Part Three: The Role of Viral Infection

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The Role of Viral Infection
bacteria
viruses
retention of aluminum
retention of heavy metals
What Causes Chronic Microbial Issues that can lead to this metal retention ?
• Viruses
• Decreased T cell response due to methylation cycle mutations. • Impaired DNA synthesis that is needed for T cell clonal expansion. • Impaired B cell response due to lack of T helper cells, and T regulatory cells. • Increased IDO, impact on self versus non self • Further Induction of IDO by interferon gamma • Interferon gamma increases in intestinal permeability and blood-brain permeability • Decreased vaccine efficiency, increased viral load • Nature of retroviruses themselves. • Reduced viral silencing due to methylation cycle mutations.
Viruses as Parasites
• Induction of Metallothionein proteins by viral infection • Trapping of heavy metals by virus
“Viruses use a “Trojan horse” strategy in which the victim assists the intruder. To extract assistance from the host cell, viruses use the detailed “inside information” that they have acquired during million of years of coevolution with their hosts.”
Science Vol 304 April 9,2004
Measles and Mumps
• Measles and mumps are retroviruses • Retroviruses have the ability to insert into host DNA • While Rubella is not a retrovirus, it can behave like a retrovirus in the presence of retroviruses like Measles and Mumps
Combination therapy for chronic retroviral infection
Nature Reviews Drug Discovery November 2005
Herpes, Measles and Streptococci can gain cell entry via the same receptor
Cell. 1999 Dec 23;99(7):817-27. CD46 is a cellular receptor for human herpesvirus 6.
Santoro F, Kennedy PE, Locatelli G, Malnati MS, Berger EA, Lusso P.
Chronic Viral Infection
• Measles, Mumps, Rubella, HHV-6, Herpes Zostar (Chicken Pox) • Streptococcus, Herpes Virus, Measles Virus use the same receptor to get into cells • Increased susceptibility to all three • Viruses • Viruses glutamate host MT proteins
bind metals inside virally infected cells
Viral Infection and MS
Multiple sclerosis and Epstein-Barr virus.
Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A. CONTEXT: Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. OBJECTIVE: To determine whether antibodies to EBV are elevated before the onset of MS. DESIGN, SETTING, AND POPULATION: Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. RESULTS: The average time between blood collection and MS onset was 4 years. The strongest predictors of MS were serum levels of IgG antibodies to VCA or EBNA complex. The risk of MS increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of VCA (> or =2560) compared with those in the lowest (< or =160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend =.004). For EBNA complex titers, the RR for those in the highest category (> or =1280) was 33.9 (95% CI, 4.1-283; P for trend <.001) vs those in the lowest category (< or =40). Similarly strong positive associations between EBV antibodies and risk of MS were already present in samples collected 5 or more years before MS onset. No association was found between cytomegalovirus antibodies and MS. CONCLUSION: These results suggest
a relationship between EBV infection and development of MS.
Viral Infection and MS
Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Soldan SS, Berti R, Salem N, Secchiero P, Flamand L, Calabresi PA, Brennan MB, Maloni HW, McFarland HF, Lin HC, Patnaik M, Jacobson S. Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described betaherpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.
Viral Infection and CFS
Methylation status affects viral load and hence metal accumulation. Since metal toxicity has been associated with CFS this has direct relevance for CFS. Thimerosal, micromercurialism and chronic fatigue syndrome. Miller R. PMID: 15780514 [PubMed - indexed for MEDLINE] Mercury toxicity presenting as Chronic Fatigue, memory impairment and depression: Diagnosis, treatment, susceptibility, and outcomes in a New Zealand general practice setting (1994-2006). Wojcik DP, Godfrey ME, Christie D, Haley BE. Northland Environmental Health Clinic, 2 Dip Rd, Kamo, Whangarei, Northland, New Zealand. wojcik@wave.co.nz. In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p< 0.001) to levels reported by healthy subjects.
Decreased methylation creates a compromised host for the virus.
“DNA methylation may maintain the large amount of non-coding DNA in an inert state.” “This process would help prevent the transcription of large parts of the genome… INSERTED VIRAL SEQUENCES.” “…consequences of loss of methylation… could cause the potentially harmful expression of inserted viral genes
New England Journal of Medicine, November 20, 2003
Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms Kalpana Ghoshal,1 Sarmila Majumder,1 Qin Zhu,1 John Hunzeker,2 Jharna Datta,1 Manisha Shah,3 John F. Sheridan,2 and Samson T. Jacob1
Copyright © 2001, American Society for Microbiology Mol Cell Biol. 2001 December; 21 (24): 8301–8317 DOI: 10.1128/MCB.21.24.8301-8317.2001
These results have demonstrated that MT-I and MT-II can be induced robustly in the liver and lung following experimental influenza virus infection by overlapping but distinct molecular mechanisms.
Effects of coxsackievirus B3 infection on the acute-phase protein metallothionein and on cytochrome P-4501A1 involved in the detoxification processes of TCDD in the mouse.
Funseth E, Pahlman M, Eloranta ML, Friman G, Ilback NG. Sci Total Environ. 2002 Feb 4;284(1-3):37-47.
• Infection had induced MT approximately 10-fold. • This may explain the observed changed pattern of accumulation, excretion and toxicity of the environmental pollutants cadmium and TCDD during this common virus infection.
Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells.
Li K, Prow T, Lemon SM, Beard MR. Hepatology. 2002 May;35(5):1237-46 .
