In October 2018, I called upon my son Michael Passwater to explain how high-dose (IV) vitamin C acts to help fight Sepsis. It is important that more physicians and lay people be aware of this proven fact, especially now.
In November 2018, we chatted with Paul Marik, M.D., FCCP, FCCM, about the details of his adjunct sepsis protocol, sometimes called “HAT” therapy, and the great life-saving success it was having.
It’s time to check on the procedure and see how it is doing. Well, surprise, surprise, a variation of the therapy also helps against COVID-19 and other serious problems as well. Improvements have been made to address hyper-inflammation, hyper-coagulation, and hypoxia caused by COVID-19, and the name has been expanded to “MATH+” for inhospital care and “I-MASK+” for outpatient care. See www.covid19criticalcare.com for the latest details. With the world health situation being what it is and persisting for some time, I feel that it is imperative to reiterate this information. Many lives are at stake.
Michael Passwater has reviewed the “MATH+” protocol in a freely circuited press release from the Orthomolecular Medicine News Service, which is presented here with permission. You can help spread the word by circulating it as well. This article may be freely circulated provided 1) that there is clear attribution to the Orthomolecular Medicine News Service and 2) that both the OMNS free subscription link http://orthomolecular.org/subscribe.html and also the OMNS archive link http://orthomolecular.org/resources/omns/index.shtml are included.
Michael Passwater is certified by the American Society for Clinical Pathology as a Medical Technologist, a specialist in Immunohematology, and a diplomate in Laboratory Management. He has worked in clinical laboratories for 28 years, and has a Bachelor of Science degree in Medical Technology from the University of Delaware. He has taken vitamin C and other nutrient supplements since before he was born.
Do the Math: “MATH+” Saves Lives
Orthomolecular Medicine News Service, December 23, 2020
By Michael Passwater
As the SARS-CoV-2 pandemic moved into North America, five experienced critical care physicians formed the “Front Line COVID-19 Critical Care Alliance” (FLCCC Alliance) (1). This working group, initially composed of critical care physicians Pierre Kory, G. Umberto Meduri, Jose Iglesias, Joseph Varon, and Paul Marik, was and remains devoted to developing and refining treatment protocols against COVID-19. In 2017, with the addition of intravenous hydroxycortisone (cortisol), ascorbic acid (vitamin C), and thiamine (vitamin B1) to standard sepsis care, Dr. Paul Marik found great success against sepsis, including septic shock. This became known as “HAT” therapy for sepsis, and was a starting point for the FLCCC Alliance in the battle against COVID-19. Given the complexity of COVID-19, the “HAT” therapy was quickly expanded to the “MATH+” protocol for the care of hospitalized COVID-19 patients.
M = Methylprednisolone; 80 mg loading dose then 40 mg q 12 hours for at least 7 days and until transferred out of the ICU
A = Ascorbic acid; 3 g IV q 6 hours for at least 7 days and/or until transferred out
T = Thiamine; 200 mg IV q 12 hours
H = Heparin (low molecular weight heparin); 1 mg/Kg subcutaneous q 12 hours, unless contraindicated
+ = Vitamin D3, melatonin, zinc, magnesium, B complex vitamins, atervastin, famotdine, and therapeutic plasma exchange if indicated
Early intervention and avoiding mechanical ventilation were also key aspects of their approach. The results through July 2020 at two hospitals implementing the MATH+ protocol have completed peer review and are now published online (2). What they found seems miraculous. Dr. Joseph Varon’s team at United Memorial Medical Center in Houston, TX, treated 140 hospitalized COVID-19 patients through July with a survival rate of 95.6%, and Dr. Paul Marik’s team at Sentara Norfolk General Hospital in Norfolk, VA, treated 191 hospitalized COVID-19 patients with a survival rate of 93.9%. A difference between the sites is that UMMC begins the protocol in the Emergency Department whereas Norfolk General begins the protocol in the ICU. In comparison, 461 other hospitals in the USA, UK, and China not using the MATH+ protocol had published survival rates ranging from 68% to 84.4%. With the CDC reporting over 5,000 hospitalized COVID-19 patients in the United States during the last week of November, wide use of the MATH+ could represent many thousands of additional survivors over the coming months. As of December 18, 2020, the number of physicians reporting using some or all of the MATH+ protocol has grown to above 120.
