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Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration
Abstract
Gulf War Syndrome is a multi-system disorder afflicting many veterans of Western armies in the 1990–1991 Gulf War. A number of those afflicted may show neurological deficits including various cognitive dysfunctions and motor neuron disease, the latter expression virtually indistinguishable from classical amyotrophic lateral sclerosis (ALS) except for the age of onset. This ALS “cluster” represents the second such ALS cluster described in the literature to date. Possible causes of GWS include several of the adjuvants in the anthrax vaccine and others. The most likely culprit appears to be aluminum hydroxide. In an initial series of experiments, we examined the potential toxicity of aluminum hydroxide in male, outbred CD-1 mice injected subcutaneously in two equivalent-to-human doses. After sacrifice, spinal cord and motor cortex samples were examined by immunohistochemistry. Aluminum-treated mice showed significantly increased apoptosis of motor neurons and increases in reactive astrocytes and microglial proliferation within the spinal cord and cortex. Morin stain detected the presence of aluminum in the cytoplasm of motor neurons with some neurons also testing positive for the presence of hyper-phosphorylated tau protein, a pathological hallmark of various neurological diseases, including Alzheimer’s disease and frontotemporal dementia. A second series of experiments was conducted on mice injected with six doses of aluminum hydroxide. Behavioural analyses in these mice revealed significant impairments in a number of motor functions as well as diminished spatial memory capacity. The demonstrated neurotoxicity of aluminum hydroxide and its relative ubiquity as an adjuvant suggest that greater scrutiny by the scientific community is warranted.
... Conventional Shaw's morin staining was performed as previously reported (Shaw and Petrik 2009) and is outlined in Table 1. Briefly, morin was prepared at 0.2% w/v in 85% v/v ethanol, containing 0.5% v/v acetic acid. ...
... A comparison of staining protocols for conventional Shaw's morin staining (Shaw and Petrik 2009) versus an optimised morin staining protocol developed herein, is given in Table 1. Shaw's morin solution omitting the addition of acetic acid was added to rehydrated tissue sections for 30 min in humidity chambers. ...
... Conventional Shaw's morin staining damaged fAD donor tissue sections as a result of the HCl pre-rinse. Such was implemented in the original protocol to prevent interferences in the binding of calcium and magnesium to morin (Shaw and Petrik 2009). Furthermore, positive intracellular fluorescence indicating the presence of aluminium in glial and non-neuronal cells in morin-stained sections herein was not detectable upon adjacent lumogallion-stained sections. ...
Aluminium is biologically reactive and its ability to potentiate the immune response has driven its inclusion in both veterinary and human vaccines. Consequently, the need for unequivocal visualisation of aluminium in vivo has created a focused research effort to establish fluorescent molecular probes for this purpose. The most commonly used direct fluorescent labels for the detection of aluminium are morin (2′,3,4′,5,7-pentahydroxyflavone) and lumogallion [4-chloro-3-(2,4-dihydroxyphenylazo)-2-hydroxybenzene-1-sulphonic acid]. While the former has gained popularity in the detection of aluminium in plants and predominantly within root tips, the latter boasts greater sensitivity and selectivity for the detection of aluminium in human cells and tissues. Herein, we have developed a simplified morin staining protocol using the autofluorescence quenching agent, Sudan Black B. This modified protocol improves tissue morphology and increases analytical sensitivity, which allows intracellular aluminium to be detected in monocytes and when co-localised with senile plaques in human brain tissue of donors diagnosed with familial Alzheimer’s disease. Overall, our results demonstrate a simple approach to minimise false positives in the use of morin to unequivocally detect aluminium in vivo.
... Given the fact that there are no known biochemical reactions that require Al, should it be surprising that introducing it into living organisms commonly leads to pathological outcomes [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]? Because of its +3 charge, Al attracts negatively charged ions and electrons, but because it cannot transition to other oxidation states besides +3, it is not a component in any redox reactions. ...
