•Face masks filter bacteria, dirt, plastic fibres, but may also cause health harms.
•Inhalation of particles and potentially toxic substances from the mask is possible.
•We found high micro- and nanoplastics release and content.
•we evidenced exceedances for volatile organic compounds, acrolein, phthalates.
•also for xylene, per/polyfluoroalkyl substances and for Pb, Cd, Co, Cu, Sb and TiO2.
24 studies were included (experimental time 17 min to 15 days) evaluating content and/or release in 631 masks (273 surgical, 228 textile and 130 N95 masks). Most studies (63%) showed alarming results with high micro- and nanoplastics (MPs and NPs) release and exceedances could also be evidenced for volatile organic compounds (VOCs), xylene, acrolein, per-/polyfluoroalkyl substances (PFAS), phthalates (including di(2-ethylhexyl)-phthalate, DEHP) and for Pb, Cd, Co, Cu, Sb and TiO2.
My Preliminary Toxicology Findings
Xylene: thrombocytopenia and forms of leukemia
PFAS: cancer of the kidneys and testis
Lead PB: IARC a probable human carcinogen
Cadmium: Carcinogen
Cobalt Co: Ions are genotoxic, increase ROS reactive oxygen, increase cancer risk, impair DNA repair
Sb: possible human carcinogen
TiO2: Possible human carcinogen, California Proposition 65
Acrolein: Immune dysfunction, increase ROS, DNA aducts, mitochondrial impacts
Owing to the large surface area and strong hydrophobicity, MPs may act as a vector to adsorb environmental pollutants efficiently, including organic pollutants, heavy metals, and pathogenic microorganisms, leading to unexpected consequences.
Oxidative stress
Oxidative stress is caused by an imbalance between ROS production and the antioxidant system (Bezek, 2005). This process is mainly manifested by increased ROS, RNS, and the change of oxidative stress-related enzymes and metabolites (Filomeni et al., 2015). So far, a large number of experimental investigations have pointed out the crucial role of oxidative stress and the antioxidant defense system failure in toxicity elicited by MPs. For instance, Wu et al. demonstrated that PS-NPs caused
Jyrkkanen Preliminary Conclusion
Face masks represent a threat to the health which must be weighed against the risk of not using them. They certainly need to be made of better less toxic materials.
3. Campanale C, Massarelli C, Savino I, Locaputo V, Uricchio VF. A Detailed Review Study on Potential Effects of Microplastics and Additives of Concern on Human Health. Int J Environ Res Public Health. 2020 Feb 13;17(4):1212. doi: 10.3390/ijerph17041212. PMID: 32069998; PMCID: PMC7068600.
Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with severe consequences, including symptoms, hemodynamic instability, increased cardiovascular mortality, and stroke. While other arrhythmias such as torsades de pointes and sinus bradycardia are more typically thought of as drug-induced, AF may also be precipitated by drug therapy, although ascribing causality to drug-associated AF is more difficult than with other drug-induced arrhythmias. Drug-induced AF is more likely to occur in patients with risk factors and comorbidities that commonly coexist with AF, such as advanced age, alcohol consumption, family history of AF, hypertension, thyroid dysfunction, sleep apnea, and heart disease. New-onset AF has been associated with cardiovascular drugs such as adenosine, dobutamine, and milrinone. In addition, medications such as corticosteroids, ondansetron, and antineoplastic agents such as paclitaxel, mitoxantrone, and anthracyclines have been reported to induce AF. Whether bisphosphonate drugs are associated with new onset AF remains controversial and requires further study. The potential contribution of specific drug therapy should be considered when patients present with new onset AF.
Cancer therapy has made major progress in the past several decades, but treatments are often accompanied by significant side effects. Arrhythmias are a widespread complication of some antineoplastic drugs, with atrial fibrillation (AF) being the most often encountered drug-associated arrhythmia. Preexisting AF risk factors are commonly present in cancer patients who develop drug-associated AF, and active cancer itself may cause or promote AF. Although anticancer drugs may induce AF in cancer patients without AF risk factors, it appears that most drug-associated AF develop when cancer drugs add or aggravate precancer-existing and/or cancer-related pro-AF factors/alterations, additively or synergistically producing AF. Abnormalities in intracellular calcium activity seem to be involved in the generation of anticancer drug-induced AF. In cancer survivors with cancer therapy-induced cardiomyopathy, AF often occurs, with most of the arrhythmias likely to develop secondary to the cardiomyopathy. AF may lead to modification or even cessation of cancer therapy. The management of AF in patients with cancer is currently conducted largely based on pragmatic assumptions. This review briefly discusses AF caused by anticancer drugs and the underlying mechanisms.
Abstract
Oxidative stress has been suggested to play a role in the pathogenesis of atrial fibrillation (AF). Indeed, the prevalence of AF increases with age as does oxidative stress. However, the mechanisms linking redox state to AF are not well understood. In this study we identify a link between oxidative stress and aberrant intracellular Ca(2+) release via the type 2 ryanodine receptor (RyR2) that promotes AF. We show that RyR2 are oxidized in the atria of patients with chronic AF compared with individuals in sinus rhythm. To dissect the molecular mechanism linking RyR2 oxidation to AF we used two murine models harboring RyR2 mutations that cause intracellular Ca(2+) leak. Mice with intracellular Ca(2+) leak exhibited increased atrial RyR2 oxidation, mitochondrial dysfunction, reactive oxygen species (ROS) production and AF susceptibility. Both genetic inhibition of mitochondrial ROS production and pharmacological treatment of RyR2 leakage prevented AF. Collectively, our results indicate that alterations of RyR2 and mitochondrial ROS generation form a vicious cycle in the development of AF. Targeting this previously unrecognized mechanism could be useful in developing effective interventions to prevent and treat AF.
Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis
Alam MS, Czajkowsky DM. SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev. 2022 Feb;63:44-57. doi: 10.1016/j.cytogfr.2021.11.001. Epub 2021 Nov 15. PMID: 34836751; PMCID: PMC8591899.
Uversky VN, Redwan EM, Makis W, Rubio-Casillas A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines (Basel). 2023 May 17;11(5):991. doi: 10.3390/vaccines11050991. PMID: 37243095; PMCID: PMC10222767.
What leaps out at me is the link between oxidative stress and atrial fibrillation. It has been of found that damage to mitochondria can be caused by spike and this can induce oxidative stress ergo potentially AFib. Repeated vaccination may induce autoimmune mycarditis. The inflammatory cascade induces fibrotic changes in the myocardium, an arrhythmogenic process that stimulates further inflammation. I have seen slides of mitochondrial damage induced by spike protein. Mitochondrial damage has been linked to heart disease and immune dysfunction.
Discussion Paper to Stimulate Inclusion of Epigenetics and Epigenetically active substances in Carcinogenicity Testing.
This is a discussion paper and advisory for initial problem attack. Comments appreciated. Please email to me directly. Jorma Jyrkkanen, BSc, PDP. Environmental Biologist, jjyrkkanen76@outlook.com
Abstract:
Recent developments in epigenetics, knowledge of lateral gene transfer LGT, impacts of antibiotics on mitochondria, antibiotic induced cancers, antibiotic resistance, technologies that enable easy weaponization of lethal viruses WLV highlight the need for premapproval testing of pollutants, industrial chemicals including pesticides, biological pesticides, genetically modified products, viruses under investigarion world-wide in military and commercial medical laboratories, antibiotics and drugs in general; for carcinogenicity, epigenetic profiles, impacts on mitochondria, LGT potential of introduced or altered genes, effects on tumor suppressor genes, effect on DNA methylation, DNA repair genes, promoters, microRNA up or down regulation, hypomethylation, hypermethylation, phosphorylation and testing genes found silenced in cancer or deleterious genes activated, impacts on the ubiquitin-proteasome pathway(UPP). There is a need for registration and UN oversight of lethal technologies and substances. Diagnosis of cancer causing infectious agents should result in rules to prevent transmission. We need to take them more seriously than previously. Vaccines must not be developed for single nations to enable aggression of pathogens they provide prophylaxis from being used as bioweapons. Vaccine must not be approved anywhere anytime if they do not prevent infection or stop transmission or if there is a drug that will cure the ailment. Draft regulatory rules are presented.