The article concludes:
“…the varied pathophysiologic mechanisms identified in COVID-19 likely require multiple therapeutic agents working in concert to counteract the diverse, deleterious consequences of this aberrant immune response. It is exceedingly unlikely that a “magic bullet” will be found, or even a medicine which would be effective at multiple stages of the disease. The MATH+ treatment protocol instead offers an inexpensive combination of medicines with a well-known safety profile based on strong physiologic rationale and an increasing clinical evidence base which potentially offers a life-saving approach to the management of COVID-19 patients.”
Surviving a hospital stay is great, but staying well enough to not need inpatient hospital care is even better. The FLCCC Alliance has developed the I-MASK protocol for outpatient care (3). In October, the medication ivermectin was added to the inpatient (MATH+) and outpatient (I-MASK) protocols. Ivermectin is an inexpensive, widely available medication earning the 2015 Nobel Prize for Physiology or Medicine for its anti-parasitic effects (4). It appears to be an effective
anti-viral agent as well (5-9).
This study adds to the pile of dozens of publications, including two prospective randomized controlled trials with vitamin D, associating better COVID-19 outcomes with sufficient vitamin D, zinc, vitamin C, and/or selenoproteins (10-20).
Dr. Joseph Varon has worked 270 consecutive days and counting. He and his team use the MATH+ protocol, and see >95% of their COVID-19 patients survive.
Discoveries and reminders from the SARS-CoV-2 pandemic:
- Ascorbic acid is very effective in the battle against known and unknown infectious agents. This has been known since the 1940s. Dr. Marik’s recent work has helped expand our understanding of the anti-inflammatory and endothelial cell (blood vessel) healing synergism from co-administration of ascorbic acid and cortisol (21-40).
- The three biggest life-threatening aspects of serious COVID-19 disease are hyper-inflammation, hyper-coagulation, and severe hypoxia. Ascorbic acid’s impact on immune cells, endothelial cells, and airway tissues helps to mitigate all three concerns (21-23,31,41-53).
- In the critical care setting, the intravenous coadministration of cortisol and ascorbic acid has been shown to begin reversal of glycocalyx and endothelial cell damage within minutes.
- Frequent dosing to maintain a steady state is better, because ascorbic acid has a short half-life. Early intervention is better, because activated white blood cells are dependent on a high level of ascorbic acid. Taking gram quantities with each meal, and increasing intake to bowel tolerance during illness, is helpful. When ill, it is necessary to take ascorbic acid throughout the day; much more than can be absorbed in one sitting.
- Nutrients do not work alone; observational and/or interventional studies that test the effect of administering single nutrients are likely to miss confounding factors and essential synergies needed for optimal benefit and accurate assessment (54-56).
- Maintaining a vitamin D blood level of 40 – 80 ng/mL is a key part of optimizing immune health.
- Vitamin D is a powerful hormone, impacting the expression and function of over 3,000 genes, and is a major component of the innate and adaptive immune systems. Dr. Will Taylor has shown that two of these genes, TRXND1 and GCLC, become an important battleground during SARS-Cov-2 infection. He has shown that the virus suppresses expression of genes associated with key antioxidants, regulators of DNA synthesis, ferroptosis, and endoplasmic reticulum stress (TXNRD1, TXNRD3, GCLC, GPX4, SELENOF, SELENOK, SELENOM, SELENOS), while vitamin D significantly upregulates two of these genes: TXNRD1 and GCLC (57).
- Studies of healthy tribal populations in non-industrialized countries have shown blood vitamin D levels of 40 ng/mL (58).