... Al also causes a condensation of brain chromatin disrupting DNA transcription [78]. Animal models of neurological disease plainly suggest that the ubiquitous presence of Al in human beings implicates Al toxicants as causally involved in Lou Gehrig's disease (ALS) [44,45], Alzheimer's disease [20,21,28] and autism spectrum disorders [9,63]. ...
... Coexposure to acidic beverages (lemon juice, tomato juice, and coffee) also increases Al absorption as well as conditions of Ca 2+ , Mg 2+ , Cu 2+ , and Zn 2+ deficiency[70,[83][84][85]. ‡ A single dose of vaccine delivers the equivalent of 204-1284 mg orally ingested Al (0.51−5.56 mg), all of which is absorbed into systemic circulation[86,91].Al hydroxide, a common vaccine adjuvant has been linked to a host of neurodegenerative diseases; it also induces hyperphosphorylation of MAP tau in vivo[44,45,87]. § The risk of antiperspirants is both from dermal exposure and inhalation of acrosols. Al is absorbed from the nasal epithelia into olfactory nerves and distributed directly into the brain[88,91]. ...
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.
(PDF) Aluminum-induced entropy in biological systems: Implications for neurological disease. Journal of Toxicology, 2014, Article ID 491316, 27 pages, 2014. doi:10.1155/2014/491316.. Available from: https://www.researchgate.net/publication/333582751_Aluminum-induced_entropy_in_biological_systems_Implications_for_neurological_disease_Journal_of_Toxicology_2014_Article_ID_491316_27_pages_2014_doi1011552014491316 [accessed Jun 03 2019].
... Aluminum is not a redox-active metal on its own in liposomes, but it does strongly potentiate Fe-mediated OH • generation [144], consistent with aluminum's ability to cause neurodegeneration in cells and animals [144,[577][578][579][580][581][582][583][584]. OH • radicals have a half-life of 1 ns and so must typically react with macromolecules in the immediate vicinity of their production, implying that there might be a source of hydroxyl radicals within the nuclei of AD brain cells [144] to account for the extensive oxidative DNA damage in PCAD, MCI, and AD patients' brains [115,116,161,321,322]. ...
... The bioaccumulation of aluminum in AD patients' brains and hippocampal nerve cell chromatin [144,585] appears to be due primarily to chronic bioaccumulation to varying extents in different individuals due to numerous environmental exposures throughout the lifetime, including the following: acid rain carrying aluminum into residential water supplies due to pollution [590]; aluminum in drinking water, exposure to elevated levels of which has been associated with an increased risk of incident AD [145,591,592]; aluminum in foods, including spinach [593] and processed, packaged, and stored foods such as pickles [590] and sodas packaged in cans or plastic bottles [594]; aluminum in medicines, including over the counter antacids [590,595], some vaccines as an adjuvant [583,[596][597][598][599], neonatal parenteral nutrition [600]; and other consumer products, including antiperspirants [601] and cookware [602][603][604][605]. ...
... This indicates that many environmental and endogenous sources of oxidative stress and/or oxidative stress-induced HNE lipotoxins may upregulate BACE1 in PCAD patients' medial temporal lobe neurons via PKR in the case of H2O2, p38 in the case of 4-HNE, and the JNK→AP1→BACE1 pathway in the case of both and other ROS, with additional upregulation of γ-secretase and downregulation of α-secretase activity via JNK at least when exposed to H2O2 and FeCl2 [71,118,235,237,400,542,546,565]. Public health efforts to stem the rising prevalence of AD should focus on decreasing environmental exposures, inhalation, ingestion, and dermal absorption of pathogens, pollutants, and metals that have been shown to drive oxidative stress experimentally and accumulate in AD patients' brains, for example iron-enriched combustion derived carbon nanoparticles, Alternaria fungi, ferrous iron, and aluminum [42,51,142,144,145,583,584,586,[590][591][592]601,[609][610][611][612]. ...
