Elevations in Nitrates in CFS - What It Could Mean As Biomarker!

A recent study has shown that nitrates increase significantly after exercise in CFS patients. Typically, nitrate elevations rise during inflammation. Outside sources of nitrates usually come from food sources. According to Wipedia - Nitrate toxicosis occurs through the metabolism of nitrate to ammonia in humans and if nitrates in CFS are significantly elevated this may stress the nitrate detoxification system.....

"In vivo conversion of nitrates to nitrites significantly enhances nitrates' toxic potency. The major metabolic pathway for nitrate is conversion to nitrite, and then to ammonia. Approximately 5%–10% of the total nitrate intake is converted to nitrite by bacteria in the saliva, stomach, and small intestine." (ATSDR) Thus, the production of elevated levels of nitrates could lead to elevations in ammonia. Ammonia has been implicated in diseases including autism and augment complications associated with metabolic defects.

As many of you know I have written extensively about ammonia and hyperammonemia in these conditions. Recently it has been demonstrated that odors through a protein CRF acts on the pathway NO/cGMP. This pathway has a number or responsibilities including activation downstream proteins as well as regulating blood flow and behavior. As I am sure you know, alterations in blood flow have been associated with CFS. This pathway is disrupted by high levels of ammonia - it has significant influence on a number of health conditions and also
behavior.

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Source: Case Studies in Environmental Medicine (CSEM)
Nitrate/Nitrite Toxicity
What Is the Biological Fate of Nitrate?
http://www.atsdr.cdc.gov/csem/nitrate/no3biologic_fate.html

Suárez, A., Guillamo, E., Roig, T., Blázquez, A., Alegre, J., Bermúdez, J., Ventura, J. L. L., García-Quintana, A. M. M., Comella, A., Segura, R., and Javierre, C. (2010). Nitric oxide metabolite production during exercise in chronic fatigue syndrome: A case-control study. Journal of women's health (2002).
http://www.citeulike.org/user/HEIRS/article/7192750

Heavy Metals, Air Pollution and Liver Toxicity -- Two New Studies

Background: Toxic metals are an important consequence of manufacturing and other exposures occur during construction and remodelling, lead paint exposure and agriculture residues that end up in the air and contribute and part of air pollution.


Two recent studies provide insight into the negative consequences of metal exposures. The first study by RG Sangani has been the first to demonstrate metals in air pollution can negatively alter the normal coagulation properties of blood which may contribute to disease. He shows that "except for nickel, all metal sulfates shortened the whole-blood coagulation time. Iron and zinc were two metals with the greatest capacity to reduce the coagulation time at test levels. This support a past study by Baccarelli that reported alterations in coagulation time, more specifically, hypercoagulability to short-term exposure to air pollutants. This condition may complicate cardiovascular and respiratory diseases as well, contribute to other complications in a wide variety of health conditions.

The second study provides further clarification of recent findings of metal toxicity and provides more support that ammonia accumulation may influence environmental diseases. In addition, it also supports the idea that defiencies in Nrf2 may augment the effects because one role for Nrf2 is protection of astrocytes. It has been notes in the past, important pathways exist between peripheral organs such as the liver and the brain. As NIOSH recently discovered through a recent study this antioxidant system along with the AhR plays an important role in determining the responses to oxidative chemicals, heavy metals and polycyclic aromatic chemicals. They also point out that effective biomarkers that target this this receptor may be used to identify the relative toxicity of an " occupational chemical" and should be able to be expanded determining toxicities to a large variety of chemicals.

"When reading the following, one must at least consider what health effects occur in limited exposures and their impact on those more vulnerable. A recent study demonstrated new findings of toxic heavy metal exposures that may lead to extremely detrimental effects. As Butterworth explains, "changes to astrocytes (Alzheimer type II astrocytosis) are a major feature of hepatocerebral disorders. Neurological symptoms include Parkinsonism, cognitive dysfunction, and ataxia. (All conditions which I have suggested could be important indicators of environmental toxicity.) Pathophysiologic mechanisms responsible for cerebral dysfunction and neuronal cell death in hepatocerebral disorders include ammonia toxicity and neurotoxic effects of metals such as copper, manganese, and iron. Molecular mechanisms of neurotoxicity include oxidative/nitrosative stress, glutamate (NMDA)-receptor-mediated excitotoxicity, and neuroinflammatory mechanisms.....Management and treatment of hepatocerebral disorders include chelation therapy (Wilson's Disease), the use of ammonia-lowering agents (lactulose, antibiotics, ornithine aspartate) and liver transplantation." Because liver injury can occur from chronic toxic exposures, some of the mechanisms above need to be considered when "formulating a toxic exposure footprint". Also, consideration of any genetic tendencies in families and chronic diseases such as inflammatory bowel disease may potentiate liver injury should be discussed with a physician.