- In 1903, Niels Ryberg Finsen received the Nobel Prize in Physiology and Medicine “in recognition of his contribution to the treatment of diseases…with concentrated light radiation, whereby he has opened a new avenue for medical science” (59).
- Vitamin D insufficiency and deficiency has been associated with increased risk of cardiovascular death, ICU death, and COVID-19 death (15,60,61).
- Magnesium is an essential cofactor in vitamin D metabolism (as well as being an essential co-factor for biologically active ATP). (60).
- Balancing D3 intake with vitamin K2 is important for optimal calcium metabolism and distribution. A ratio of 125-250 mcg (5,000-10,000 IU) D3 to 100 mcg K2 MK7 is helpful (62,63).
- Renal disease seriously impairs D3 and selenoprotein metabolism (64,65).
- Vitamin D and Selenium are intimately connected in human biochemistry.
- Dr. Schutze et al published in 1999 that the effective upregulation of TXNRD1 by vitamin D3 required an adequate level of selenium (66).
- Both D3 and the essential amino acid selenocysteine must be present in adequate quantities for effective production of several selenoproteins in humans (67).
- Co-supplementation with D3 and L-cysteine has been shown to improve the status of GSH, CYP24A1, and vitamin D regulatory genes including greater upregulation of PGC-1alpha, NRF2, and GLUT-4 gene expression compared to D3 alone (68).
- GSH, in turn, increases circulating vitamin D and augments the actions of vitamin D (69-71).
- Vitamin D and selenoproteins are necessary for the formation and maintenance of immune memory cells. Not only does insufficiency increase the risk of infectious illness, it also impacts the lasting benefit of adaptive immunity from the infection. This may also have implications for the success of vaccination efforts (12,13,72-75).
- Selenium concentrations of 70-150 ng/mL are consistent with good health in the general population. Blood selenoprotein P levels of 4.3 +/- 1.0 mg/L have been associated with improved outcomes in COVID-19 patients; maintenance of Zn and SELENOP within the reference range has been shown to indicate high survival odds (14,76-78).
- Germ theory is helpful, but the host constitution still matters. Inadequate nutrition remains global and national public health enemy #1.
- Host factors impact the pathogenicity of many viruses. Many impactful host factors are modifiable and related to nutrition (79-83).
- Some viruses mutate into more harmful strains when they replicate within a malnourished environment—particularly in selenium deficient environments. “Second-hand malnutrition” is an underappreciated concept. As long as people are malnourished, more virulent strains are likely to continue to emerge which then also put nourished people at risk due to the viral mutations (84).
- Fighting infections greatly increases metabolic demand on the human body. Viruses need nutrients too; theft and/or destruction of host nutrients and essential proteins further impacts the need for additional nutrients for people to eliminate and recover from infections (76, 85-87).
As a reminder for those conducting and reviewing nutrient research, here are “rules” published by Robert P. Heaney in his landmark article “Guidelines for optimizing design and analysis of clinical studies of nutrient effects” doi:10.1111/nure.12090 Nutrition Reviews® Vol. 72(1):48–54
Box 1 Rules for individual clinical studies of nutrient effects.
- Basal nutrient status must be measured, used as an inclusion criterion for entry into study, and recorded in the report of the trial.
- The intervention (i.e., change in nutrient exposure or intake) must be large enough to change nutrient status and must be quantified by suitable analyses.
- The change in nutrient status produced in those enrolled in the trials must be measured and recorded in the report of the trial.
- The hypothesis to be tested must be that a change in nutrient status (not just a change in diet) produces the sought-for effect.
- Conutrient status must be optimized in order to ensure that the test nutrient is the only nutrition related, limiting factor in the response.
Box 2 Rules for study inclusion in systematic reviews and meta-analyses.
- The individual studies selected for review or meta-analysis must themselves have met the criteria listed in Box 1 for nutrient trials.
- All included studies must have started from the same or similar basal nutrient status values.