Abstract. Consistent with the numerous Aβ-targeting clinical trials that failed to meet their primary endpoints, Aβ does not correlate spatiotemporally with oxidative stress (OS), oxygen/glucose hypometabolism, or other AD hallmarks in sporadic Alzheimer’s disease (AD) patients, suggesting it is a compensatory response and an amplifying signal in sporadic AD, not the distal or primary cause of sporadic AD as some still believe. Diverse bacteria, fungi, and DNA viruses accumulate in AD patients’ brains. OS occurs in the preclinical AD (PCAD) medial temporal lobe (MTL), but not the PCAD neocortex. However, oxidatively damaged DNA (oxoDNA) accumulates in the MTLs and neocortices of PCAD, mild cognitive impairment (MCI), and AD patients. DNA-oxidizing iron and aluminum accumulate in AD patients’ hippocampal neuron chromatin. OS, pathogens, and cytokines drive Aβ42 deposition. At the intersection of OS and poly-microbial infections in AD, we hypothesize oxoDNA drives multiple AD hallmarks at all stages of AD pathogenesis. OxoDNA appears to drive Aβ42 deposition via <cGAS/cGAMP/STING/IFN/AIM2>, <MYD88→NFκB→BACE1>, <MAP4K4→JNK→AP1>, and <CK2→pSer529-p65-NFκB→BACE1>. OxoDNA appears to spread OS via Nrf2 mislocalization. OxoDNA appears to drive tau hyperphosphorylation via mitochondrial OS induction. OxoDNA appears to drive oxygen hypo-metabolism, ATP depletion, and mitochondrial OS via <PARP1→PAR→PARG→ADPR→TPRM2→AMP→ANT→ADP→ATP synthase inhibition>. OxoDNA appears to drive neurotoxicity via <PARP1→PAR→mPTP→AIF→parthanatos>, <ROS,ADPR,Ca2+→TRPM2→Ca2+,Zn2+→(Zn2+/LKB1/pThr172-AMPKα2)→p-FOXO3→Bim→oxytosis/ferroptosis>, <CK2→pSer529-p65→Noxa+Bim>, <ATM→p53→caspase9+BAX+APAF1→apoptosis>, <AIM2→caspase1→gasderminD→pyroptosis>. OxoDNA appears to drive synaptoxicity via PARP1, <ADPR→TRPM2→Ca2+>, p53, NFκB, IL-6, <AIM2→caspase1→IL-1β>. OxoDNA appears to drive immunosuppression via IFNs+IL-6→SOCS1/3, and <AIM2+(Ca2+/CaMKKβ/pThr183-AMPKα1)+EB1+LC3→IL-1β>. Via <ROS,ADPR,Ca2+→TRPM2→Ca2+,Zn2+→ZnT6→S-SMase→ceramide> and possibly <AIM2+(Ca2+/CaMKKβ/pThr183-AMPKα1)+EB1→LC3>, oxygen-hypometabolic and partially immortalized medial temporal lobe pyramidal neurons excite each other, neocortical neurons with trans-synaptic extracellular vesicles bearing Aβ42, Zn2+, p-tau, ceramides, IL-1β, RNA, and oxoDNA, promoting synaptotoxicity. The multi-dsDNA repair factor depletion/suppression in AD neurons appears to have been selected for to evade viral integration, e.g. HHV-6A telomere integration. The ATM and BRCA1 loss in AD neurons appears to have been selected for to evade chromosomal fusions at telomeres deprotected by Ku80 downregulation and triaging to dsDNA breaks. BRCA1 and sporadic-AD-specific BMI1 loss derepress heterochromatin. Tau-associated derepressed endogenous retroviruses induce immunodeficiency. In the hippocampus, oxoDNA/IFN/IL-6-induced SOCS1 and oxoDNA/IFN- plus oxoDNA/IL-6-induced SOCS3 promote JAK/STAT suppression. oxoDNA/IFNs may drive IL-1 resistance. Hippocampal <LPS→TLR4→NFκB→pro-IL-1β> + <oxoDNA→cGAS→IFNs→AIM2> + <AIM2+(Ca2+/CaMKKβ/pThr183-AMPKα1)+EB1+LC3>-mediated IL-1β secretion suppresses neocortex IFN immunity, enabling opportunistic herpesvirus-6A and herpesvirus-7, and drives glucose hypo-metabolism, evading parthanatos and sepsis. Stress-associated glucocorticoids also drive immunodeficiency. AD is an inflammatory/autoimmune/immunosuppressive/pseudo-cancerous brain acquired immunodeficiency meta-syndrome (AIDS) driven by chronic oxidative DNA damage, dsDNA repair factor depletion/suppression, endogenous retrovirus derepression, cytokines, and poly-pathogen dysbiosis.