• Changes in gene expression profiles in response to core expression were determined using commercial oligonucleotide microarrays (Affymetrix GeneChip). • Significant increases were observed in the abundance of mRNA-encoding members of the metallothionein (MT) family
Toxic Metal Burden
• Heavy metals from the mother
• Amalgam (mercury) • Contact lens solution (thimerosal) • Vaccination of mother (mercury, aluminum) • Eating fish
• Metals from environment
• Coal burning power plants • 50 tons of mercury emissions annually from chlorine production • 1,000 times more lead in our bones since the industrial age
• Metals from vaccination
• Thimerosal, aluminum • Viral Trapping of heavy metals
• 630,000 children born annually with unsafe mercury
Heavy Metal Concentrations in Human Eyes
Jay C. Erie John A. Butz Department of Ophthalmology Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota Metals Laboratory Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota
Purpose:To measure the concentration of toxic heavy metals in the fluids and tissues of human eyes. Methods: Thirty autopsy eyes of 16 subjects were dissected to obtain the aqueous, vitreous, lens, ciliary body, retina, and retinal pigment epithelium/choroid. Concentrations of lead, cadmium, mercury, and thallium in ocular tissues, ocular fluids, and blood were determined using an inductively coupled plasma-mass spectrometer and expressed as ng/g. Heavy metal concentrations in ocular tissues were compared using a paired t test. Results: Lead and cadmium were found in all of the pigmented ocular tissues studied, concentrating to the greatest extent in the retinal pigment epithelium/choroid (mean, 432 ± 485 ng/g and 2,358 ± 1,522 ng/g). Cadmium was found in the retina in all eyes (mean, 1,072 ± 489 ng/g) whereas lead was found in the retina in 9 (30%) of 30 eyes (mean, 53 ± 54 ng/g). Trace concentrations of lead and cadmium were detected in the vitreous (mean, 0.5 ± 1.0 ng/dl and 19 ± 29 ng/dl), lens (mean, 13 ± 18 ng/g and 20 ± 18 ng/g), and blood (mean, 0.5 ± 1.2 μg/dl and 3.1 ± 4.1 μg/l) but were not detected in the aqueous. Mercury and thallium were not detected in any ocular tissues or fluids or in the blood. Conclusions: Lead and cadmium accumulate in human ocular tissues, particularly in the retinal pigment epithelium and choroid. The potential ocular toxicity of these heavy metals and their possible role in eye disease requires further study.
Relationship between Virus and Metals
J Toxicol Environ Health A. 2001 Aug 10;63(7):511-23.
Mortality in mice infected with an amyocarditic coxsackievirus and given a subacute dose of mercuric chloride.
South PK, Morris VC, Levander OA, Smith AD. Beltsville Human Nutrition Research Center, US Department of Agriculture, Agricultural Research Service, Maryland 207052350, USA.
An amyocarditic strain of coxsackievirus B3 (CVB3/0) induces heart damage when inoculated into selenium (Se)-deficient mice. Mercury (Hg), an Se antagonist, is known to aggravate viral infections. The experiments reported here assessed the effect of prior Hg treatment in mice subsequently inoculated with an amyocarditic strain of coxsackievirus. A pilot study showed that under our conditions the maximum tolerated dose of HgCl2 in uninfected mice was 6 mg HgCl2/kg body weight. In the main study, doses of 0, 3 or 6 mg HgCl2/kg body weight were administered intraperitoneally (ip) to 7-wk-old male mice fed a standard chow diet. Two hours later, half the mice were inoculated ip with CVB3/0. Ten days postinoculation, no mortality was observed in mice given only virus. In mice not given virus, 10% injected with 6 mg HgCl2/kg body weight died. On the other hand, 64% of the mice given both virus and 6 mg HgCl2/kg body weight died. Fifteen percent of the hearts from virus-infected mice given 3 mg HgCl2/kg body weight and 33% of the hearts from virus-infected mice given 6 mg HgCl2/kg body weight exhibited a higher incidence of lesions than hearts from mice-given virus alone. Moreover, viral heart titers were elevated in infected mice injected with 6 mg HgCl2/kg body weight compared to infected mice receiving no Hg. Thus, an amyocarditic coxsackievirus given to mice after a nonlethal subacute dose of Hg results in mortality, increased incidence of heart lesions, and elevated viral heart titers. These results demonstrate the important role of toxic elements in determining the severity of viral infections.
Relationship between Virus and Metals
Toxicol Lett. 1996 Dec;89(1):19-28
Effects of methyl mercury on cytokines, inflammation and virus clearance in a common infection (coxsackie B3 myocarditis).
Ilback NG, Wesslen L, Fohlman J, Friman G. Pharmacia and UpJohn, Helsingborg, Sweden.
A myocarditic coxsackievirus B3 (CB3) infection in Balb/c mice was used to investigate the effects of 12 weeks of methyl mercury (MeHg) exposure (3.69 mg/g diet) on inflammatory heart lesions, virus in the heart, the cytokine response, i.e. cachectin/TNF-alpha and gamma-interferon (IFN-gamma) levels in plasma, and on disease complications and mortality. This dose of MeHg did not influence mortality in this infection model. The inflammatory and necrotic lesions in the ventricular myocardium 7 days after the inoculation covered 2.2% of the tissue section area in infected control mice. This damage was increased (n.s.) by 50% (to 3.3% of the tissue section area) in MeHg-treated mice. The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was corroborated using an immune histological technique. MeHg treatment tended to increase (2.2-fold, n.s.) the number of Mac 2+ cells (macrophages) in the heart muscle in this infection. Plasma levels of both TNF-alpha and IFN-gamma increased on day 3 of the infection in MeHgtreated as well as in non-MeHg-treated mice, but the mean IFN-gamma response was more pronounced in the MeHg-treated mice. On day 7 of the infection, when most animals still showed clinical signs of disease, cytokine levels were back to normal. MeHg-exposure in non-infected mice did not affect cytokine levels. In situ hybridization of virus RNA in myocardial tissue showed remaining virus in those mice who had the lowest plasma IFN-gamma levels. A 20% increased (P < 0.05) lymphoproliferative response to the T cell mitogen Con A was observed as a result of the MeHg treatment. Even heart tissue lesions and virus persistence tended to be influenced by MeHg in a direction compatible with the development of chronic disease.