- All included studies must use the same or closely similar doses.
- All included studies must have used the same chemical form of the nutrient and, if foods are used as the vehicle for the test nutrient, all studies must have employed the same food matrix.
- All included studies must have the same conutrient status.
- All included studies must have had approximately equal periods of exposure to the altered intake.
- Front Line Covid-19 Critical Care Alliance https://covid19criticalcare.com
- Kory P, Meduri GU, Iglesias J, Varon J, Marik PE. Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19. Journal of Intensive Care Medicine. https://doi.org/10.1177/0885066620973585
- FLCC Alliance (2020) I-MASK+ Protocol. https://hardball.parkoffletter.org/wp-content/uploads/2020/12/FLCCC-I-MASK-Protocol-v6-2020-12-09-ENGLISH.pdf
- The Nobel Prize in Physiology or Medicine 2015. NobelPrize.org. Nobel Media AB 2020. https://www.nobelprize.org/prizes/medicine/2015/summary
- Tay MYF, Fraser JE, Chan WKK, et al. (2013) Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Research. 99:301-306. https://pubmed.ncbi.nlm.nih.gov/23769930
- Varghese FS, Kaukinen P, GlÃ¤sker S, et al. (2016) Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Research. 126:117-124. https://pubmed.ncbi.nlm.nih.gov/26752081
- Wagstaff KM, Sivakumaran H, Heaton SM, et al. (2012) Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochemical Journal. 443:851-856. https://pubmed.ncbi.nlm.nih.gov/22417684
- King CR, Tessier TM, Dodge MJ, et al. (2020) Inhibition of Human Adenovirus Replication by the Importin alpha/beta1 Nuclear Import Inhibitor Ivermectin. Journal of Virology. 94:e00710-20. https://pubmed.ncbi.nlm.nih.gov/32641484
- Caly L, Druce JD, Catton MG, et al. (2020) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 178:104787. https://pubmed.ncbi.nlm.nih.gov/32251768
- Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF (2020) SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS ONE 15:e0239252. https://doi.org/10.1371/journal.pone.0239252
- Mercola J, Grant WB, Wagner CL. (2020) Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients, 12:3361. https://www.mdpi.com/2072-6643/12/11/3361
- Zhang J, Taylor EW, Bennett K, Saad R, Rayman MP. (2020) Association between regional selenium status and reported outcome of COVID-19 cases in China. Am J Clin Nutr, 111:1297-1299. https://doi.org/10.1093/ajcn/nqaa095
- Moghaddam A, Heller RA, Sun Q, et al. (2020) Selenium deficiency is associated with mortality risk from COVID-19. Nutrients 12:2098. https://doi.org/10.3390/nu12072098
- Heller RA, Sun Q, Hackler J et al. (2021) Prediction of survival odds in COVID-19 by zinc, age, and selenoprotein P as composite biomarker. Redox Biology 38:101764. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/33126054
- Merzon E. (2020) Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS J. 287:3693-3702. https://pubmed.ncbi.nlm.nih.gov/32700398
- Castillo ME, Costa LME, Barrios JMV, et al. (2020) Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol 203:105757. https://pubmed.ncbi.nlm.nih.gov/32871238
- Jungreis I, Kellis M. (2020) Mathematical analysis of Cordoba calcifediol trial suggest strong role for vitamin D in reducing ICU admissions of hospitalized COVID-19 patients. MedRxiv preprint. https://doi.org/10.1101/2020.11.08.20222638
- Grassroots Health Nutrient Research Institute. https://www.grassrootshealth.net