... Morin (3,5,7,2 0 ,4 0 -pentahydroxyflavone) staining. The Al-Morin fluorescence assay was performed for visualization and detection of Al in the SGZ/GCL, according to the protocol by Shaw and Petrik (2009). Brain sections from 5 male pups per group were stained with Morin, a fluorochrome that forms a fluorescent complex with Al fluorescing green with an excitation wavelength of 420 nm (Crapper et al., 1973;De Boni et al., 1974). ...
... Interestingly, Alaccumulated granule cells as evident by Morin-staining were dose-dependently increased at !900 ppm on PND 21. Neuronal cell apoptosis has been suggested in relation with their Al accumulation (Abdel Moneim, 2012;Shaw and Petrik, 2009). Because Al can induce ER stress-mediated apoptosis (Mustafa Rizvi et al., 2014), an increase of granule cell apoptosis at !900 ppm may be related to the cytotoxic effect of accumulated Al in granule cells in the present study. ...
Aluminum (Al) is neurotoxic to adults and also to infants. In this study, we investigated the developmental exposure effect of AlCl3 on postnatal hippocampal neurogenesis. Pregnant mice were administered 0-, 900- or 1800-ppm AlCl3 via drinking water from gestational day 6 to postnatal day (PND) 21, with their offspring examined on PND 21 and PND 77. On PND 21, GFAP-immunoreactive (+) neural stem cells (NSCs) and p21Cip1/Waf1+ cells were decreased in number in the subgranular zone at 900 and ≥ 900 ppm, respectively. Pcna transcript level examined at 1800 ppm was decreased in the dentate gyrus. These results suggest induction of compromised cell quiescence that caused impaired self-renewal capacity of NSCs accompanying slowing down of cell cycling, which ultimately resulted in exhaustion of the NSC pool. At 1800 pm, Reelin+ hilar GABAergic interneurons were also decreased, suggesting a contribution to the NSC reduction. At this dose, TBR2+ or DCX+ progenitor and immature granule cells and PVALB+ interneurons were increased. Moreover, COX-2+ granule cells were increased at ≥ 900 ppm. These results suggest facilitation of transient progenitor cell proliferation and differentiation during exposure. Moreover, TUNEL+ or Morin-stained granule cells were increased, together with Casp12 transcript upregulation, suggesting induction of Al accumulation-related endoplasmic reticulum stress-mediated granule cell apoptosis. Transcript expression changes on cholinergic and glutamatergic signals and synaptic plasticity suggested contribution to disruptive neurogenesis. The NSC-targeting effects sustained through the adult stage despite no sustained Al-accumulation. These results suggest that developmental AlCl3-exposure irreversibly affects postnatal hippocampal neurogenesis involving multiple functions in mice.
... Another form of aluminum, Al hydroxyde, a compound poorly soluble in water, but injected as a vaccine adjuvant, has nevertheless been found to be neurotoxic. In contrast to control mice injected with a saline physiological serum, those injected with Al hydroxyde suffered from apoptosis of motor neurons and from motor function impairments (such as a lower linear speed and a higher sinuosity) as well as from spatial learning and memory decreases [57]. The present study also showed that ants fed with sugar water containing pieces of Al foil walked with a higher sinuosity, were less able to orient themselves and to follow a trail. ...