Relationship between Virus and Metals
Biol Trace Elem Res. 2003 Feb;91(2):111-24
Sequential changes in Fe, Cu, and Zn in target organs during early Coxsackievirus B3 infection in mice.
Ilback NG, Benyamin G, Lindh U, Friman G. Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden.
In Coxsackievirus B3 (CB3) infection, the heart and pancreas are major target organs and, as a general host response, an associated immune activation and acute phase reaction develops. Although iron (Fe), copper (Cu), and zinc (Zn) are involved in these responses, sequential trace element changes in different target organs of infection have not been studied to date. In the present study, Fe, Cu, and Zn were measured through inductively coupled plasma mass spectrometry (ICP-MS) in the plasma, liver, spleen, heart, and pancreas during the early phase (d 1 and 3) of CB3 infection in female Balb/c mice. The severity of the infection was assessed through clinical signs of disease and histopathology of the heart and pancreas, including staining of CD4 and CD8 cells in the pancreas. During infection, the concentrations of Fe, Cu, and Zn changed in the plasma, liver, and pancreas, but not in the spleen and heart. The changes in plasma Cu, Zn, and Fe seemed to be biphasic with a decrease at d 1 that turned into increased levels by d 3. Cu showed similar biphasic changes in the liver, spleen, and pancreas, whereas, for Zn and Fe, this pattern was only evident in the liver. In the pancreas, the reverse response occurred with pronounced decreases in Fe (23%, p < 0.05) and Zn (64%, p < 0.01) at d 3. Although the pathophysiological interpretation of these findings requires further research, the sequential determination of these elements may be of clinical value in enterovirus infections in deciding the stage of disease development.
Relationship between Virus and Metals
Biol Trace Elem Res. 2000 Aug;76(2):149-60
Trace element changes in the myocardium during coxsackievirus B3 myocarditis in the mouse.
Funseth E, Lindh U, Wesslen L, Friman G, Ilback NG. Department of Medical Sciences, Uppsala University Hospital, Sweden.
During most infections plasma, concentrations of trace elements change, but it is unclear if this reflects changes in infected target tissues. In coxsackievirus B3 (CB3) infection, the myocardium is a target in both humans and mice. The concentrations of 12 trace elements were analyzed by inductively coupled plasmamass spectrometry (ICP-MS) in the myocardium of sham-inoculated controls and infected A/J mice 4 and 7 d postinoculation. The size of the inflammatory lesion was positively correlated to the virus content of the heart, as estimated by histopathology and in situ hybridization, respectively. Iron, cobalt, vanadium, and selenium showed transient changes, whereas for the other elements, tendencies on d 4 were manifest on d 7. A threefold increase in calcium on d 7 suggests prestages of calcification, whereas increases in zinc, selenium, and copper may be the result of the accumulation of immune cells. The magnesium decrease may contribute to the increased sensitivity to cardiac arrhythmias in myocarditis.
Relationship between Virus and Metals
Biol Trace Elem Res. 1998 Jul;63(1):51-66
Effects of selenium supplementation on virus-induced inflammatory heart disease.
Ilback NG, Fohlman J, Friman G. Toxicology Division, National Food Administration, Uppsala, Sweden.
The effects of 10 wk of selenium (Se) supplementation (5 ppm) in drinking water on immune responses and resistance to a myocarditic Coxsackie virus B3 (CB3) infection were studied in female Balb/c mice. Se supplementation reduced CB3-induced mortality: at day 14 postinoculation, survival was 58% in the Se-treated group as compared to 25% in the untreated group. Whole-blood glutathione peroxidase (GSH-Px) activity was elevated by 68% (p < 0.001) and Se content in the liver by 24% (p < 0.001). Red (RBC) and white blood cell (WBC) counts, as well as the number of cells in the spleen and thymus, were unaffected. The cellular counts of T-lymphocytes (CD4+, CD8+) and natural killer (NK+) cells in the blood were not affected. However, the CD4+/CD8+ ratio (5.2) tended to increase after Se supplementation (5.9). The spleen lymphoproliferative response to T- and B-cell mitogens were increased by 9 and 43%, respectively (ns), in the Se-supplemented group. The total NK cell activity in blood and spleen showed minor increases, but when the activity in the blood was expressed per cell, the increase amounted to 35% (ns) with Se supplementation. The inflammatory and necrotic lesions in the ventricular myocardium at 7 and 14 d postinoculation were not significantly reduced by Se treatment, probably owing to the increased survival with Se even of mice with the most pronounced heart damage; comparable untreated mice were estimated to have died at day 14. Results indicate that modest doses of Se can improve immune function, which may increase the general resistance to this viral infection.
Relationship between Virus and Metals
Eur Heart J. 1995 Dec;16 Suppl O:20-4
New aspects of murine coxsackie B3 myocarditis--focus on heavy metals.
Ilback NG, Lindh U, Fohlman J, Friman G. Kabi Pharmacia AB, Helsingborg, Sweden.
The magnitude of inflammatory lesions in the hearts of coxsackie B3 (CB3)-virus infected mice can be affected by the potentially toxic heavy metals cadmium (Cd), nickel (Ni) and methyl mercury (MeHg). The infection is associated with a changed distribution, such as Cd accumulation in the spleen and kidneys. New target organs for Ni during the infection were the heart, pancreas and lungs in which inflammatory lesions were present. This increased uptake was correlated with the disturbed function of immune cells and an increased inflammatory reaction. Ni and MeHg appeared to have a direct effect on immune cells that resulted in changed natural killer cell activity and decreased mobilization of macrophages, CD4+ and CD8+ cells into the inflammatory lesions. Although MeHg increased spleen T cell activity and gamma-interferon (IFN-gamma) levels, the inflammatory lesions in the heart increased. Another detrimental effect of MeHg treatment was evident by an increased calcium and decreased zinc content in the inflamed heart, which may partly explain the more severe inflammatory lesion. The host's response, CB3 infection, changed the distribution of each metal in a specific way, a fact which may subsequently result in altered target organ toxicity and resistance to the infection.