- Polonikov, A. (2020) Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in COVID-19 patients. ACS Infect Dis 2020, 6, 7, 1558-1562. https://doi.org/10.1021/acsinfecdis.0c00288
- Horowitz RI, Freeman PR, Bruzzese J. (2020) Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir Med Case Rep 2020, 101063. https://doi.org/10.1016/j.rmcr.2020.101063
- Zhao B, Fei J, Chen Y, et al. (2014) Vitamin C treatment attenuates hemorrhagic shock related multi-organ injuries through the induction of heme oxygenase-1. BMC Complementary and Alternative Medicine 2014, 14:442-454. https://pubmed.ncbi.nlm.nih.gov/25387896
- Oudemans-van Straaten HM, Spoelstra-de Man AME, de Waard MC. (2014) Vitamin C revisited. Critical Care 18:460-473. https://pubmed.ncbi.nlm.nih.gov/25185110
- Fowler AA, Syed AA, Knowlson S, Natarajan R, et al. (2014) Phase I Safety trial of intravenous ascorbic acid in patients with severe sepsis. Journal of Translational Medicine, 12:32. https://pubmed.ncbi.nlm.nih.gov/24484547
- Gu W, Cheng A, Barnes H, Kuhn B, Schivo M. (2014) Vitamin C Deficiency Leading to Hemodynamically Significant Bleeding. JSM Clinical Case Reports. 2:1046. http://www.jscimedcentral.com/CaseReports/casereports-2-1046.pdf
- Manning J, Mitchell B, Appaduras DA, May JM, et al. (2013) Vitamin C Promotes Maturation of T-Cells. Antioxid Redox Signal. 19:2054-2067. https://pubmed.ncbi.nlm.nih.gov/23249337
- Ladumer A, Schmitt CA, Schachner D, et al. (2012) Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status. Free Radic Biol Med. 2012 May 15; 52:2082-2090. https://pubmed.ncbi.nlm.nih.gov/22542797
- Reddell L, Cotton BA. (2012) Antioxidant and micronutrient supplementation in trauma patients. Curr Opin Clin Nutr Metab Care. 15:181-187. https://pubmed.ncbi.nlm.nih.gov/22261953
- May JM, Qu ZC. (2010) Ascorbic Acid Prevents Increased Endothelial Permeability Caused by Oxidized Low Density Lipoprotein. Free Radical Res. 44:1359-1368. https://pubmed.ncbi.nlm.nih.gov/20815791
- Duconge J, Miranda-Massari JR, Gonzalez MJ, et al. (2008) Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate. P R Health Sci J. 27:7-19. http://prhsj.rcm.upr.edu/index.php/prhsj/article/view/13
- Deicher R, Ziai F, Begknayer C, et al. (2005) Low Total Vitamin C Plasma Level Is a Risk Factor for Cardiovascular Morbidity and Mortality in Hemodialysis Patients. J Am Soc Nephrol. 16:1811-1818. https://pubmed.ncbi.nlm.nih.gov/15814831
- Heller R, Munscher-Paulig F, Grabner R, Till V. (1999) L-Ascorbic Acid Potentiates Nitric Oxide Synthesis in Endothelial Cells. J Biol Chem, 274:8254-8260. https://pubmed.ncbi.nlm.nih.gov/10075731
- Leibovitz B, Siegel BV. (1978) Ascorbic acid, neutrophil function, and the immune response. Int J Vitam Nutr Res. 48:159-164. https://pubmed.ncbi.nlm.nih.gov/357320
- Klenner FR. (1971) Observations on the Dose and Administration of Ascorbic Acid When Employed Beyond the Range of a Vitamin in Human Pathology. J Applied Nutrition, 1971, Vol 23:61-87. https://jeffreydachmd.com/wp-content/uploads/2013/07/Ascorbic_Acid_Fred_klenner_1971.pdf
- Lee RE. (1961) Ascorbic Acid and the Peripheral Vascular System. Ann N Y Acad Sci. 92:295-301. https://pubmed.ncbi.nlm.nih.gov/13760268
- Lee RE, Holze EA. (1951) Nutritional factors in hemodynamics: dissociation of pressor response and hemorrhage resistance in avitaminosis C. Proc Soc Exp. Biol Med. 76:325-329. https://pubmed.ncbi.nlm.nih.gov/14827915
- McCormick WJ. (1951) Vitamin C in the Prophylaxis and Therapy of Infectious Diseases. Arch Pediatr, 68:1-9.