Background
The ability to manipulate genetic material has undergone a quantum leap in recent years such that a large variety of altered genes and genetic products and means of manipulation of those genes as well as delivery mechanisms has been developed. Our understanding of the epigenetic determinants of cancer has also grown immensely in recent times ( Stephen B Baylin and Peter A Jones. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016 Sep; 8(9): a019505.)
Cancer causing infectious agents that have epigenetic components and are potential targets for cut and paste technologies have been reviewed by IARC recently. (https://gco.iarc.fr/causes/infections/help).
Epigenetic Overview Figure
Carcinogenic Infectious agents
Ten infectious agents that have been classified as well-established (Group 1) carcinogenic agents in humans by the International Agency for Research on Cancer (IARC) were considered, namely: Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 — known collectively as high-risk types), Epstein–Barr virus (EBV), human herpesvirus type 8 (HHV-8; also known as Kaposi sarcoma-associated herpesvirus), human T-cell lymphotropic virus type 1 (HTLV-1), Opisthorchis viverrini, Clonorchis sinensis, and Schistosoma haematobium. Prevention of contagion should be a consequence of the knowledge of their serious potential. As well, synergisms and promoters need to be identified. The search for their epigenetic action potential needs elaboration and classification and opportunities for pharmaceutical targeting to reset methylation tags and develop potential vaccines.
Population attributable fraction (PAF) of cancer incidence attributable to infections
The PAF for carcinogenic infections is an estimate of the proportion of new cancer cases that would have been prevented in a population if all infections had been avoided or successfully treated before they caused cancer. The number of cancer cases that would have been prevented in a population if all infections had been avoided or successfully treated was calculated by multiplying the PAF by the total cancer burden (i.e. the total number of all cancers in the population).
Infection-related cancers
Cancers for which there is well-established evidence of a causal link with the above-mentioned infectious agents; these include carcinoma of the oral cavity, oropharynx including tonsil and base of tongue, larynx, anus, cervix, vulva, vagina, and penis (HPV); adult T-cell leukaemia and lymphoma (HTLV-1); Kaposi sarcoma (HHV-8); Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma (EBV); non-cardia and cardia gastric carcinoma, and gastric non-Hodgkin lymphoma (H. pylori); liver cancer (HBV); liver cancer and non-Hodgkin lymphomas (HCV); bile duct cancer (Opisthorchis viverrini and Clonorchis sinensis); and bladder carcinoma (Schistosoma haematobium).
These were discussed further by myself at the Second Annual Conference on Genetics, Genetic Diseases and Stem Cells in Copenhagen in May 2019.
From GMO technologies of pesticide corporations (Bt by Monsanto) to CRISPR and epigenetic drugs and creation of killer strains deliberately by military weaponization. The latter might create more lethal gene profiles by pharmacological alteration of methylation, hypomethylation, alkylation or hypermethylation of DNA or microRNA. These could be used to turn genes off found silenced in various cancers or even possibly deleterious genes turned on. The following genes have been found turned off epigenetically in cancer by European Researchers. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update. Pere Llinàs-Arias and Manuel Esteller. Published: 20 September 2017 https://doi.org/10.1098/rsob.170152
Carcinogenesis. 2011 Jul;32(7):1033-42. doi: 10.1093/carcin/bgr081. Epub 2011 May 11.
MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Wang H1, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W.
These abnormally methylation altered DNA and miRNA genes raise the need for regulatory reform that recognizes that substances which can affect genes epigenetically and can contribute to cancers.
These developments imply that a wide panoply of newly synthesized means exist to alter genomic transcription and translation and this creates the potential for errors to be introduced into genomes which may have unforeseen deleterious consequences. Genes can also be transferred laterally between organisms (Ed Yong, The Scientist, June 20 2013; Crisp et al. Genome Biology 2015 16:50), (University of Illinois at Urbana-Champaign. “Microbes in the human body swap genes, even across tissue boundaries, study indicates. (ScienceDaily, 11 April 2019). Retroviruses Ex: (HIV, herv-k (hml-2), HTLV) are of course the quintessential gene transfer agents for humans. Lateral gene transfer risks need evaluation and especially retroviral risks call for special investigation and oversight and more stringent rules for public health .
Life-time exposures to pathogens, carcinogens, mutagens, methylators, alkylators, phosphorylators, damage to our bodies is often multi-factorial, cumulative, synergistic, genetic, epigenetic, potentially heritable, different for everybody.
There will be folks whose immune systems having been compromised who will be susceptible to these diseases much more than others and genetics plays a large role as well. Example AIDS patients, scleroderma pigmentosum patients, patients with genetic defects, epigenetic defects. A questionnaire may help identify these cumulative risk factors.
Synergies exist between drugs, pesticides, pathogens and the strength of these will vary also from person to person depending on history of exposure. Cancers exhibit epigenetic on/off switching.
Special Case of Mitochondrial Contribution to Cancer via Antibiotics.
Another problem has raised its head. Antibiotics induce mitochondrial dysfunction leading to increased ROS, lipid peroxidation both raising cancer risk and reduced glutathione (Kalghatigi, S. Et al . Antibiotic harms mammalian mitochondria. Sci Trans Med Sept 3 2013). Antibiotics can increase the likelihood of cancer particularly with repeat courses of exposure (Tim Newman. Medical News Today, Antibiotics may increase the risk of bowel cancer. April 5, 2017). Dietary sources of antibiotic treated meat products fall into this category of repeated exposure as might some pesticides. Mitochondrial health is associated with cancers. I postulate that antibiotic induced cancers may do so by the lipid peroxidation route the same as they do for red and treated meats. Why this matters is because we are entering an era where antibiotic resistance is a huge issue and we need to know that those we produce will not harm the mitochondria. Antibiotics will of course be considered for therapeutic use in infections by carcinogens such as Helicobacter pylori.
A new problem has been identified. Nine commonly used pesticides in China, 9 were found to have affect mitochondria and have effects on the ubiquitin-proteasome UPS system at low concentrations which prevents normal recycling of proteins by blocking their breakdown into amino acid constituents. Seven induced mitochondrial fragmentation (T. Chen et al. Int J Mol Sci Nov 23;18(12) at low concentrations. I postulate that this may also increase cancer risk by a novel mechanism, lipid peroxide production, the same as in red and treated meat.
Ben Boursi MD et al, Eur J Cancer. 2015 Nov; 51(17): 2655–2664 (Published online 2015 Aug 31) found among 125,441 cases and 490,510 matched controls were analyzed. For gastro-intestinal malignancies, the use of penicillin was associated with an elevated risk of esophageal, gastric, and pancreatic cancers. The association increased with the number of antibiotic courses and reached 1.4 for gastric cancers associated with >5 courses of penicillin (95%CI 1.2–1.8). Lung cancer risk increased with the use of penicillin, cephalosporines, or macrolides (AOR for >5 courses of penicillin: 1.4 95%CI 1.3–1.6). The risk of prostate cancer increased modestly with the use of penicillin, quinolones, sulphonamides and tetracyclines. The risk for breast cancer was modestly associated with exposure to sulphonamides.
Because antibiotics and pesticides can affect the same genetic systems that are linked to increased cancer risk via ROS, lipid peroxide and the ubiquitin proteasome system and the SVIPgen both need to be included in regulatory monitoring and cancer prevention management. SVIP gen Mutation in Squamous cell cancer found that facilitates aerobic glycolysis and prevents Protein breakdown disrupting normal metabolism. Blocking it w drugs against glucose receptor starves the cancer. Trials underway. https://www.ub.edu/…/en/menu_eines/noticies/2019/03/029.html).
Role of Epigenetics in Inflammation
Shanmugam MK, Sethi G. Role of epigenetics in inflammation-associated diseases. Subcell Biochem. 2013;61:627-57. doi: 10.1007/978-94-007-4525-4_27. PMID: 23150270.
