,936 pmol/ h/mg of protein) and was maintained at that level until day 28.' ―Fujigaki​

The body ostensibly does this as a device to lower tryptophan, starving the parasite in this manner.

View attachment 7526 click to embiggen: Western blot before, and seven days after, Toxoplasma gondii infection.

This high enzymatic activity would naturally result in greatly‐increased brain levels of N‐formylkynurenine and everything downstream: kyneuric acid, 3‐hydroxykynurenine, 3‐hydroxyanthranilic acid, picolinic acid, quinolic acid, and nicotic acid.

'However, local accumulation of kynurenine metabolites, in particular, quinolinic acid, following IDO induction may also represent a potentially detrimental event. In fact, quinolinic acid is a potent excitotoxin, and its overproduction has been linked to neuronal damage occurring in brain inflammation, initiation of lipid peroxidation, and other conditions. Indeed, quinolinic acid concentration was significantly increased by T. gondii infection. Therefore, it is possible that increased levels of quinolinic acid and other kynurenine pathway metabolites play a detrimental role following T. gondii infection.' ―Fujigaki​

The only metabolite he'd measured was kyneurenine; he'd also measured the tryptophan concentrations:

View attachment 7527 click to embiggen: Brain kyneurenine concentrations before, and after, Toxoplasma gondii infection.

It does seem largely mediated by interferon‐γ: You wouldn't know by looking at the tryptophan concentrations alone, but the kyneurenine concentrations are more specific for the enzyme. Tryptophan concentrations depend on so many more things than then the enzyme indoleamine 2,3‐dioxygenase.

View attachment 7528 click to embiggen: Western blots taken throughout Toxoplasma gondii infection.

This effect is not limited only to Toxoplasma gondii infection, and can be observed with infections of all types. Besides those listed by Fujigaki, schistosomes—a parasititic flatworm—are well‐known to increase interferon‐γ.

'Furthermore, the antimicrobial effects induced by IDO‐dependent mechanisms were also demonstrated for both Chlamydia psittaci and group B streptococcal infections.' ―Fujigaki

'Indeed, previous observations indicated that IDO immunoreactivity is markedly increased in the spinal cord of macaques with poliovirus infection,' ―Fujigaki​

This would also of course act to lower brain serotonin, although he hadn't measured this. But since this appears to be mediated by interferon‐γ, you would expect certain food allergies to also cause similar changes (but perhaps only in certain areas). Ingestion of wheat among celiacs causes a a spike in interferon‐γ. Any interferon‐γ, anywhere, would naturally result in increased prostaglandin synthesis as well as the aforementioned effects on indoleamine 2,3‐dioxygenase.

'Indeed, especially in human fibroblasts, epithelial cells, and glioblastoma cells, IDO induction by IFN‐γ results in L-TRP depletion and inhibition of parasite growth.' ―Fujigaki

'Several studies suggest that IDO induction by IFN‐γ exerts antimicrobial and antiproliferative effects, possibly by depletion of L-TRP.' ―Fujigaki
​

People in certain geographic areas are more prone to parasitic infection, so these areas would have a higher prevalence of citizens having the behavioral effects—assuming they exist—resulting from greatly elevated interferon‐γ and brain quinolic acid.

A lot of that is probably correct to my knowledge, but the tryptophan depletion for starving pathogens idea is highly criticized and possibly wrong in most cases: The end of the road for the tryptophan depletion concept in pregnancy and infection
Also not only quinolinic acid, but the other kynurenine metabolites influence neurotransmission (e.g. NMDA) and they have much longer half-lives.

 

[pimpnamedraypeat]

All that shows is that some of the same rich people who were involved with the East India Company were also involved with the Virginia Company, which lasted less than 20 years, being dissolved in the 1620s. So much for "muh East India Company."

also next time don't waste our time with quotes from a novel or its web page. Thomas Pynchon is not an historian but a writer of fiction.

Lol the virginia company became the plymouth council for new england. You've heard of new england right? The point remains, this country was colonized by for profit merchants at the kings behest and in a method based of the east india company and ran by such same people.

The quotes are accurate.

Before you go hail the flag with tears in your eyes like a true american patriot remember what you're showing your allegience to

The STRIPED FLAG of the EAST INDIA COMPANY, and its CONNEXION with the AMERICAN "STARS and STRIPES"

The present tendency in the United States is to treat the origin of the Grand Union Flag as a mystery, which is unlikely to be solved(76). And in recent publications about the "Stars and Stripes" no mention is made of the East India Company's flag. Thus the reference to it that appeared in the 1917 edition of Flags of the World by the National Geographic Society finds no place in the 1934 edition. This may be partly due to the doubt that has hitherto existed whether the Company's flag was the same as the Grand Union Flag; but now that it seems clear that the two flags were identical, I feel sure that better recognition will be given to the claim of the former. Even if the identity of pattern is due to mere coincidence, it is a fact which deserves to be noticed in any discussion as to the origin of the American flag. And as the Company's flag had a long and honourable history, no discredit can attach to the American flag from a connexion between the two colours