- Klenner FR. (1949) The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C. Journal of Southern Medicine and Surgery, 111:209-214. https://pubmed.ncbi.nlm.nih.gov/18147027 https://www.seanet.com/~alexs/ascorbate/194x/klenner-fr-southern_med_surg-1949-v111-n7-p209.htm
- Klenner FR. (19448) Virus Pneumonia and its Treatment with Vitamin C. Journal of Southern Medicine and Surgery, 110:36-38. https://pubmed.ncbi.nlm.nih.gov/18900646 https://www.mv.helsinki.fi/home/hemila/CP/Klenner_1948_ch.pdf
- Lee RE, Lee NZ. (1947) The peripheral vascular system and its reactions in scurvy; an experimental study. Am J Physiol, 149:465-475. https://pubmed.ncbi.nlm.nih.gov/20239975
- Jungeblut CW. (1935) Inactivation of Poliomyelitis Virus in vitro by Crystalline Vitamin C (Ascorbic Acid). J Exp Med, 62:517-521. https://pubmed.ncbi.nlm.nih.gov/19870431
- Colunga Biancatelli RM, Berrill M, Catravas JD, Marik PE. (2020) Quercetin and Vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol, 11:1451. https://pubmed.ncbi.nlm.nih.gov/32636851
- Colunga Biancatelli RM, Berrill M, Marik PE. (2020) The antiviral properties of vitamin C. Expert Rev Anti Infect Ther, 18:99-101. https://pubmed.ncbi.nlm.nih.gov/31852327
- Barabutis N, Khangoora V, Marik PE, Catravas JD. (2017) Hydrocortisone and Ascorbic Acid synergistically protect and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Chest, 152:954-962. https://pubmed.ncbi.nlm.nih.gov/28739448
- de Melo AF, Homem-de-Mello M. (2020) High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection. Crit Care, 24:500. https://pubmed.ncbi.nlm.nih.gov/32792018
- Marik PE. (2018) Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) for the treatment of sepsis. Focus on ascorbic acid. Nutrients, 10:1762. https://pubmed.ncbi.nlm.nih.gov/30441816
- May JM, Qu ZC. (2011) Ascorbic acid prevents oxidant-induced increases in endothelial permeability. Biofactors, 37:46-50. https://pubmed.ncbi.nlm.nih.gov/21328627
- Utoguchi N, Ikeda K, Saeki K et al. (1995) Ascorbic acid stimulates barrier function of cultured endothelial cell monolayer. J Cell Physiol, 163:393-399. https://pubmed.ncbi.nlm.nih.gov/7706381
- Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. (2010) Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A. Free Radic Biol Med 2010; 48:128-35. https://pubmed.ncbi.nlm.nih.gov/19840845
- Khan HMW, Parikh N, Megah SM, Predeteanu GS. (2020) Unusual Early Recovery of a Critical COVID-19 After Administration of Intravenous Vitamin C. Am J Case Rep, 21:e925521 https://pubmed.ncbi.nlm.nih.gov/32709838
- Bharara A, Grossman C, Grinnon D, et al. (2016) Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome. Case Rep Crit Care. 2016:8560871. https://pubmed.ncbi.nlm.nih.gov/27891260
- May JM, Harrison FE. (2013) Role of Vitamin C in the Function of the Vascular Endothelium. Antioxid Redox Signal. 19:2068-2083. https://pubmed.ncbi.nlm.nih.gov/23581713
- Marik PE, Khangoora V, Rivera R, et al. (2017) Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest, 151:1229-1238. https://pubmed.ncbi.nlm.nih.gov/27940189
- Barabutis N, Khangoora V, Marik PE, Catravas JD. (2017) Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest, 152:954-962. https://pubmed.ncbi.nlm.nih.gov/28739448