Abstract
There is considerable evidence suggesting that epigenetic mechanisms may mediate development of chronic inflammation by modulating the expression of pro-inflammatory cytokine TNF-α, interleukins, tumor suppressor genes, oncogenes and autocrine and paracrine activation of the transcription factor NF-κB. These molecules are constitutively produced by a variety of cells under chronic inflammatory conditions, which in turn leads to the development of major diseases such as autoimmune disorders, chronic obstructive pulmonary diseases, neurodegenerative diseases and cancer. Distinct or global changes in the epigenetic landscape are hallmarks of chronic inflammation driven diseases. Epigenetics include changes to distinct markers on the genome and associated cellular transcriptional machinery that are copied during cell division (mitosis and meiosis). These changes appear for a short span of time and they necessarily do not make permanent changes to the primary DNA sequence itself. However, the most frequently observed epigenetic changes include aberrant DNA methylation, and histone acetylation and deacetylation. In this chapter, we focus on pro-inflammatory molecules that are regulated by enzymes involved in epigenetic modifications such as arginine and lysine methyl transferases, DNA methyltransferase, histone acetyltransferases and histone deacetylases and their role in inflammation driven diseases. Agents that modulate or inhibit these epigenetic modifications, such as HAT or HDAC inhibitors have shown great potential in inhibiting the progression of these diseases. Given the plasticity of these epigenetic changes and their readiness to respond to intervention by small molecule inhibitors, there is a tremendous potential for the development of novel therapeutics that will serve as direct or adjuvant therapeutic compounds in the treatment of these diseases.
Risk of Oversight or Deliberate Regulatory Mischief
In 2008 I reported the following contaminants of 2,4-D. Amongst the dioxins there are the following found by Federal Researchers in Canada: 2,7-dichlorodibenzodioxin, 1,3,7-trichlorodibenzodioxin, 1,3,6,8-tetrachlorodibenzodioxin, 1,3,7,9-tetrachlorodibenzodioxin (Cochran, et. al. 1981, Agriculture Canada). Other contaminants revealed by the USA Government House Senate Oversight Committee to the International Agent Orange Committee of which I was a member are: octachlorobisfirone, xanthen-9-ones (Coddling Moth Ovicide), mono, di, tri, and tetradioxins (repeat of above), n-nitrosomethylamines, n-nitrosodiethylamines, ortho and para monochlorophenol isomers, (2,6-Di, 2,4,6 tri-) chloromethoxy phenol isomers, n-nitrosodiethanolamine, 3 chlorophenoxymethanes. These were kindly provided to me by my deceased friend, Joe Cole, Chairman of the IAOC. RIP Old buddy and thanks for your service to humanity. http://pr-rp.hc-sc.gc.ca/pi-ip/result-eng.php…
Clearly there needs to be independent environmentalist led oversight at the technical level of active ingredients, inerts, surfactants and contaminants or a complete accounting of the final products contents and the effects of these in combination needs to be assessed for epigenetic impacts and for shaping regulatory advisories.
Weaponization of Pathogens Risk to Global Health and Regulation. Cambridge Working Group Recommendations.
Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control.
Experiments involving the creation of potential pandemic pathogens should be curtailed until there has been a quantitative, objective and credible assessment of the risks, potential benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches.
A modern version of the Asilomar process, which engaged scientists in proposing rules to manage research on recombinant DNA, could be a starting point to identify the best approaches to achieve the global public health goals of defeating pandemic disease and assuring the highest level of safety. REPLACE with World Wide Ban on Weaponization [make more lethal, contagious, useful for military assassinations] of organisms. Its time has come. CRISPR and Epigenetic Manipulation has made it too dangerous. Too easy to create cut and paste pandemic lethals. LGT also means creations have lateral transfer potential.
Proposed Regulatory Reforms
1. A UN imposed worldwide ban on weaponization of genetic material or organisms for military use. Global UN Convention ban requiring signatures from all participating countries on weaponizing disease vectors or production of any substance that affects methylation profiles and uses GM technologies for said purposes.
2. I propose that all carcinogens in Proposition 65, known mutagens, endocrine disrupters, pesticides, inerts, pesticide contaminants, GMO’s be tested for their ability to turn DNA and microRNA genes off in cancers or altered in expression and any future genes added to this list and those that do have this effect alert users by listing this on the MSDS sheets.
3. Test antibiotics and all other drugs for potential to produce ROS and lipid peroxide in mitochondria and or to rupture mitochondrial cells and their effects on epigenetic cancer profiles.
4. To existing regulatory approval requirements add assays of biological pesticides, phthalates, flame retardants, to DNA, RNA(s) including microRNA’s to epigenetic impact challenge testing for both methylating and alkylation.
5. Testing of all pollutants, industrial chemicals, food additives for epigenetic profiles in both DNA and microRNA.
6. Product or substance effects on tumor suppressor genes, DNA repair genes, microRNA deleterious disease genes activated, impacts on the ubiquitin-proteasome system(UPS).
7. Examine lateral gene transfer potential of introduced modified genes in the microbiome and in human cells.
8. Examine heritability of epigenetic results found for at least 3 generations.
9. Agency policy. i). Stop the revolving door of corporate executives in government regulatory jobs. ii). Prohibit lobbying for laws Any such use to suit chemical companies and pharmaceuticals.
10. Those infected with cancer causing infectious agents are to seek isolation during acute infective stages and recurrent outbreaks as carriers if that is applicable and are required to inform intimate partners and associates who might become contaminated of their condition. They need to avoid situations where the may contaminate others or take necessary precautions as per the best medical advice available.
11. It is deemed a War Crime and a violation of human rights to use any disease causing infectious agent, natural or genetically engineered, or mutation or epigenetic modification thereof or synthetic to kill, harm or alter the health or mind of any persons foreign or domestic or to introduce any such agent into any environment so as to cause harm including hunger, deliberate or by carelessness. Any such use for domestic purposes shall be deemed domestic terrorism.
12. The growing epigenetic Database needs to be included in this regulatory framework.
13. The role of epigenetics in chronic inflammation needs to also be investigated with assessment of development of pharmacological approaches in inflammation prevention.
Baylin Stephen B and Peter A Jones. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016 Sep; 8(9): a019505
Ben Boursi, Kevin Haynes, Ronac Mamtani, Yu‐Xiao Yang Eur J Cancer. 2015 Nov; 51(17): 2655–2664 (Published online 2015 Aug 3). Antibiotics increased risk of cancer.
Chen T, Tan J, Wan Z, Zou Y, Afewerky HK, Zhang Z, Zhang. Pesticides induced mitochondrial fragmentation at low levels. Int J Mol Sci Nov 23;18(12).
W.P.CochraneJ, SinghW, MilesB.Wakeford. 1981. Determination of chlorinated dibenzo-p-dioxin contaminants in 2,4-D products by gas chromatography-mass spectrometric techniques. J. Of Chromatography. Volume 217, 6 November 1981, Pages 289-299.
Newman Tim. Medical News Today, Antibiotics may increase the risk of bowel cancer. April 5, 2017
University of Illinois at Urbana-Champaign. “Microbes in the human body swap genes, even across tissue boundaries, study indicates. (ScienceDaily, 11 April 2019
Wang H1, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W. MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis. 2011 Jul;32(7):1033-42. doi: 10.1093/carcin/bgr081. Epub 2011 May 11.
Yong Ed. The Scientist, June 20 2013; Crisp et al. Genome Biology 2015
Acquired immunodeficiency syndrome (AIDS) of humans is caused by two lentiviruses, human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2). Here, we describe the origins and evolution of these viruses, and the circumstances that led to the AIDS pandemic. Both HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M-the principal cause of the AIDS pandemic. We discuss how host restriction factors have shaped the emergence of new SIV zoonoses by imposing adaptive hurdles to cross-species transmission and/or secondary spread. We also show that AIDS has likely afflicted chimpanzees long before the emergence of HIV. Tracing the genetic changes that occurred as SIVs crossed from monkeys to apes and from apes to humans provides a new framework to examine the requirements of successful host switches and to gauge future zoonotic risk.
Reference:
Sharp PM, Hahn BH. Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a006841. doi: 10.1101/cshperspect.a006841. PMID: 22229120; PMCID: PMC3234451.
My Observation is that gut inflammation sends a signal to cancer stem cells that there is suitable habitat present to move in. It now appears that TLRs are the intermediary between viruses, pesticides, mitochondria and the inflammation signals that trigger both CRC and demyelinating disease and may play a key role in covid-19 and covid vaccine cardiomyopathy.
What are Toll Like Receptors TLRs
Increase in CRC recently suggest immune impairment and carcinogen exposure
What does SARS-CoV-2 spike do to the TLR Mechanism? Sepsis where the Bodies Immune system Attacks itself is a Common Finding.
Yinchi Zhao et al.