Relationship between Virus and Metals
Toxicol Appl Pharmacol. 1992 May;114(1):166-70
A common viral infection can change nickel target organ distribution.
Ilback NG, Fohlman J, Friman G. Toxicology Laboratory, National Food Administration, Uppsala, Sweden.
The autoradiographic distribution of the toxic heavy metal nickel (Ni) was studied at 4 and 7 days postcoxsackievirus B3 (CB3) infection in Balb/c mice. The distribution of the iv injected 63Ni was studied 10 min, 4 hr, and 24 hr after administration. Results clearly show that the site of 63Ni accumulation is greatly changed during this viral infection. This newly discovered distribution was mainly visible as a greatly increased accumulation in the pancreas and the wall of the ventricular myocardium. Healthy animals showed almost no 63Ni accumulation in these tissues. These results for the first time show that an invading microorganism can change the distribution of an environmental pollutant
Relationship between Virus and Metals
Scand J Infect Dis Suppl. 1993;88:93-8
Altered distribution of heavy metals and lipids in coxsackievirus B3 infected mice.
Ilback NG, Fohlman J, Friman G. Kabi Pharmacia AB, Helsingborg, Sweden.
This report presents evidence that a micro-organism common in our environment, coxsackievirus B3 (CB3) and the host responses it causes, can change the body distribution of heavy metals and lipids. The present results show that the distributions of intravenously injected 109Cd, 63Ni and 14C-Cholesterol are changed during infection, in a way that is specific for each of the studied compounds. Increased accumulation of 109Cd in the spleen and kidneys, 63Ni in the pancreas and ventricular myocardium, and 14C-Cholesterol in the heart and pancreas was observed during CB3 infection. This may affect the development of inflammatory lesions and subsequently result in altered and/or increased target organ toxicity as well as lipid accumulation. Thus, risk assessment in exposed populations may have to be evaluated depending on individual nutritional and exposure status.
Relationship between Virus and Metals
Chemosphere. 1994 Sep;29(6):1145-54
Immune responses and resistance to viral-induced myocarditis in mice exposed to cadmium.
Ilback NG, Fohlman J, Friman G, Ehrnst A. Kabi Pharmacia AB, Helsingborg, Sweden.
The effects of 10 weeks of treatment with cadmium (Cd) on the immune function and resistance to coxsackievirus B3 (CB3)-induced myocarditis in female Balb/c mice were investigated. A 2mM dose of Cd in the drinking water did not influence mortality due to the CB3 infection. The inflammatory and necrotic lesions in the ventricular myocardium seven days after inoculation (2.94% of tissue section area) were not increased by Cd (2.82% of tissue section area). The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was elucidated by an immune histochemical staining technique. With Cd treatment the number of cytotoxic T cells and B cells in these lesions decreased by 22% (n.s.) and 21% (p < 0.05), respectively. Spleen weight and the lymphoproliferative response to the B-lymphocyte mitogen increased by 19% (p < 0.05) and 23% (n.s.), respectively. The titers of neutralizing antibodies increased by 22% (n.s.) with Cd treatment. However, the activity of spleen T lymphocytes and spontaneous cell-mediated cytotoxicity (NK-cell) was unchanged. Thymus weight and WBC count in peripheral blood tended to decrease. Thus, Cd exposure seems to result in a decreased maturation and mobilization of T and B lymphocytes, but increased humoral immune host responses.
Relationship between Virus and Metals
Toxicology. 1992;71(3):193-202
Altered distribution of 109cadmium in mice during viral infection.
Ilback NG, Fohlman J, Friman G, Glynn AW. Toxicology Laboratory, National Food Administration, Uppsala, Sweden.
The distribution of the toxic heavy metal cadmium (Cd) was studied in Coxsackie virus B3 (CB3)-infected Balb/c mice by whole-body autoradiography and gamma-counting. The distribution of 109Cd was studied 4 days post CB3-inoculation and 10 min after intravenous injection of 0.21 microgram of Cd/kg body weight. Whole-body autoradiography results showed that the distribution of 109Cd is greatly changed during this viral infection. This newly discovered distribution was mainly visible as a greatly increased accumulation in the renal and adrenal cortices. After impulse counting of selected organs it was found that the normal accumulation of 109Cd in the kidneys (184,354 +/- 30,961 c.p.m.) was increased by 47% (P less than 0.05) during CB3 infection (270,503 +/- 54,780 c.p.m.). In contrast to healthy animals, some infected mice showed accumulation of 109Cd in the spleen. These results show for the first time that an invading microorganism can change the distribution of an environmental pollutant.
Relationship between Virus and Metals
Biol Trace Elem Res. 2000 Winter;78(1-3):131-47
Trace element distribution in heart tissue sections studied by nuclear microscopy is changed in Coxsackie virus B3 myocarditis in methyl mercury-exposed mice.
Ilback NG, Lindh U, Wesslen L, Fohlman J, Friman G. Toxicology Division, National Food Administration, Uppsala, Sweden.