- Parker WH, Rhea EM, Qu ZC, Hecker MR, May JM. (2016) Intracellular ascorbate tightens the endothelial permeability barrier through Epac1 and the tubulin cytoskeleton. Am J Physiol Cell Physiol. 311:C652-C662. https://pubmed.ncbi.nlm.nih.gov/27605450
- Ferry M, Coley N, Andrieu S, et al. (2013) How to design nutritional intervention trials to populations and apply for efficacy claims: a statement from the international academy on nutrition and aging task force.J Nutr Heal Aging. 17:619-523. https://pubmed.ncbi.nlm.nih.gov/23933873
- Bieri JG. (1964) Synergistic effects between antioxidants and selenium or vitamin E. Biochem Pharmacol. 13:1465-1470. https://pubmed.ncbi.nlm.nih.gov/14239620
- Badmaev V, Majeed M, Passwater RA. (1996) Selenium: A Quest for Better Understanding. Altern Ther Health Med. 2:59-62, 65-67. https://pubmed.ncbi.nlm.nih.gov/8795924
- Taylor, E.W. RNA viruses vs. DNA synthesis: a general viral strategy that may contribute to the protective antiviral effects of selenium. Preprints 2020, 10.20944/preprints202006.0069.v1, 2020060069, http://doi.org/10.20944/preprints202006.0069.v1
- Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA. (2012) Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 108:1557-1561. https://pubmed.ncbi.nlm.nih.gov/22264449
- The Nobel Prize in Physiology or Medicine 1903. NobelPrize.org. Nobel Media AB 2020. https://www.nobelprize.org/prizes/medicine/1903/summary
- Dean C (2017) The Magnesium Miracle, 2nd Ed. Ballantine Books. ISBN-13 : 978-0399594441
- Deng X, Song Y, Manson JE, et al. (2013) Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med, 11:187. https://pubmed.ncbi.nlm.nih.gov/23981518
- Flore R, Ponziani FR, Di Rienzo TA, et al. (2013) Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis. Eur Rev Med Pharmacol Sci. 17:2433-2440. https://pubmed.ncbi.nlm.nih.gov/24089220
- Schwalfenberg GK. (2017) Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. J Nutr Metab. 2017:6254836. https://pubmed.ncbi.nlm.nih.gov/28698808
- Bosworth C, de Boer IH. (2013) Impaired vitamin D metabolism in CKD. Semin Nephrol. 33:158-168. https://pubmed.ncbi.nlm.nih.gov/23465502
- Reinhardt W, Dolff S, Benson S, et al. (2015) Chronic Kidney Disease Distinctly Affects Relationship Between Selenoprotein P Status and Serum Thyroid Hormone Parameters. Thyroid. 25:1091-1096. https://pubmed.ncbi.nlm.nih.gov/26348725
- SchÃ¼tze N, Fritsche J, Ebert-Dumig R, et al. (1999) The selenoprotein thioredoxin reductase is expressed in peripheral blood monocytes and THP1 human myeloid leukemia cells–regulation by 1,25-dihydroxyvitamin D3 and selenite. Biofactors, 10:329-338, https://pubmed.ncbi.nlm.nih.gov/10619700
- Jain SK, Micinski D. (2013) Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun 437:7-11, https://pubmed.ncbi.nlm.nih.gov/23770363
- Alvarez JA, Chowdhury R, Jones DP, et al. (2014) Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin Endocrinol (Oxf) 81:458-466. https://pubmed.ncbi.nlm.nih.gov/24628365
- Parsanathan R, Jain SK. (2019) Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice. Sci Rep. 9:14784. https://pubmed.ncbi.nlm.nih.gov/31616013
- Fan YG, Pang ZQ, Wu TY, et al. (2020) Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity. Free Radic Biol Med. 161:139-149. https://pubmed.ncbi.nlm.nih.gov/33068737