... Moreover, they had their audacity and pain perception reduced. Thus, ants clearly revealed the effects of Al on the nervous system and muscular systems, and our results converged with those of Shaw & Petrick [57]. An epidemiological study indicates a correlation between the presence of Al in injected vaccines and the occurrence of autism spectrum disorders [8], revealing once more an impact of Al on the brain functioning. ...
... Other additives that may act as toxicants and which are frequently found in vaccines include phenol red, formaldehyde, polysorbate 80, and phenoxyethanol (Eldred et al., 2006;CDC 2020). Though, these potentially toxic constituents are not considered harmful as their formulation quantity is very low (Offit and Jew 2003;Eldred et al., 2006), evidence from animal experiments show that when aluminum and mercury are administered individually in the same dosages as found in vaccines, they were both able to induce serious detrimental neuro-immunological outcomes (Hornig et al., 2004;Authier et al., 2006;Petrik et al., 2007;Shaw and Petrik 2009;Hewitson et al., 2010;Olczak et al. 2010Olczak et al. , 2011Dorea 2011;Duszczyk-Budhathoki et al., 2012). Furthermore, studies have shown that aluminum adjuvants in vaccines are strongly associated with CNS disorders and autoimmune/inflammatory conditions in human adults (Passeri et al., 2011;Shoenfeld and Agmon-Levin 2011;Terhune and Deth 2013;Cadusseau et al., 2014;Exley 2014;Rigolet et al., 2014;Shaw et al., 2014a,b;Gherardi et al., 2015). ...
... At least 13 cytokines and chemokines are produced within 4 h of Al adjuvant injection, including pro-inflammatory IL-1β and IL-6 (McKee et al., 2009). Although historically vaccine Al adjuvants have been portrayed as inherently safe (Eickhoff and Myers 2002;Offit and Jew 2003), studies in animal models and humans have demonstrated their ability to inflict inflammatory manifestations and immune-mediated diseases (Gherardi et al. 2001Shaw and Petrik 2009;Zivkovic et al., 2012bib_Gherardi_et_al_2015). Moreover, studies by Khan et al. and other research groups showed that administration of Al or an Al-containing vaccine was associated with Al deposits in distant organs such as lymph nodes, spleen, liver, and brain (Wen and Wisniewski 1985;Redhead et al., 1992;Flarend et al., 1997;Khan et al., 2013) where in some cases they were still detected up to one year after injection (Khan et al., 2013). ...
Introduction
A recent study from our laboratory demonstrated a number of neurobehavioural abnormalities in mice colony injected with a mouse-weight equivalent dose of all vaccines that are administered to infants in their first 18 months of life according to the U. S. pediatric vaccination schedule.
Cytokines have been studied extensively as blood immune and inflammatory biomarkers, and their association with neurodevelopmental disorders. Given the importance of cytokines in early neurodevelopment, we aimed to investigate the potential effects of the post-administration of the U.S. pediatric vaccines on circulatory cytokines in a mouse model.
In the current study, cytokines have been assayed at early and late time points in mice vaccinated early in postnatal life and compared with placebo controls.
Materials and methods
Newborn mouse pups were divided into three groups: i) vaccine (V1), ii) vaccine ×3 (V3) and iii) placebo control. V1 group was injected with mouse weight-equivalent of the current U. S. pediatric vaccine schedule. V3 group was injected with same vaccines but at triple the dose and the placebo control was injected with saline. Pups were also divided according to the sampling age into two main groups: acute- and chronic-phase group. Blood samples were collected at postnatal day (PND) 23, two days following vaccine schedule for the acute- or at 67 weeks post-vaccination for the chronic-phase group. Fifteen cytokines were analysed: GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, MCP-1, TNF-α, and VEGF-A. Wilcoxon Rank Sum test and unpaired Student’s t-test was performed where applicable.