Methyl mercury (MeHg) has been shown to change Coxsackie virus type B3 (CB3) myocarditis in a direction compatible with the development of chronic disease. Murine models of CB3 myocarditis closely mimic the pathogenesis in humans. There are also indications that metals, such as mercury, and trace elements may interact and adversely affect viral replication and development of inflammatory lesions. The effects of low-dose MeHg exposure on myocardial trace element distribution, as determined by means of nuclear microscopy, was studied in CB3 myocarditis. Balb/c mice were fed a MeHg-containing diet (3.9 mg/kg diet) for 12 wk prior to infection. Areas of inflammatory lesions in the myocardium were identified by traditional histologic examination, and serial tissue sections in these selected areas were used for immune histology (macrophages), in situ hybridization of virus genomes, and nuclear microscopy of tissue trace element distribution. Areas with no inflammation or virus were compared with areas of ongoing inflammation and viral replication. In the inflammatory lesions of MeHg-exposed mice as compared to nonexposed mice, the myocardial contents of calcium (Ca), manganese (Mn), and iron (Fe) were significantly increased, whereas the zinc (Zn) content was decreased. The increased Ca and decreased Zn contents in the inflamed heart may partly explain a more severe disease in MeHg-exposed individuals. Although not significant in the present study, with a limited number of mice, the inflammatory and necrotic lesions in the ventricular myocardium on d 7 of the infection was increased by 50% (from 2.2% to 3.3% of the tissue section area) in MeHg-exposed mice and, also, there was a tendency of increased persistence of virus with MeHg exposure. No increased MeHg uptake, either in the inflammatory lesions or in the areas of noninflamed heart tissue in infected mice, could be detected. The present results indicate that a "competition" exists between potentially toxic heavy metals from the environment/diet and important trace elements in the body and that a disturbed trace element balance adversely influences the development of pathophysiologic changes in inflammatory heart disease.
Relationship between Virus and Metals
Pancreas. 2003 Mar;26(2):190-6
Trace element changes in the pancreas during viral infection in mice.
Ilback NG, Benyamin G, Lindh U, Fohlman J, Friman G. Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Sweden.
The trigger for some cases of juvenile diabetes has been suggested to be an interaction between a virus and various trace elements. Infection with human coxsackievirus B3 (CB3) in the murine model results in viral replication and inflammation in the pancreas. AIM: To determine how infection affects the trace element balance in the pancreas. METHODOLOGY: Concentrations of the following trace elements were measured in the serum and pancreas during the early phase (days 1 and 3) of CB3 infection in female Balb/c mice: aluminium, arsenic, cadmium (Cd), calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), magnesium (Mg), manganese (Mn), mercury (Hg), selenium, silver, vanadium (V), and zinc (Zn). The trace element concentrations were measured through inductively coupled plasma mass spectrometry. The histopathology was established by hematoxylin-eosin techniques and immunohistochemical staining of both CD4 and CD8 cells of the pancreas. RESULTS: Infected mice developed expected clinical signs of disease. The only changes at day 1 occurred in the serum, with a pronounced decrease in the Zn concentration and a small increase in the V concentration. At day 3, concentrations of several trace elements, including Cu, Zn, Fe, Ca, V, and Mn, showed pronounced changes in both the serum and the pancreas. Ca, Cu, Mg, Mn, and V, but none of the potentially toxic elements, accumulated in the pancreas. Cu and V concentrations increased in the serum as well. CONCLUSION: Several trace element changes, preceding the development of pancreatitis, occurred in the pancreas in this viral infection, the exact pathogenic interpretation of which warrants further studies.
Relationship between Virus and Metals
Biometals. 2000 Dec;13(4):361-7
Relation between trace element levels in plasma and myocardium during coxsackievirus B3 myocarditis in the mouse.
Funseth E, Lindh U, Friman G, Ilback NG. Department of Medical Sciences, Uppsala University Hospital, Sweden.
During most infections the plasma levels of trace elements change, but it is not clear if this reflects changes in the infected tissues. Coxsackievirus B3 (CB3) infection may result in viral replication, subsequent inflammation and changed trace element levels in the myocardium. In the present study, the trace element levels in the plasma and heart of adult male A/J mice were determined during the pre-inflammatory stage (day 4) of CB3 myocarditis for the following trace elements: aluminium (Al), arsenic (As), calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), selenium (Se), silver (Ag), vanadium (V) and zinc (Zn). The severity of the infection was assessed through clinical signs of disease and trace element levels were measured through inductively-coupled plasma mass-spectrometry (ICP-MS). In the heart, the levels decreased for V (59%; p < 0.01), Co (38%; p < 0.01), Al (81%; p < 0.01), As (66%; p < 0.01) and Se (16%; p < 0.01). Increased levels were detected for Mn (13%; p < 0.05), Fe (48%; p < 0.01), Cu (34%; p < 0.01) and Ag (46%; p < 0.01). In the plasma, decreases were detected in the level of Zn (32%; p < 0.05), whereas increases were seen in Mn (362%; p < 0.05), Fe (272%; p < 0.01), Co (71%; p < 0.05), Cu (25%; n.s.) and Mg (43%; p < 0.01) levels. A correlation was found between the levels in plasma and myocardium for Co (r(s) = -0.636; p < 0.05), Fe (r(s) = 0.764; p < 0.05), Mn (r(s) = 0.682; p < 0.05) and Mg (r(s) = -0.791; p < 0.05). Thus, determination of some of these trace elements in the plasma may be useful to indicate target tissue involvement in the early pre- inflammatory stage of an infectious disease. Some of these elements are important nutrients for the immune system, while others may be associated with the development of disease complications, such as cardiac arrhythmias.
Relationship between Virus and Metals
Chem Biol Interact. 1998 May 1;113(1):79-89
The intestinal absorption of cadmium increases during a common viral infection (coxsackie virus B3) in mice.
Glynn AW, Lind Y, Funseth E, Ilback NG. Toxicology Division, National Food Administration, Uppsala, Sweden.