Accumulating clinical data suggest the main causes of death by COVID-19 include respiratory failure and the onset of sepsis.1 Importantly, sepsis has been observed in nearly all deceased patients.2,3,4,5 It remains elusive how SARS-CoV-2 infection results in viral sepsis in humans. Toll-like receptor 4 (TLR4) mediates anti-gram-negative bacterial immune responses by recognizing lipopolysaccharide (LPS) from bacteria.6We recently found that SARS-CoV-2 infection provoked an anti-bacterial like response at the very early stage of infection via TLR4. However, the identity of the original trigger initiating these abnormal immune responses during SARS-CoV-2 infection is unknown.
Previous in silico studies predicted cell surface TLRs, especially TLR4, are most likely to be involved in recognizing molecular patterns, probably spike protein, from SARS-CoV-2 to induce inflammatory responses.7,8 Consistently, we found that the induction of IL1B by SARS-CoV-2 was completely blocked by TLR4-specific inhibitor Resatorvid (Fig. 1a). Combined with our recent data that TLR4 signaling was activated by SARS-CoV-2, we hypothesized that spike protein could activate TLR4 pathway. A recent study has reported that trimeric SARS-CoV-2 spike proteins are high quality antigens.9 To this end, we purified the trimeric spike protein (1–1208 aa) (Fig. 1b; Supplementary information, Fig. S1a), as this form of spike protein presents on the surface of viral particle, which most likely interacts with the proteins on the cell surface. Results of the surface plasmon resonance (SPR) assay showed that SARS-CoV-2 spike trimer directly bound to TLR4 with an affinity of ~300 nM (Fig. 1b), comparable to many virus-receptor interactions.
In another SARS-CoV-2 Study Spike induce Inflammatory cytokines and chemokines IL6, IL1beta, TNFalpha, CXCL1, CXCL2, CCL2
Khan S, Shafiei MS, Longoria C, Schoggins JW, Savani RC, Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. Elife. 2021 Dec 6;10:e68563. doi: 10.7554/eLife.68563. PMID: 34866574; PMCID: PMC8709575.
My Observation is that gut inflammation sends a signal to cancer stem cells that there is suitable habitat present to move in. It now appears that TLRs are the signalling intermediary between viruses, pesticides, antibiotics, mitochondria and the inflammation signals that potentially may trigger both CRC, and possibly demyelinating disease and appear to play a key role in covid-19 and covid vaccine cardiomyopathy. Multi origin chronic inflammation aided by TLRs is an agent of pathology when overwhelmed by antigens. With covid, sepsis accompanied the majority of deaths. In sepsis, responses including pro-inflammatory and anti-inflammatory processes in addition to the Toll-Like Receptor 4 (TLR4) signals leading to the release of inflammatory mediators like chemokines and cytokines have been suggested to be fundamental pathways in the pathophysiology of sepsis.
Forwarded this email? Subscribe here for moreWhoops! FOIA response from Santa Clara County reveals that the COVID shots INCREASED your risk of getting COVID! The COVID vaccines worked in reverse making people more susceptible. Attempts to contact Santa Clara County Public Health Department for comment were totally ignored.Steve KirschMar 26READ IN APPThey tell you to get the shot, but their own data shows that the shots make it more likely you’ll get COVID.Executive summaryBased on new data I just got from a FOIA request, it appears that the public health epidemiologists in Santa Clara County knew in January 2022 that the vaccines made people more likely to get COVID, but they remained silent.I predict that there will be further silence on this matter: no accountability and no opportunity for public challenges. They will continue to push the shots as if nothing had happened and the mainstream media will ignore this important data.Here is the data for you to download yourselfDownload it here.
When you click the link, it will silently download the Excel file to your Downloads folder.
Summary of the data. The data in the spreadsheet is from January 2022 and contains a line for each person who was diagnosed with COVID in that month.N means unvaccinated. Y means vaccinated. U means unknown. Blank means unknown.Santa Clara County is highly vaccinated (95%), but it isn’t that highly vaccinated!The rows are 10 year age groups.So the percentage of people who were diagnosed with COVID (98% or more) was higher than the percentage of people who got the vaccine (under 95%).In other words, the vaccine made you more likely to get COVID instead of 10X less likely that they claimed in the clinical trials.This is consistent with the SummaryThe COVID vaccine trials were fraudulent. There is no possible way they got 90% efficacy (a 10X reduction in infection risk). They did it through deception as described here. The vaccines actually made you more likely to get COVID as we learned from the Santa Clara data, the Cleveland Clinic study, and numerous other sources (see this article for example). The numbers here are highly statistically significant. It appears that the Santa Clara County Health epidemiologists knew something was wrong by January 2022, but instead of warning people, they kept their mouths shut about it. There was no public admission of this, no public warning. I predict that there will NEVER be any public accountability of what happened because public officials never like to admit they were responsible for killing people with these useless and deadly vaccines.The Santa Clara County Health Department ignored all my attempts (multiple phone calls and emails) to solicit a response to this article. Share
Summary: I see 3 options. Vaccine either harmed the immune system or possibly provided harmful spike protein that increased disease susceptibility or both.
Doctors know covid was a scam and a weaponized program and the vaccines were dangerous. Urged to come clean and confess the truth.
Safe Range 19.5 to 23.5 ppm atmospheric composition recommended lower limit exceeded by an elevation of 2000 ft or 609 m or more. The question is why?
Preamble
Oxygen
OSHA dictates that the minimum “safe level” of oxygen in a confined space is 19.5%, while the maximum “safe level” of oxygen in a confined space is 23.5%.
With low oxygen levels being the biggest cause of death in confined spaces, accurate oxygen level measurements are essential. Workers must sample the oxygen level prior to entering a confined space and should monitor it continuously throughout the work.
If a confined space’s oxygen concentration surpasses 23.5%, the space is too oxygen-rich and could result in the ignition of combustible gases. On the other hand, low oxygen levels impair judgment and coordination. Extremely low levels of oxygen cause nausea, vomiting, and loss of consciousness.
Our medical experience with oxygen deprivation has taught us much about its physiological and pathological consequences.
Oxygen is essential for the survival of animals owing to its role in aerobic ATP production in the mitochondria. In most terrestrial habitats (except underground or at high altitudes), ambient oxygen levels are not limiting for aerobic metabolism, and hypoxic episodes are rare and transient followed by reoxygenation. However, low oxygen levels might occur in the tissue when oxygen demand exceeds oxygen supply (e.g. in exercising muscle) or under pathological conditions that restrict oxygen delivery to the tissue (ischemia)1,2. Hypoxia-reoxygenation (H-R) stress can severely damage organs and tissues as shown in human pathologies caused by heart attack, stroke, respiratory failure, sleep apnea, surgery, or organ transplantation.
Notice a dive in O2 associated with major extinction events in geological time
Effects of Prenatal Hypoxia on Nervous System Development and Related Diseases
The fetal origins of adult disease (FOAD) hypothesis, which was proposed by David Barker in the United Kingdom in the late 1980s, posited that adult chronic diseases originated from various adverse stimuli in early fetal development. FOAD is associated with a wide range of adult chronic diseases, including cardiovascular disease, cancer, type 2 diabetes and neurological disorders such as schizophrenia, depression, anxiety, and autism.
Intrauterine hypoxia/prenatal hypoxia is one of the most common complications of obstetrics and could lead to alterations in brain structure and function; therefore, it is strongly associated with neurological disorders such as cognitive impairment and anxiety. However, how fetal hypoxia results in neurological disorders remains unclear. According to the existing literature, we have summarized the causes of prenatal hypoxia, the effects of prenatal hypoxia on brain development and behavioral phenotypes, and the possible molecular mechanisms.
1I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
2Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
3Research Centre, Saint-Petersburg State Pediatric Medical University, St. Petersburg, Russia
This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent
increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory.
Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus.
On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation.
This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions,
in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration.
Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.
Climate Related Decline of Atmospheric Oxygen
I have identified a number of contributory factors to this O2 decline. 1. 40% Loss of Phytoplankton and their photosynthesis in a 1% per year decline. 2. Extreme combustion from forest, shrub lands and grass land fires. 3. Oxidation of exposed permafrost. 4. Combustion of vehicles and engines worldwide and heating and air conditioning with fossil fuels. 4. Industrial processes and transportation. 5. Garbage and waste digestion. 6. The present atmosphere contains (by volume) 78.05% N2, 20.95% O2, 0.93% Ar, 0.038% CO2, and various trace gases (Encyclopedia of Astrobiology, 2011 ISBN : 978-3-642-11271-3 David C. Catling 2011).