Results
IL-5 levels in plasma were significantly elevated in the V1 and V3 group compared with the control only in the acute-phase group. The elevation of IL-5 levels in the two vaccine groups were significant irrespective of whether the sexes were combined or separated. Other cytokines (VEGF-A, TNF-α, IL-10, MCP-1, GM-FSF, IL-6, and IL-13) were also impacted, although to a lesser extent and in a sex-dependent manner. In the acute-phase group, females showed significant increase in IL-10 and MCP-1 levels and decrease in VEGF-A levels in both V1 and V3 group compared to controls. In the acute-phase, significant increase in MCP-1 levels in V3 group and CM-CSF levels in V1 and V3 group and decrease in TNF-α levels in V1 group were observed in males compared with controls. In chronic-phase females, levels of VEGF-A in V1 and V3 group, TNF-α in V3 group, and IL-13 in V1 group were significantly decreased in contrast with controls. In chronic-phase males, TNF- α levels increased in V1 group and IL-6 levels decreased in V3 group significantly in comparison to controls. The changes in levels of most tested cytokines were altered between the early and the late postnatal assays.
Conclusions
IL-5 levels significantly increased in the acute-phase of the treatment in the plasma of both sexes that were subjected to V1 and V3 injections. These increases had diminished by the second test assayed at week 67. These results suggest that a profound, albeit transient, effect on cytokine levels may be induced by the whole vaccine administration supporting our recently published observations regarding the behavioral abnormalities in the same mice. These observations support the view that the administration of whole pediatric vaccines in a neonatal period may impact at least short-term CNS functions in mice.
... Using a single injection of FSH in different diluted degradable agents such as propylene glycol (PG), polyvinylpyrrolidone (PVP), aluminum hydroxide gel, or hyaluronan was previously tested in cattle and ewes (Lopez-Sebastian et al., 1993;Dattena et al., 1994;Yamamoto et al., 1994;Takedomi et al., 1995;D‖Alessandro et al., 2001;Kimura et al., 2007;Tríbulo et al., 2012). Although these agents effectively cause a slow release of circulatory FSH to induce a superovulatory response, evidence has shown that PG and PVP has caused allergic reactions in humans (Catanzaro and Smith, 1991;Gonzalo et al., 1999;Yoshida et al., 2007;Marques et al., 2011) while aluminum hydroxide induced neuropathological reactions and macrophagic myofascitis in humans (Gherardi et al., 2001;Shaw and Petrik, 2009). On the other hand, there have been no reports of side effects from HA administered in mammals. ...
The present thesis aims to utilize the assisted reproductive technology (ARTs) as Laparoscopic Insemination and Embryo Transfer (ET) for genetic and reproduction improvement in sheep and also to apply to commercial farm in Thailand. The seasonality and environmental may affect the semen traits in imported ram under tropical conditions. Semen qualities and scrotal circumference of an imported ram varied monthly related to season and environment especially during summer. Indeed, the ram’s reproductive performances correlated with ambient temperature, humidity and day length. These results showed that the peak reproductive performances of imported ram were from December to March. Next, the effect of various and combination of sugars in semen extender for increasing frozen-thawed sperm quality have been investigated. Our findings showed that the combined sucrose and trehalose (ST) supplementation in semen freezing extender significantly improved frozen-thawed sperm qualities (motility, viability, longevity and acrosome integrity) when compared with other sugars (P < 0.05). The fertility rate after laparoscopic artificial insemination (LAI) with frozen-thawed ram semen with the best semen extender revealed the similar pregnancy rates compared with fresh semen (82% vs. 84%, respectively). Regarding the development of simplify superovulation technique in ewes, in vivo experiment was performed to compare ovarian responses and embryo yields by superovulatory stimulation with split-single FSH administration dissolved with hyaluronan (treated group; S) compared to a conventional method (multiple injections of FSH programs; control; M). The results showed no difference of the ovarian responses and embryo yields between the two groups. However, grade 1 and 2 recovered embryos in treated group tended to be higher than in the control group. Following the embryo transfer (ET), the pregnancy rates in S group (90.5%) were significantly higher (P < 0.05) than in M group (78.9%). Finally, the overall results obtained in this thesis were carried out to verify the possibility of application of both AI and ET techniques to commercial scale in sheep farm. It is found that the techniques proposed on this context can successfully translate from laboratory scale to commercial scale.