Murine intestinal absorption, tissue accumulation and redistribution of 109Cd during infection were studied using the common human virus Coxsackie virus B3 (CB3) adapted to the mouse. Female Balb/c mice were infected with CB3 and, on day 4 of the infection, dosed orally with 0.3 or 750 microgram Cd/kg body weight, with 109Cd as a tracer, in order to study intestinal absorption and tissue distribution of Cd during infection (Experiment 1). Other mice were dosed with 0.3 microgram Cd/kg body weight 3 days before being infected and, on day 4 of the infection, Cd redistribution was studied (Experiment 2). In both experiments non-infected control animals received the same treatment as infected animals. Results showed that the infected animals had a higher gastrointestinal absorption of Cd than noninfected animals when Cd was administered during infection. In the infected animals the absorption at the low Cd dosage was increased by 70% and was tripled at the high dosage. The increased absorption enhanced the accumulation of Cd in all organs studied. Moreover, the infection caused a Cd dose-dependent change in the organ distribution of Cd, when Cd was administered during the infection. However, no redistribution of previously accumulated Cd occurred during ongoing disease, indicating that Cd was not mobilised from body stores by the infection. These results show, for the first time, that an invading micro-organism can increase the intestinal absorption and concomitantly alter the tissue distribution of an environmental pollutant (Cd) if exposure occurs during the course of viral infection.
Virus Induced Metallothionein Synthesis
Toxicology. 2004 Jul 1;199(2-3):241-50
Metallothionein is induced and trace element balance changed in target organs of a common viral infection.
Ilback NG, Glynn AW, Wikberg L, Netzel E, Lindh U. Toxicology Division, Swedish National Food Administration, P.O. Box 622, Uppsala S-751 26, Sweden. nilsgunnar.ilback@slv.se
In experimental studies on the common human coxsackievirus B type 3 (CB3) infection, administered cadmium (Cd) is known to accumulate in the liver and kidneys. CB3 adapted to Balb/c mice was used to study whether infection affects the Cd-binding protein, metallothionein (MT) and if this alters the normal physiological trace element balance in the liver, kidney, spleen and brain. On day 3 of infection, degradation of liver proteins (44%, P<0.01) occurred, whereas in the spleen, protein increased (63%, P<0.05). The infection increased MT five-fold (P<0.01) in liver and kidneys, and in spleen by 34% (P<0.05). A redistribution of Cd and copper (Cu) from the liver to the kidney was associated with this increase in MT, resulting in an increased (P<0.01) kidney/liver ratio for both elements. The infection increased the zinc (Zn) concentration more in the kidney than in the liver, but the kidney/liver ratio was not significantly affected. Results show that MT is increased in several organs during the early phase of infection and is associated with redistribution of both essential and non-essential trace elements. This may be a normal response in common infections that could adversely influence the pathogenesis when the host is concomitantly exposed to potentially toxic trace elements, even at levels in the physiological range.
Virus Induced Metallothionein Synthesis
Sci Total Environ. 2002 Feb 4;284(1-3):37-47
Effects of coxsackievirus B3 infection on the acute-phase protein metallothionein and on cytochrome P-4501A1 involved in the detoxification processes of TCDD in the mouse.
Funseth E, Pahlman M, Eloranta ML, Friman G, Ilback NG.
During acute infections, the synthesis of acute-phase proteins and other proteins participating in the host defence are stimulated in the liver and kidney. In previous studies of coxsackievirus B3 (CB3) infection in mice, we found that cadmium (Cd) accumulates in the kidney, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) accumulates in the liver. To study if CB3 infection affects the synthesis of the Cd-binding protein metallothionein (MT) and the TCDD-binding/detoxifying cytochrome P-450 (CYP-450) isozyme CYP1A1, the basal and TCDD-induced levels of serum MT and liver CYP1A1 isozyme were determined in healthy and CB3-infected A/J mice. Furthermore, because interferons affect CYP450 activity, the serum levels of the interferons alpha (IFN-alpha) and -beta (IFN-beta) were measured in CB3-infected mice and in mice treated with the interferon-inducer polyinosinic/polycytidylic acid (poly I/C). Virus or poly I/C was administered intraperitoneally (i.p.) on day 0 and 500 ng TCDD/kg bodyweight on day 1. On day 4, CB3 infection had induced MT approximately 10-fold, regardless of TCDD treatment (P < 0.01 in infected mice and P < 0.001 in infected, TCDD-treated mice). TCDD alone induced a 10-fold increase in CYP1A1 activity (P < 0.001), whereas infection alone suppressed the normal CYP1A1 activity by 75% (P < 0.001). Infection also suppressed the TCDD-induced CYP1A1 activity by approximately 30% (n.s.). Poly I/C suppressed CYP1A1 by 20-25% (n.s.) at both basal and TCDD-induced levels. Serum IFN-alpha and IFN-beta levels were undetectable in controls, in TCDD-treated and in the poly I/C-treated groups on day 4, probably because the short IFN peak is detectable only hours after injection. Conversely, on day 4 of the infection, IFN-alpha and IFN-beta were consistently raised in the TCDD-treated infected mice, whereas increased IFNs as a result of infection alone could be detected in only one individual. These results suggest that the normal host responses during acute infections down-regulate detoxifying processes in favour of acutephase protein synthesis. This may explain the observed changed pattern of accumulation, excretion and toxicity of the environmental pollutants cadmium and TCDD during this common virus infection.
Virus Induced Metallothionein Synthesis
Mol Cell Biol. 2001 Dec;21(24):8301-17
Influenza virus infection induces metallothionein gene expression in the mouse liver and lung by overlapping but distinct molecular mechanisms.
Ghoshal K, Majumder S, Zhu Q, Hunzeker J, Datta J, Shah M, Sheridan JF, Jacob ST. Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 333 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210, USA.