Computed years to FOAD hazard in atmospheric sea level environments.
Rate of decline is .001 %/yr. To get to 19.5% at .001 %/yr would take {[20.95-19.5]/0.001}=1450 years but the rate of decline is accelerating so it will be sooner.
Another Estimate
Second Computation from IPCC Data. [(2100-2024)x1.45]/0.121=910 yrs to FOAD hazard.
Summary Comments: The impact on health is bound to be highly variable depending on a persons genetic inheritance, elevation of birth place and rearing, movements later in development. The Big Question for the majority raised near sea level is when does the Atmospheric Concentration hit 19.5%. Crude preliminary estimates suggest 910-1450 years. These sea will in all likelihood also be much higher at that time.
Review Not peer-reviewed version Concerns regarding Transfusions of Blood Products Derived from Genetic Vaccine Recipients and Proposals for Specific Measures Jun Ueda * , Hideyuki Motohashi , Yuriko Hirai , Kenji Yamamoto , Yasufumi Murakami , Masanori Fukushima , Akinori Fujisawa * Posted Date: 15 March 2024 doi: 10.20944/preprints202403.0881.v1 Keywords: COVID-19 vaccine; genetic vaccine; blood product; blood transfusion; spike protein; post- vaccination syndrome; harm–benefit assessment; prion; spikeopathy; inspection standard; diagnostic criteria Preprints.org is a free multidiscipline platform providing preprint service that is dedicated to making early versions of research outputs permanently available and citable. Preprints posted at Preprints.org appear in Web of Science, Crossref, Google Scholar, Scilit, Europe PMC. Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Review Concerns regarding Transfusions of Blood Products Derived from Genetic Vaccine Recipients and Proposals for Specific Measures Jun Ueda 1,, Hideyuki Motohashi 2, Yuriko Hirai 3, Kenji Yamamoto 4, Yasufumi Murakami 5, Masanori Fukushima 6 and Akinori Fujisawa 7, 1 Department of Advanced Medical Science, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan; junueda@asahikawa-med.ac.jp 2 Pre-Clinical Research Center, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Tokyo, Japan; moto@tokyo-med.ac.jp 3 MCL Corporation, Jimukino-Ueda bldg. 603, 21 Sakaimachi Gojo-Takakurakado, Shimogyo-Ku, Kyoto 600- 8191, Kyoto, Japan; hirai@mcl-corp.jp 4 Department of Cardiovascular Surgery, Center of Varicose Veins, Okamura Memorial Hospital, 293-1 Kakita Shimizu-cho, Sunto-gun, Shizuoka 411-0904, Japan; yamamoto@okamura.or.jp 5 Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan; yasufumi@rs.tus.ac.jp 6 Foundation of Learning Health Society Institute, Nagoya 450-0003, Aichi, Japan; mfukushima@imrd.jp 7 Kokoro Medical Corporation, Honbetsu Cardiovascular Medicine Clinic, Honbetsu 089-3314, Hokkaido, Japan; fujisawa.peace@mac.com
Correspondence: junueda@asahikawa-med.ac.jp (J.U.); fujisawa.peace@mac.com (A.F.); Tel.: +81-166-68-2385 (J.U.); +81-156-22-8888 (A.F.) Abstract: The coronavirus pandemic was declared by the World Health Organization (WHO) in 2020, and a global genetic vaccination program has been rapidly implemented as a fundamental solution. However, many countries around the world have reported that so-called genetic vaccines, such as those using modified mRNA encoding the spike protein and lipid nanoparticles as the drug delivery system, have resulted in post-vaccination thrombosis and subsequent cardiovascular damage, as well as a wide variety of diseases involving all organs and systems, including the nervous system. In this article, based on these circumstances and the volume of evidence that has recently come to light, we call the attention of medical professionals to the various risks associated with blood transfusions using blood products derived from people who have suffered from long COVID and from genetic vaccine recipients, including those who have received mRNA vaccines, and we make proposals regarding specific tests, testing methods, and regulations to deal with these risks. We expect that this proposal will serve as a basis for discussion on how to address post- vaccination syndrome and its consequences following these genetic vaccination programs. Keywords: COVID-19 vaccine; genetic vaccine; blood product; blood transfusion; spike protein; post-vaccination syndrome; harm–benefit assessment; prion; spikeopathy; inspection standard; diagnostic criteria
Overview of Cases of Blood Abnormalities after Genetic Vaccination A wide variety of diseases related to blood and blood vessels, such as thrombosis, have developed after genetic vaccination, including with mRNA vaccines, and many cases of serious health injuries have been reported. For example, a PubMed search on diseases such as thrombocytopenia, thrombotic disorders with thrombocytopenia, deep vein thrombosis, thrombocytopenic purpura, cutaneous vasculitis, and sinus thrombosis combined with the essential keywords “COVID-19 vaccine” and “side effects” yielded several hundred articles in only about two years since the rollout of genetic vaccines [14,17,20,21,48]. In addition to abnormally shaped red blood cells, amorphous material has been found floating in the blood of mRNA-vaccinated individuals under microscopic observation, some of which has shown grossly abnormal findings (Table 1, point 5) [7–10,49]. Recent studies have also reported that the spike protein has amyloidogenic potential [50– 54], is neurotoxic [55–57], and can cross the blood–brain barrier [58–60]. Thus, there is no longer any doubt that the spike protein used as an antigen in genetic vaccines is itself toxic [22,61,62]. In addition to thrombosis, individuals who have received multiple doses of a genetic vaccine may have multiple exposures to the same antigen within a brief period, thereby being imprinted with a preferential immune response to that antigen [63,64]. This phenomenon, called original antigenic sin or immune imprinting, has caused COVID-19 vaccine recipients to become more susceptible to contracting COVID-19 [65]. In addition, antibody-dependent enhancement of infection is also known; antibodies produced by vaccination may rather promote viral infection and symptoms [66,67]. On the other hand, it has also been suggested that repeated administration of genetic vaccines may result in immune tolerance because of a class switch to non-inflammatory immunoglobulin G4 (IgG4) [68– 71], whereby the immune system of the recipient does not mount an excessive response such as cytokine storm [27,72], and case reports of IgG4-related disease have begun to appear [73–75]. This raises concern that alterations in immune function due to immune imprinting and immunoglobulin class switching to IgG4 may also occur in genetic vaccine recipients. This may increase the risk of serious illness due to opportunistic infections or pathogenic viruses that would not normally be a problem if the immune system were normal [76–82]. For example, cases of suspected viremia have been reported [82]. Therefore, from the perspective of traditional containment of infectious diseases, greater caution is required in the collection of blood from genetic vaccine recipients and the subsequent handling of blood products, as well as during solid organ transplantation and even surgical procedures [83–87] in order to avoid the risk of accidental blood-borne infection (Table 1, point 3) [84–87]. The phenomenon of immune imprinting can occur even when spike protein is not used as an antigen or when another antigen is used (e.g. inactivated influenza vaccine) [88]. However, compared to conventional inactivated vaccines, genetic vaccines, which produce an antigen within the body, are expected to prolong the period of exposure to the same antigen, and as a result, the risk of immune imprinting may be higher than with conventional vaccines. It is not actually known how long the vaccine components remain in the body after a person has received a genetic vaccine [22,40,43], but it is expected that they will remain in the body for a longer period than originally thought, in part because spike protein has been detected in the bodies of people several months after vaccination (Table 1, point 1) [22,28,41,42]. In addition, since long-term exposure to a specific identical antigen (in this case, spike protein) causes immunoglobulins to become IgG4 [68,70] and some of the Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 4 B cells that produce them are likely to differentiate into memory B cells that survive in the body for a sustained period [70,89], the immune dysfunction of genetic vaccine recipients is expected to be prolonged (Table 1, point 3 & 6). More details on these points are expected to be revealed in the future. In summary, there is an undeniable risk that patients may experience some problems if they receive blood products derived from blood collected in, at least, a brief deferral period after genetic vaccination. Although it is unknown at present whether secondary damage is caused by transfusion of blood products derived from genetic vaccine recipients, it is necessary for medical institutions and administrative organizations to respond and investigate cooperatively, keeping various possibilities in mind, because mechanisms such as the toxicity of the spike protein itself and the effects of LNPs and modified mRNA on the immune response have not been fully elucidated and are still under study. It should be emphasized that a significant proportion of the COVID-19 PVS in mRNA vaccine recipients is