... 44,46,47 Several studies claimed that such deposition of aluminum in brain via vaccine injection or other administration is associated with behavior, neuropathological impairment. [48][49][50] Such side effects always depend on the dose and the type of alum adjuvant used. ...
Alum adjuvant has always been the first choice when designing a vaccine. Conventional aluminum adjuvant includes aluminum hydroxide, aluminum phosphate, and amorphous aluminum hydroxyphosphate (AAHS), which could effectively induce the humoral, and to a lesser extent, cellular immune responses. Their safety is widely accepted for a variety of vaccines. However, conventional alum adjuvant is not an ideal choice for a vaccine antigen with poor immunogenicity, especially the subunit vaccine in which cellular response is highly demanded. The outbreak of COVID-19 requires a delicately designed vaccine without the antibody-dependent enhancement (ADE) effect to ensure the safety. A sufficiently powerful adjuvant that can induce both Th1 and Th2 immune responses is necessary to reduce the risk of ADE. These circumstances all bring new challenges to the conventional alum adjuvant. However, turning conventional microscale alum adjuvant into nanoscale is a new solution to these problems. Nanoscale alum owns a higher surface volume ratio, can absorb much more antigens, and promote the ability to stimulate the antigen-presenting cells (APCs) via different mechanisms. In this review, the exceptional performance of nano alum adjuvant and their preparation methods will be discussed. The potential safety concern of nano alum is also addressed. Based on the different mechanisms, the potential application of nano alum will also be introduced.
... As a result, the effects of toxic metals such as lead, mercury, and aluminum, when interacting with fluoride compounds, merit further study. Reviews of the known effects of lead, mercury and aluminum can be found: lead [202,236], mercury [128,129,237,238], and aluminum [4,53,68,117,119,[239][240][241][242][243][244]. The following sections will therefore review synergies involving toxic metals, silicofluoride compounds, and/or genetic mutations now found in a number of specific health conditions in which normal biochemical and biophysical processes have been disrupted. ...
Despite enjoying a high standard of living, the United States ranks 46th among nations reporting infant survival rates to the World Health Organization. Among factors that increase infant mortality are environmental toxicants. Toxic metals such as mercury, aluminum, and lead interact synergistically with uoride compounds to produce metal fuoride complexes (e.g., AlF3 and AlF4−). Such toxicants act as biophosphate mimetics disrupting biological signaling processes governing development, immune defenses, and ordinary maintenance systems. Sources for the metals include mother’s mercury amalgams, mercury and aluminum in injected medicines, and lead contaminated drinking water. All of them are made even more toxic by fuorides as evidenced recently by water contamination in Flint, Michigan. Fluorides interact with other toxins increasing their harmful impact. Among the interactants are glyphosate and phosphate containing fertilizers that end up in the food and water because of their widespread use in agriculture. The negative synergy for neonates in the U.S. is increased by the hepatitis B injection containing both mercury and aluminum, and infant formula contaminated with aluminum and the glyphosate in genetically modified soy milk reconstituted with water containing fluoride, aluminum, lead, and other toxic substances. The harmful interactions of such chemicals are associated with rising infant mortality in the U.S. We propose, therefore, a modest but urgent policy change: under TSCA §5, silicofluoride addition to public water supplies should be suspended.