Notes:

I recently posted a link that discusses the hazards of copper and one should look diligently for alternative sources of metal exposures including drinking from copper pipes." The following article is short and a must read http://www.allheadlinenews.com/articles/7018340136

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Baccarelli, A., Zanobetti, A., Martinelli, I., Grillo, P., Hou, L., Giacomini, S., Bonzini, M., Lanzani, G., Mannucci, P. M., Bertazzi, P. A., and Schwartz, J. (2007). Effects of exposure to air pollution on blood coagulation. Journal of thrombosis and haemostasis : JTH, 5(2):252-260. http://www.citeulike.org/user/HEIRS/article/1053682
Sangani, R. G., Soukup, J. M., and Ghio, A. J. (2010). Metals in air pollution particles decrease whole-blood coagulation time. Inhalation toxicology. http://www.citeulike.org/user/HEIRS/article/7074904
Butterworth, R. F. (2010). Metal toxicity, liver disease and neurodegeneration. Neurotoxicity research. http://www.citeulike.org/user/HEIRS/article/7074949
Butterworth, R. F. (2010). Metal toxicity, liver disease and neurodegeneration. Neurotoxicity research. http://www.citeulike.org/user/HEIRS/article/7074949
Ma, Qiang. February 10, 2010. Protection Against Occupational Disease by Xenobiotic-Activated Receptors.NIOSH. Retrieved on April 23, 2010. http://wwwtest.cdc.gov/niosh/programs/manuf/noragoals/projects/927ZGFU.html

Ornithine Enzymes, Tregs, X-Linked Mutations In Autoimmunity and Disease

Background: We have suggested that environmental illnesses may involve the loss of suppression of regulatory T cells and that several different proteins may be involved which changes the dynamics or "immunological footprint" of these conditions in each individual. Previously we mentioned how high ammonia levels may account for some of the symptoms associated with multiple chemical sensitivity. We also noted recently how alterations in ornithine enzymes levels may effect ammonia levels and the Nrf2 gene regulator has some control over its expression. The following article discusses findings related to how a mutation in ornithine transcarbamalase may influence the immune system and play a role in autoimmune type disease. Interestingly, the author points out the condition is X-linked which might account for higher number of females presenting with them because males usually die in utero and do not live but a few days after birth. There is usually a large sexual dimorphism in the prevalence of many environmental diseases.

The author writes, "Antigen expression in the thymus leads to the deletion of self-reactive T cells and generation of regulatory lymphocytes, including regulatory T cells(Treg) and NKT cells. We show an Ornithine transcarbamylase(OTC) mutation causes ineffective presentation of self antigens in the thymus. As such, deletion of self reactive T cells is compromised and production of Treg and NKT cells is reduced in OTC mutant mice. More importantly the heterozygous mice have increased susceptibility to autoimmune diseases, including the generation of autoantibodies and more severe EAE by MOG immunization"

Comment: This article is a good representation of why only qualified medical professionals that understand the multitude of genetic conditions, their complexity and environmental conditions which activate them should be treating these conditions. There is no evidence thus far, that a "therapeutic recipe" is effective at treating all of them.


Chang, X. (2006). X linked foxp3 & otc in immune tolerance and autoimmunity. Ohio State University. http://www.citeulike.org/user/HEIRS/article/6650098

Glutamine Synthetase Deficiency Results in Neonatal Death in Experimental Animals

GS deficiency caused a 14-fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6-fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS-KO/A mice.

HEIRS Environmental Illness Research Blog: Endotoxin Inactivates Glutamine Synthetase and Impairs Ammonia Elimination in Rats#links

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