due to toxic spike proteins, and the inclusion of structures in the receptor-binding domain within these proteins that may induce prion disease is particularly alarming, as Seneff et al. and Perez et al. have warned [50,90–96]. Furthermore, it has been shown that prion similarity in the receptor-binding domain exists not only in the spike protein of the Wuhan strain, which is still used as an antigen in genetic vaccines, but also in the spike protein of variants of SARS-CoV-2, such as the Delta strain, with the exception of the Omicron strain [93,97]. Whether we should be uniformly vigilant for the spike protein of the coronavirus or just the spike protein of certain variants, such as the Wuhan strain, awaits further analysis. Table 1. Major concerns with the use of blood products derived from gene vaccine recipients. Concerns Description References 1 Spike protein contamination The spike protein, which is the antigen of SARS-CoV-2 and genetic vaccines, has already been found to have various toxicities, including effects on red blood cells and platelet aggregation, amyloid formation, and neurotoxicity. It is essential to recognize that the spike protein itself is toxic to humans. It has also been reported that the spike protein can cross the blood–brain barrier. Therefore, it is essential to remove the spike protein derived from the gene vaccine itself from blood products. [22,29,55– 60] 2 Contamination with amyloid aggregates and microthrombi formed by spike proteins It is not yet clear how the amyloid aggregates and microthrombi formed by the spike proteins develop into visible thrombi. However, once formed, amyloid aggregates may not be readily cleared and therefore need to be removed from blood products. These amyloid aggregates have also been shown to be toxic. [51,52,98] 3 Events attributable to decreased donor immune system and immune abnormalities due to immune imprinting or class switch to IgG4, etc. resulting from multiple doses of genetic vaccines When the immune function of a donor is impaired by gene vaccination, there is a risk that the donor has some (subclinical) infectious disease or is infected with a pathogenic virus and has developed viremia or other conditions, even if the donor has no subjective symptoms. For this reason, healthcare professionals who perform surgical procedures, including blood sampling and organ transplantation, as well as using blood products, should manage the blood of genetic vaccine recipients with care to prevent infection through blood. It will also be necessary to inform all healthcare professionals of these risks. [63–65,68– 71,76–80,82– 87] 4 Lipid nanoparticles (LNPs) and pseudouridinated mRNA (mRNA vaccines only) In the case of mRNA vaccines, LNPs and pseudouridinated mRNA may remain in the blood of recipients if blood is collected without a sufficient deferral period after gene vaccination. LNPs are highly inflammatory and have been found to be thrombogenic themselves, posing a risk to transfusion recipients. LNPs itself has potent adjuvant activity and is at risk of inducing Adjuvant-Induced Autoimmune Syndrome (ASIA syndrome). An additional risk is that if the pseudouridinated mRNA is incorporated into the recipient’s blood while still packaged in LNPs, additional spike protein may be produced in the recipient’s body. [23,40,44,99– 105] 5 Contamination with aggregated red blood cells or platelets The spike protein causes red blood cells and platelets to aggregate and therefore these aggregates will be carried into the recipient’s blood unless they are removed from the blood product. [7–11,49] 6 Memory B cells producing IgG4 and IgG4 produced from them Large amounts (serum concentration typically above 1.25–1.4 g/L) of non- inflammatory IgG4-positive plasma cells can cause chronic inflammation such as fibroinflammatory disease. [73– 75,106,107] Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 5
Specific Proposals for Blood Sampling and Blood Products from Vaccine Recipients In the previous section, we discussed a variety of blood-related abnormalities that have occurred following genetic vaccination. In this section, we provide specific proposals on how to respond to these circumstances. Because blood contamination affects so many areas of health care, it is especially important to anticipate the worst [95,96,108–110] and to plan and act from the start to ensure that there are no lapses or omissions. 3.1. Additional Requirements for Blood Collection (Donation) Currently, in Japan, the Japanese Red Cross Society (https://www.jrc.or.jp/english/) plays a central role in blood collection activities, and its blood products are used for blood transfusions and other purposes. The Japanese Red Cross Society has a rule that blood can be collected from genetic vaccine recipients after a deferral period (48 hours for mRNA vaccine recipients and 6 weeks for AstraZeneca DNA vaccine recipients), but the data and rationale for the rule have not been specified. As with infections such as human immunodeficiency virus (HIV) and prion diseases, a history of genetic vaccination (DNA and/or mRNA type), including timing and number of doses, should be obtained by interview, and kept in the official record when blood is collected (Figure 1, Table 2). Additional caution is needed, particularly if not many days have passed since the genetic vaccine was administered, because LNPs [23,101–103] and spike protein mRNA, which can induce inflammation, may remain in the blood (Table 1, point 4) [22,40,43,44]. If certain events such as anaphylactic shock occur immediately after genetic vaccination, the effects of LNPs should also be suspected [100]. It has also been reported that negatively charged LNPs themselves interact with fibrinogen to form thrombi [99]. Therefore, the presence of LNPs may itself be a factor in the need for caution with transfusion products. On the other hand, even if a person has not received a genetic vaccine, if they have had long COVID, it is possible that the spike protein remains in their body, and thus it would be better to keep an official record of whether they have long COVID or not [51,111–113]. As the degradation rates of pseudouridinated mRNA and spike protein in the body are unknown at present, blood products derived from genetic vaccine recipients should be used with extreme caution, being conscious of the cases of AIDS, bovine spongiform encephalopathy (BSE), and variant Creutzfeldt-Jakob disease (vCJD) caused by the use of contaminated blood products in the past [110,114–121]. Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 6 Figure 1. Summary of items and procedures required for management of blood products derived from gene vaccine recipients or contaminated with spike protein and modified genes. As with any risk management exercise, it is important to constantly revise policies and procedures as risks and problems are identified. PVS, post-vaccination syndrome. Table 2. Tests needed to confirm the safety of blood products. Concerns Description References 1 Spike protein content in blood Immunochemical techniques include enzyme-linked immunosorbent assay, immunophenotyping, mass spectrometry, liquid biopsy, and a combination of liquid biopsy and proteomics. First, we propose mass spectrometry that can directly measure the protein itself. [28,29,122– 126] 2 Spike protein mRNA PCR and/or liquid biopsy are the options. If mRNA for the spike protein is detected, LNPs may be present (mRNA vaccines only). [124,127,128 ] 3 Spike protein DNA PCR and liquid biopsy are the options. This test is necessary because AstraZeneca’s viral vector is a DNA vaccine. For mRNA vaccines, it is believed that pseudouridinated mRNA is not reverse transcribed, but this test is required if the spike protein remains for a prolonged period. [124,128] 4 Markers associated with autoimmune disorders Long-term persistence of the spike protein in the blood increases the risk of autoimmune disease. Therefore, it would be useful to test for autoimmune disease using antinuclear antibodies as biomarkers in people who are positive for the spike protein, taking into account the results of interviews regarding the subjective symptoms. [27,105,129,1 30] 5 Interview A history of genetic vaccination and COVID-19, current and previous medical history, and subjective symptoms (e.g. headache, chest pain, shortness of breath, malaise) should be obtained from blood donors and formally recorded. The types of questions included in the interview are critical to facilitate diagnosis and treatment of COVID-19 PVS, as more people are complaining of psychiatric and neurological symptoms after genetic vaccination. [15,131,132] Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 7 6 Proteins resulting from frameshifting of pseudouridinated mRNA Although it is not yet clear whether proteins other than the spike protein are translated from pseudouridinated mRNAs, mass spectrometry may be useful in confirming this. [133] 7 Components of amyloid aggregates and thrombi Common markers of thrombosis, such as D-dimer, are used first. Once the major components of amyloid aggregates and thrombi have been identified, their use as biomarkers is proposed. Understanding the composition of amyloid aggregates will be important in the future, as amyloid aggregates have been reported to be toxic. Understanding the composition of amyloid aggregates may provide clues to how amyloid is broken down. [51,52,98,134 ] 8 