- Jain SK, Parsanathan R, Achari AE, et al. (2017) Glutathione Stimulates Vitamin D Regulatory and Glucose Metabolism Genes, Lowers Oxidative Stress and Inflammation, and Increases 25-Hydroxy-Vitamin D Levels in Blood: A Novel Approach to Treat 25-Hydroxyvitamin D Deficiency. Antioxid Redox Signal. 29:1792-1807. https://pubmed.ncbi.nlm.nih.gov/30160165
- Guillin OM, Vindry C, Ohlmann T, Chavatte L. (2019) Selenium, Selenoproteins, and Viral Infection. Nutrients, 11:2101. https://doi.org/10.3390/null092101
- Huang Z, Rose AH, Hoffman PR. (2012) The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities. Antioxid Redox Signal. 16:705-743. https://pubmed.ncbi.nlm.nih.gov/21955027
- Cantorna MT, Snyder L, Lin Y0D, Yang L. (2015) Vitamin D and 1,25(OH)2D Regulation of T cells. Nutrients, 7:3011-3021. https://pubmed.ncbi.nlm.nih.gov/25912039
- Looman KIM, Jansen MAE, Voortman T, et al. (2017) The role of vitamin D on circulating memory T cells in children: The generation R Study. Pediatr. Allergy Immunol. 28:579-587. https://pubmed.ncbi.nlm.nih.gov/28686349
- Taylor EW, Radding W. (2020) Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the Viral M pro Protease Target Host Selenoproteins and Glutathione Synthesis? Front Nutr 7:143. https://pubmed.ncbi.nlm.nih.gov/32984400
- Bellinger FP, Ramoy AV, Reeves MA, Berry MJ. (2009) Regulation and function of selenoproteins in human disease. Biochem J, 422:11-22. https://pubmed.ncbi.nlm.nih.gov/19627257
- Hiffler L, Rakotoambinina B. (2020) Selenium and RNA viruses interactions: Potential implications for SARSCov-2 infection (COVID-19). Front Nutr. 7:164. https://pubmed.ncbi.nlm.nih.gov/33015130
- Beck MA, Levander OA, Handy J. (2003) Selenium deficiency and viral infection. J Nutr. 133(5 Suppl 1):1463S-1467S. https://pubmed.ncbi.nlm.nih.gov/12730444
- Cunningham-Rundles S, McNeeley DF, Moon A.(2005) Mechanisms of nutrient modulation of the immune response. J Allergy Clin Immunol. 115:1119-1128; quiz 1129. https://pubmed.ncbi.nlm.nih.gov/15940121
- Hoffmann PR, Berry MJ. (2008) The influence of selenium on immune responses. Mol Nutr Food Res. 52:1273-1280. https://pubmed.ncbi.nlm.nih.gov/18384097
- Taylor AK, Cao W, Vora KP, et al. (2013) Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis. 207:501-510. https://pubmed.ncbi.nlm.nih.gov/22949306
- Beck MA, Handy J, Levander OA. (2004) Host nutritional status: the neglected virulence factor. Trends Microbiol, 12:417-423. https://pubmed.ncbi.nlm.nih.gov/15337163
- Harthill M. (2011) Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases. Biol Trace Elem Res. 143:1325-1336. https://pubmed.ncbi.nlm.nih.gov/21318622
- Mak TW, Grusdat M, Duncan GS, et al. (2017) Glutathione Primes T cell Metabolism for Inflammation. Immunity. 46:675-689, 1089-1090. https://pubmed.ncbi.nlm.nih.gov/28423341, https://pubmed.ncbi.nlm.nih.gov/28636957
- Leibovitz B, Siegel BV. (1978) Ascorbic acid, neutrophil function, and the immune response. Int J Vitam Nutr Res. 48:159-164. https://pubmed.ncbi.nlm.nih.gov/357320
- Manning J, Mitchell B, Appadurai DA, et al. (2013) Vitamin C Promotes Maturation of T-Cells. Antioxid Redox Signal. 19:2054-2067. https://pubmed.ncbi.nlm.nih.gov/23249337