Metallothionein I (MT-I) and MT-II have been implicated in the protection of cells against reactive oxygen species (ROS), heavy metals, and a variety of pathological and environmental stressors. Here, we show a robust increase in MT-I/MT-II mRNA level and MT proteins in the livers and lungs of C57BL/6 mice exposed to the influenza A/PR8 virus that infects the upper respiratory tract and lungs. Interleukin-6 (IL-6) had a pronounced effect on the induction of these genes in the liver but not the lung. Treatment of the animals with RU-486, a glucocorticoid receptor antagonist, inhibited induction of MT-I/MT-II in both liver and lung, revealing a direct role of glucocorticoid that is increased upon infection in this induction process. In vivo genomic footprinting (IVGF) analysis demonstrated involvement of almost all metal response elements, major late transcription factor/antioxidant response element (MLTF/ARE), the STAT3 binding site on the MTI upstream promoter, and the glucocorticoid responsive element (GRE1), located upstream of the MT-II gene, in the induction process in the liver and lung. In the lung, inducible footprinting was also identified at a unique gamma interferon (IFN-gamma) response element (gamma-IRE) and at Sp1 sites. The mobility shift analysis showed activation of STAT3 and the glucocorticoid receptor in the liver and lung nuclear extracts, which was consistent with the IVGF data. Analysis of the newly synthesized mRNA for cytokines in the infected lung by real-time PCR showed a robust increase in the levels of IL-10 and IFN-gamma mRNA that can activate STAT3 and STAT1, respectively. A STAT1-containing complex that binds to the gamma-IRE in vitro was activated in the infected lung. No major change in MLTF/ARE DNA binding activity in the liver and lung occurred after infection. These results have demonstrated that MT-I and MT-II can be induced robustly in the liver and lung following experimental influenza virus infection by overlapping but distinct molecular mechanisms.
Virus Induced Metallothionein Synthesis
J Virol. 2001 May;75(9):4321-31
Global impact of influenza virus on cellular pathways is mediated by both replication-dependent and -independent events.
Geiss GK, An MC, Bumgarner RE, Hammersmark E, Cunningham D, Katze MG. Department of Microbiology, School of Medicine, University of Washington, Seattle 98195, USA.
Influenza virus, the causative agent of the common flu, is a worldwide health problem with significant economic consequences. Studies of influenza virus biology have revealed elaborate mechanisms by which the virus interacts with its host cell as it inhibits the synthesis of cellular proteins, evades the innate antiviral response, and facilitates production of viral RNAs and proteins. With the advent of DNA array technology it is now possible to obtain a large-scale view of how viruses alter the environment within the host cell. In this study, the cellular response to influenza virus infection was examined by monitoring the steady-state mRNA levels for over 4,600 cellular genes. Infections with active and inactivated influenza viruses identified changes in cellular gene expression that were dependent on or independent of viral replication, respectively. Viral replication resulted in the downregulation of many cellular mRNAs, and the effect was enhanced with time postinfection. Interestingly, several genes involved in protein synthesis, transcriptional regulation, and cytokine signaling were induced by influenza virus replication, suggesting that some may play essential or accessory roles in the viral life cycle or the host cell's stress response. The gene expression pattern induced by inactivated viruses revealed induction of the cellular metallothionein genes that may represent a protective response to virus-induced oxidative stress. Genome-scale analyses of virus infections will help us to understand the complexities of virus-host interactions and may lead to the discovery of novel drug targets or antiviral therapies.
Virus Induced Metallothionein Synthesis
Hepatology. 2002 May;35(5):1237-46
Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells.
Li K, Prow T, Lemon SM, Beard MR. Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX 775550133, USA.
Data suggesting that the hepatitis C virus (HCV) core protein influences normal cellular processes remain controversial. To determine the effects of core on cellular gene expression in hepatocytes, we developed a human hepatoma (Huh7)-derived cell line with tightly regulated core expression under the control of a tetracycline-regulated promoter. Cells expressing core did not have impaired proliferative abilities. Changes in gene expression profiles in response to core expression were determined using commercial oligonucleotide microarrays (Affymetrix GeneChip). Significant increases were observed in the abundance of mRNA-encoding members of the metallothionein (MT) family, as well as nicotinamide Nmethyltransferase (NNMT) and glutathione peroxidase-like protein (GPLP). These changes did not result from removal of tetracycline from growth media, and were confirmed in reverse-transcription polymerase chain reaction (RT-PCR) assays. They suggest that core protein expression leads to intracellular oxidative stress, and that vital cellular functions are, in turn, protected by up-regulation of cellular antioxidant defense mechanisms. In conclusion, these findings can explain many potentially conflicting prior observations concerning the effects of core on cellular physiology, and are of relevance to the role of core protein in the pathogenesis of HCV-related fibrosis and hepatocellular carcinoma.
Measles Rubella
Mumps
Nutrigenomics Support methylation cycle mutations
Excretion of metals
NO Excretion of metals Metals 1,2,3
Liver and Kidney Support
Liver and Kidney Support
Layer in additional herbs/supplements for viral support including IMF 4
Layer in additional herbs/supplements for viral support including IMF 4
Herpes Virus
Nutrigenomics Support methylation cycle mutations
Excretion of metals
NO Excretion of metals Metals 4 + IMF 1,2,6
Liver and Kidney Support
Liver and Kidney Support
Layer in additional herbs/supplements for viral support including IMF 1,2,6
Layer in additional herbs/supplements for viral support
Other DNA Viruses
Nutrigenomics Support methylation cycle mutations
Excretion of metals
NO Excretion of metals Metals 4,5 + IMF 1,2,3
Liver and Kidney Support
Liver and Kidney Support
Layer in additional herbs/supplements for viral support including IMF 1,2,6
Layer in additional herbs/supplements for viral support
How do we evaluate progress? •Methylation cycle progress glutathione/taurine global methylation assay •Viral titers •Metal excretion
Methylation cycle progress
glutathione/taurine
http://heartfixer.com/AMRI-Nutrigenomics.htm James C. Roberts MD FACC
CBS
So, we can look at the levels of taurine and glutathione as a way to assess methylation cycle balance
Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia by Neil Nathan, M.D. and Richard A. Van Konynenburg, Ph.D 9th International IACFS/ME Conference Reno, Nevada March 12-15, 2009
At the 2007 conference of the IACFS, one of us (RVK) proposed a hypothesis for the pathogenesis of CFS, called the Glutathione Depletion—Methylation Cycle Block hypothesis [1]. This hypothesis is based on research that had been done by James et al. in autism [2], and a recognition of similarities between the biochemical abnormalities in autism and those in CFS. Deth et al. [3] have published a somewhat similar hypothesis for autism. Shortly after the conference, with the help of a CFS patient (name withheld to protect privacy), RVK extracted part of the comprehensive treatment program developed by Amy Yasko, Ph.D., N.D., for autism and adult neurological diseases [4], and suggested the use of the resulting seven supplements for treating CFS. Initial experience with this
Metabolite
Reference value
Time on treatment (months) 0 3 3.97** (0.57) 0.50 (0.14) 8.54 (2.51) 227**** (16) 48.4 (11.0) 17.2 (10.2) 6 4.34** (0.67) 0.53 (0.15) 8.75 (2.91) 234** (14) 51.7 (10.9) 20.9*** (11.4)
Glutathione (GSH) (plasma) (nmol/mL) Glutathione (oxidized) (GSSG) (plasma) (nmol/mL) GSH / GSSG S-adenosylmethionine (SAM) (RBC) (mcmol/dL) S-adenosylhomocysteine (SAH) (RBC) (mcmol/dL) 5-Methyl-tetrahydrofolate (plasma) (nmol/L)
4.65 (0.42) 0.33 (0.09) 14.1 238.5 (8.8) 43.5 (2.8) 8.4 to 72.6
3.31* (0.49) 0.48* (0.15) 7.48 (2.47) 214* (20) 45.8 (13.2) 14.2 (9.6)
Time on treatment Figure 1. Plasma reduced glutathione in 21 CFS patients initially and after 3 and 6 months of treatment, compared to the laboratory reference range
Figure 2. Plasma S-adenosylmethionine in 21 CFS patients initially and after 3 and 6 months of treatment, compared to the laboratory reference range
As these figures show, glutathione, Sadenosylmethionine, and tetrahydrofolate all monotonically approached their laboratory reference values during the 6 months of treatment, but it appears that this period of treatment was not long enough for their mean values to reach the mean laboratory reference values. (As mentioned earlier, in fact treatment was continued for an additional 3 months, but since individualized treatments were added during this period, the results at 9 months were not included in the statistical analysis. It is interesting to note, however, that after 9 months of treatment the mean glutathione and SAM levels had reached and exceeded their laboratory reference values.)
Figure 5. Number of symptoms reported by 21 patients before and after 6 months of treatment
Discussion The objectives of this study were to test the Glutathione Depletion—Methylation Cycle Block hypothesis and to assess the potential efficacy of a treatment based upon it. The hypothesis predicts that CFS patients are depleted in glutathione and have a partial block in their linked methylation cycle and folate metabolism. It furthermore predicts that the abnormalities in glutathione, methylation, and the folate metabolism are linked together, and that the key to correcting these abnormalities is to stimulate the activity of the enzyme methionine synthase…. It is particularly noteworthy that treatment directed at assisting the methylation cycle produced a significant increase in the level of
How do we evaluate progress? •Methylation cycle progress glutathione/taurine global methylation assay •Viral titers •Metal excretion
Methylation cycle progress
global methylation assay
Principle & Procedure
The Methylamp™ Global DNA Methylation Quantification Kit contains all reagents required for quantification of global DNA methylation. In this assay, DNA is immobilized to the strip well specifically treated to have high affinity to the DNA. The methylated fraction of DNA can be recognized by 5-methylcytosine antibody and quantified through an ELISA-like reaction. The amount of methylated DNA is proportional to the OD intensity.
SCHEMATIC PROCEDURE:
Quantification of Methylated DNA
RECALL: Your DNA cannot change so we cannot change mutations in the methylation cycle, BUT the epigenetics can change. Epigenetics is the methylation of your DNA. This is inherited so it is really important as it is your “fallback” system. Changes in global methylation that are related to improvements in status help to validate the reasoning behind focusing on the methylation cycle.
To illustrate the difference between "genetics" and "epigenetics" in several different ways. Perhaps the easiest to explain in writing is to think about the following...if your computer has a broken "M" key, then when you go to type a document the letter "M" will always be missing from the words that include "M" .  This would be analogous to the mutations that we look at. It is like having a broken letter "M"  and so that will not change over time. This is part of the reason that the nutrigenomic profile is so useful is that the information you get today, will also be applicable 5 years from now, 10 years from now, 50 years from now. So, your actual genetics and mutations will not change, just as the broken "M"  will not magically fix itself.  On the other hand, when you type a document your computer also has an edit or word processing function, so that if you typed "_iss" your computer might say...did you mean "miss"??  In this way the editing function will catch the mistakes that occur because of the broken "M" key. While you still will not be able to type a letter "M" , you will be able to spell the words correctly in your document because the editing function will find the mistakes and point them out to you so that all you need to do is click on the correct spelling which gets around the broken "M"  key.
Okay, now the editing function on your computer is analogous to epigenetics in this example. And that can change over time. It is also inherited. So that while your actual DNA does not change, the way in which it is "edited" can change over time. Now, where we get into the catch 22...the editing function relies on methylation. The way that the editing works is to add methyl groups to the DNA to turn on and off certain areas. SO...while mutations in other areas would be less of an issue, the mutations that we look at, in the methylation cycle are of such central importance as they affect the actual DNA sequence, as well as the editing function. While the actual mutations will not change with methylation cycle support, the editing function should be able to change over time.
1
2
Pair 1 Pair 2
4/16/2006 2/13/2008 3/14/2006 8/1/2007
721 3533 579 2923
1.063 1.588 1.316 1.867
1.119 1.935 1.087 1.845
How do we evaluate progress? •Methylation cycle progress glutathione/taurine global methylation assay •Viral titers •Metal excretion
Viral titers
12/01
6/02
10/04
MUMPS Virus
5/06
5/07
How do we evaluate progress? •Methylation cycle progress glutathione/taurine global methylation assay •Viral titers •Metal excretion
Metal excretion
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