Components of SARS-CoV-2 other than the spike protein gene This test will help determine whether the spike protein is from the genetic vaccine or from SARS-CoV-2. Potential candidates include nucleocapsid. [4,5,41,128] 9 Immunoglobulin subclasses It may be necessary to analyze immunoglobulin subclasses (the amount of IgG4) if immunosuppression from multiple doses of the genetic vaccine is a concern. [68–71] 10 Anti-nucleocapsid antibodies The presence or absence and amount of anti-nucleocapsid antibodies as well as antibody isotypes may be an indicator(s) in distinguishing whether genetic vaccination or long COVID is the cause. [135–137] 11 Other Myocarditis and pericarditis after genetic vaccination have been reported in various countries. Therefore, those with subjective symptoms may also be tested for myocarditis marker, such as cardiac troponin T. [18,19,29,138 –140] 3.2. Handling of Existing Blood Products At present, the genetic vaccination status of blood donors is not confirmed or controlled by organizations including medical institutions, and the use of blood collected from these donors for transfusions may pose risks to patients. Therefore, when blood products derived from gene vaccine recipients are used, it is necessary to confirm the presence or absence of spike protein or modified mRNA as in other tests for pathogens (Figure 1, Table 2). These should be quantified by an immunochemical enzyme-linked immunosorbent assay (ELISA), by immunophenotyping, by direct mass spectrometry of the protein itself, by an exosome-based liquid biopsy as used in cancer screening, or by PCR [28,29,122–128]. For protein assays, as it may take time to generate a good- quality anti-spike protein antibody or a positive control for a recombinant spike protein to be compared with, and to sort and distribute them to each laboratory, we suggest that mass spectrometry be used as an initial step to identify and quantify the spike protein itself in blood [28,125]. In parallel with this, an analysis of the components of the spike protein-induced amyloid material will be needed [51,98]. Once the components of amyloid aggregates are identified, they can be used as biomarkers in the future. Exosome analysis will also be useful as a test as it has already been shown that spike proteins and their genes are transported in the circulation around the body by exosomes [24–27]. If the blood product is found to contain the spike protein or a modified gene derived from the genetic vaccine, it is essential to remove them. However, there is currently no reliable way to do so. As noted above, the prion-like structure within the spike protein molecule [91,95,96] suggests that this molecule may be a persistent, sparingly soluble, heat-resistant, and radiation-resistant protein [141,142]. The prion protein can be inactivated by thiocyanate, hydroxide, and hypochlorite [143– 145], but it is not yet known whether these can be applied to the spike protein and the resulting amyloid materials. Therefore, as there is no way to reliably remove the pathogenic protein or mRNA, we suggest that all such blood products be discarded until a definitive solution is found. Discarding blood products prepared from blood collected from many dedicated blood donors can be very painful, but it is necessary because the spike protein itself has been shown to induce thrombosis and similar diseases. However, some medical facilities may have difficulty disposing of blood products immediately, in which case it is essential to add the possibility of contamination with spike protein or other foreign substances to the transfusion consent form and to fully explain this to the patient. In any case, to prevent and reduce medical accidents caused by contaminated blood, it is imperative to underscore the importance of confirming the history and frequency of genetic vaccination at the time of blood collection and this information should be documented as an official record, managed and stored by both medical and governmental organizations (see Figure 1, Table 2). Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 8 3.3. The Need for Regular Checkups and Cohort Studies to Gain a Complete Picture of Blood Contamination As the residual status of spike protein or modified gene fragments derived from genetic vaccines is currently unknown, it will be necessary in the future to include measurement of these amounts in routine health checkups. It is also necessary to include a section in the routine medical checkup questionnaire to check genetic vaccination status and the number of vaccinations to obtain an overall picture of the residual status of spike proteins in the blood. This is because a variety of conditions following genetic vaccination involve thrombosis and immunological conditions [12,14,16,17,21,22,68,70]. Therefore, abnormalities in blood components related to these events should also be analyzed. On the other hand, when exosomes collected from vaccine recipients were administered to mice that had not been vaccinated with the genetic vaccine, the spike protein was transmitted [25]. Therefore, it cannot be denied that the spike protein and its modified genes can be transmitted through exosomes. For this reason, we suggest that full testing be done initially, regardless of genetic vaccination status, and that a cohort study be conducted to quickly capture the full picture (Figure 1). This is a steady, labor-intensive effort that requires collaboration between all parties involved, but such analyses may lead to the development of diagnostic criteria and testing for COVID-19 PVS. In addition, as mentioned above, it cannot be ruled out that even those who have not been vaccinated with the genetic vaccine, but have had long COVID, may have residual spike proteins or fibrin- derived microthrombi in their bodies, so it would be advisable to conduct the same testing and follow-up as for genetic vaccine recipients [51,52,111–113]. The presence or absence and amount of anti-nucleocapsid antibodies as well as antibody isotypes may be an indicator(s) in distinguishing whether genetic vaccination or long COVID is the cause (Table 2, point 10) [135–137]. In any case, these cohort studies are expected to help establish cutoff values for blood levels of spike protein and other substances to determine the safety of blood products. Faksova et al. conducted a large cohort study of 99 million people using a multinational Global Vaccine Data Network™ (GVDN ®) and found a significantly increased risk of myocarditis, pericarditis, Guillain-Barre syndrome, and cerebral venous sinus thrombosis in genetic vaccine recipients [140]. This type of study will be increasingly necessary in the future. 3.4. The Need for Early Development of Clinical Practice Guidelines and Diagnostic Criteria for COVID-19 PVS Although the spectrum of COVID-19 PVS is diverse, it is characterized by a high prevalence of hematologic and immune-related diseases [21]. Considering this, regardless of the transfusion issues discussed in this review, blood tests are likely to be the first step in the diagnosis of COVID-19 PVS. The ability to rapidly develop highly accurate testing systems, particularly blood tests, in collaboration with other countries will be critical in treating patients suffering from PVS due to the COVID-19 vaccine. Additional meta-analysis of data from systematic reviews and cohort analyses will be needed to prevent bias in diagnostic criteria and to develop appropriate clinical practice guidelines (Figure 1) [146–148].
Problems following Blood Transfusion Using Blood Products Prepared from Donated Blood of Genetic Vaccine Recipients and the Need for Traceability of Blood Products for Transfusion With the advent of genetic vaccination, there has been considerable debate about the safety of blood products prepared from donated blood of the vaccine recipients and their use in blood transfusion [36–39]. However, what happens in the body when a genetic vaccine such as an mRNA vaccine is administered in the first place is not well understood at this stage, and as mentioned above, the results of tests on the vaccine recipient’s blood need to be evaluated. Cases of encephalitis caused by blood from dengue vaccine recipients have been reported as recently as 2023 [149], indicating that the current system for managing and tracking blood products is not adequate. Unless accurate tests are established, no conclusions can be drawn about the risk or safety of blood transfusions using blood products from gene vaccine recipients. Thorough and continuous investigation is therefore Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 9 necessary. To accomplish this, all potential donors should be registered, traceability of blood products should be ensured, and rigorous recipient outcome studies and meta-analysis should be maintained. Furthermore, as we have repeatedly stated, it is essential to rigorously obtain from donors a history of vaccination and COVID-19 infection, preserve official records, and store samples of blood products for later detection and verification of substances such as spike proteins and exosomes (Figure 1). Given the wide variety of tests and records, the movement of people around the world, and the import/export of blood products, it may be necessary in the future to establish traceability by introducing blockchain technology into the management of blood products while maintaining anonymity [150,151].
The Need for the Development of Relevant Legislation The issue of blood products derived from genetic vaccine recipients described in this review is expected to affect a very wide range of areas in countries around the world. In Japan, the “Act on Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases” (https://www.japaneselawtranslation.go.jp/en/laws/view/2830/en) has been enacted to prevent the spread of infectious diseases through blood products, and the “Act on Organ Transplantation” has been enacted to handle organ transplants. The Ministry of Health, Labour and Welfare (MHLW) has issued the “Guidelines for Blood Transfusion Therapy” regarding blood transfusions. These laws and guidelines specify the responsibilities of the public, physicians, and national and local governments and protect their rights. However, as the spike protein used as an antigen or its gene is not an organism, there are likely to be number of difficult issues, such as how to legally define its pathogenicity. From this point of view, when the risks of and health injuries caused by blood products derived from genetic vaccination recipients have been roughly clarified (Table 2), it will be essential to formulate regulations to reduce and prevent risks and contamination, by developing related laws with the participation of the legislative branch, legal experts, medical administration personnel, healthcare providers, and medical researchers, and by taking measures such as checking vaccination status and dates, and legally regulating the import/export of blood products (Figure 1). The wide range of issues makes coordination between agencies and healthcare professionals essential from the outset. Second, it is expected that the situation will already be complicated because, in contrast to previous drug disasters, genetic vaccination was implemented on a global scale and simultaneously for a substantial number of people [2,3]. This means, as in the context of the coronavirus pandemic, or even more critically, that there is an urgent necessity for legislation and international treaties explicitly elucidating bilateral and multilateral agreements concerning the management of blood products. These legal frameworks should delineate regulations governing the handling of blood products and establish protocols for governmental compensation and response to issues and hazards associated with these products, including penalties and prohibitions. For example, the International Health Regulations (IHR) 2005 may be helpful [152,153], but given the WHO’s strong push for genetic vaccination [154], another framework may be needed. In relation to the cohort studies described in Section 3.3 of this article, it will also be necessary for countries to conduct active epidemiological surveys [155], as was the case with COVID-19, to compile the results of these surveys, and to establish an international organization tasked with monitoring response efforts and assessing damages within each country (Figure 2). It is expected that it will be important to incorporate not only the perspective of infectious diseases but also biosafety and biosecurity [153,156]. As for Japan, Article 15 (2) of the Infectious Disease Act (https://www.japaneselawtranslation.go.jp/ja/laws/view/2830/en#je_ch3at5) stipulates that the Japanese government is responsible for conducting epidemiological studies. Given the significant health risks associated with COVID-19 PVS, we urge the Japanese government to prioritize the analysis and safety verification of blood products derived from gene vaccine recipients. This is imperative given the urgent nature of the situation. Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 10 Figure 2. An example of a system for managing health injuries among genetic vaccine recipients. Given the global nature of genetic vaccination and the movement of vaccine recipients and blood products between countries, there will be a need for an international surveillance network to coordinate countries.
Other Important Considerations There is an urgent need to develop methods to identify as well as remove spike proteins and modified genes derived from gene vaccines in blood products. In order to develop a uniform inspection standard, there is an urgent need in Japan for the Japanese Society of Hematology (http://www.jshem.or.jp/modules/en/index.php?content_id=1), the Japanese Society of Transfusion and Cell Therapy (http://yuketsu.jstmct.or.jp/en/), and their related organizations to develop guidelines on how to handle blood products that contain residual spike proteins or their modified genes. Also, as noted earlier, gene vaccination has been promoted on a global scale [2,3], which will necessitate coordination and exchange of information with national administrations and relevant international medical societies (Figure 1). International guidelines on the handling of blood products and the establishment of an international investigatory organization will be necessary (Figure 2). However, there is an urgent need to share the risks of transfusion of blood products derived from genetic vaccine recipients among the parties concerned, and prompt investigation and response by all parties concerned is essential. The most important initial action is to make the relevant medical personnel aware of this situation. In the development of various guidelines, it will be helpful to refer to the response of each country when the transmission of BSE and vCJD, also through blood transfusion, became a problem (e.g. the Creutzfeldt-Jakob Disease International Surveillance Network in Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 11 https://www.eurocjd.ed.ac.uk/) [110,114,115,121,157]. For example, in the United Kingdom, when BSE became a social problem and the mode of transmission of prion protein was unknown, leukodepletion of blood products was conducted universally. Whether this was effective in preventing transmission of BSE and vCJD through blood products is controversial [110,120,121,158], but it was not common at the time to remove white blood cells from all blood products, as is now routinely done with collected blood. However, because of leukodepletion, the safety of blood products has increased [159]. In the case of the spike protein, which causes abnormalities such as agglutination of red blood cells and platelets [8–11,49], we do not expect the problem to be eliminated by leukodepletion alone. However, it is worth confirming whether washing of red blood cells can be effective [160,161]. In urgent cases, autotransfusion may be an option [162]. Recent studies have shown that RNA pseudouridylation can result in frameshifting [133]. It is not yet clear whether a portion of the pseudouridinated mRNA for the spike protein is translated into another protein of unknown function in vaccine recipients. If these proteins are also pathogenic, additional testing for such frameshift proteins may be needed in the future. Even if a frameshift protein is not toxic, it must be foreign to the body and could cause autoimmune disease. In addition, LNPs themselves are highly inflammatory substances [23,100–102], as described in Section 3.1, but LNPs have been found to have stronger adjuvant activity than the adjuvants used in conventional vaccines [104], and there is also concern about autoimmune diseases resulting from this aspect (Table 1, point 4) [105,163]. Thus, although it is not clear what the causative agent of autoimmune disease is, the large number of reported cases of autoimmune disease following genetic vaccination is extremely concerning [15,21,27,30,105,164]. The very mechanism of gene vaccines that causes one’s own cells to produce the antigens of pathogens carries the risk of inducing autoimmune diseases, which cannot be completely avoided even if mRNA pseudouridylation technology is used. In this context, individuals with a positive blood test for spike protein may need to have interviews and additional tests for autoimmune disease indicators, such as antinuclear antibodies (Table 2, point 4) [27,105,129,130]. Alternatively, if the amino acid sequence of the protein resulting from the frameshift is predictable, these candidate proteins could be included in the initial mass spectrometry assay (Table 2, point 6). In any case, it is particularly important to develop tests and establish medical care settings in anticipation of these situations.
Conclusion Finally, we would like to state that if we continue to use genetic vaccines such as pseudouridinated mRNAs and mRNA-LNP platforms [46,103], there will be further risks like those described in this review. It should also be stressed that the issues discussed here are matters that pertain to all organ transplants, including bone marrow transplants, and not just blood products. The impact of these genetic vaccines on blood products and the actual damage caused by them are unknown at present. Therefore, in order to avoid these risks and prevent further expansion of blood contamination and complication of the situation, we strongly request that the vaccination campaign using genetic vaccines be suspended and that a harm–benefit assessment be carried out as early as possible, as called for by Fraiman et al. and Polykretis et al. [27,31–33]. As we have repeatedly stated, the health injuries caused by genetic vaccination are already extremely serious, and it is high time that countries and relevant organizations take concrete steps together to identify the risks and to control and resolve them. Author Contributions: Conceptualization, J.U. M.F. and A.F.; investigation, J.U. H.M. Y.M. M.F. and A.F.; resources, Y.H.; data curation, J.U. H.M. M.F. and A.F.; writing—original draft preparation, J.U.; writing— review and editing, J.U. H.M. Y.H. K.Y. M.F. and A.F.; visualization, J.U.; supervision, J.U. M.F. and A.F.; project administration, J.U. M.F. and A.F.; funding acquisition, M.F. and A.F. All authors have read and agreed to the published version of the manuscript. Funding: The study was supported by donations from members of the Japanese Society for Vaccine-related Complications and the Volunteer Medical Association. Institutional Review Board Statement: Not applicable. Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2024 doi:10.20944/preprints202403.0881.v1 12 Acknowledgments: We would like to express our deep appreciation to the members of the Volunteer Medical Association for their help in the discussions that led to the preparation of this review. Conflicts of Interest: The authors declare no conflict of interest in connection with this research. References
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In natural selection evolution picks the fittest to survive. The genes that give improved performance and are most likely to be passed on. Humans have undergone relaxation of evolutionary fitness so that the accumulation of deleterious genes has become a burden. Its why so many of us need glasses and surgeries.
Much selected diversity must be just random damage, deleterious mutations that are eventually removed by natural selection. Many rare genetic disorders are probably in this category. Since the highest known spontaneous mutation rates for disorders like this are on the order of 10−4, anything with a total fitness cost greater than 10−4 is almost certainly not in this category.
Many polymorphic systems that have health and fitness consequences are leftovers, adaptations to past environments. For example, sickle cell heterozygotes enjoy some protection from falciparum malaria. Malaria can be eliminated in a region instantly in evolutionary time, but the genetic variation that evolved in response to the malaria persists as detrimental or lethal in the new environment.
Gene editing to replace genes that are defective, drugs that alter epigenetics through gene blocking and gene activation and possibly inheritance, drugs to improve performance, increase fertility and number of offspring are proxys for natural selection of genes ostensibly to improve survival or extend it. Genes to replace DNA repair mechanisms are probably in the future.
Environment Gene Interactions 