... In a seminal study, Alhydrogel® adjuvant, subcutaneously injected in mice at doses relevant to the dose received by US veterans with GWI, induced motor deficits and cognitive alterations associated with motor neuron death and a significant increase of reactive astrocytes indicative of an inflammatory process [167]. Subsequently, toxicity on the adult or developing mouse brain of either Al adjuvant or whole Al-containing vaccines has been reported in Canada [168][169][170], Israël [171][172] and France [158]. Of note, small animal studies showing toxic effects of Al adjuvants are often suspected to be irrelevant to the human situation but this is not the case of large animal models. ...
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly undersood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants. Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms. It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II. Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery. Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).
... As a result, the effects of toxic metals such as lead, mercury, and aluminum, when interacting with fluoride compounds, merit further study. Reviews of the known effects of lead, mercury and aluminum can be found: lead [202,236], mercury [128,129,237,238], and aluminum [4,53,68,117,119,[239][240][241][242][243][244]. The following sections will therefore review synergies involving toxic metals, silicofluoride compounds, and/or genetic mutations now found in a number of specific health conditions in which normal biochemical and biophysical processes have been disrupted. ...
p>Despite enjoying a high standard of living, the United States ranks 46th among nations reporting infant survival rates to the World Health Organization. Among factors that increase infant mortality are environmental toxicants. Toxic metals such as mercury, aluminum, and lead interact synergistically with fluoride compounds to produce metal fluoride complexes (e.g., AlF3 and AlF4−). Such toxicants act as biophosphate mimetics disrupting biological signaling processes governing development, immune defenses, and ordinary maintenance systems. Sources for the metals include mother’s mercury amalgams, mercury and aluminum in injected medicines, and lead contaminated drinking water. All of them are made even more toxic by fluorides as evidenced recently by water contamination in Flint, Michigan. Fluorides interact with other toxins increasing their harmful impact. Among the interactants are glyphosate and phosphate containing fertilizers that end up in the food and water because of their widespread use in agriculture. The negative synergy for neonates in the U.S. is increased by the hepatitis B injection containing both mercury and aluminum, and infant formula contaminated with aluminum and the glyphosate in genetically modified soy milk reconstituted with water containing fluoride, aluminum, lead, and other toxic substances. The harmful interactions of such chemicals are associated with rising infant mortality in the U.S. We propose, therefore, a modest but urgent policy change: under TSCA §5, silicofluoride addition to public water supplies should be suspended.
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... The number of veterinary vaccines licensed in Hungary is 261, the number of live, attenuated vaccines is 192 AZ ÁLLATORVOSI VAKCINÁK ADJUVÁNSAINAK HATÁSMECHANIZMUSAI Normális körülmények között, ha az alumínium kis dózisban van jelen, kiválasztódik a vesében, viszont a veseműködés zavara esetén lerakódik a testben, ami toxikus is lehet (18). Emellett, bár rákkeltő és magzatkárosító hatásuk egyelőre nem bizonyított, néhányan idegrendszeri károsodások kialakulásának elősegítéséért teszik őket felelőssé (amyotrophiás lateralsklerosis, Guillain-Barrebetegség, szklerózis multiplex) (61). ...
2. NÉBIH Állatgyógyászati Termékek Igazgatósága Az állatorvosi vakcinák adjuvánsainak hatásmechanizmusai ÖSSZEFOGLALÁS Az inaktivált és az alegységvakcinákban a hatékonyabb immunválasz kiváltását mind az állatorvosi, mind pedig a humán gyógyászatban különféle adjuvánsok hozzáadásával segítik elő. A vakcinagyártók számára komoly kihívást jelent a hatékony, de mellékhatás nélküli adjuvánsok fejlesztése. A közelmúltban a kez-deti, próbálgatáson alapuló megközelítéseket felváltották a célzott fejlesztések, amelyek nem jöhettek volna létre az adjuvánsok hatásmechanizmusának egyre részletesebb megismerése nélkül. Az alábbi irodalmi összefoglalóban a szer-zők ismertetik az állatorvosi gyakorlatban leggyakrabban használt és a jelenleg legígéretesebbnek tűnő, fejlesztés alatt álló adjuvánsok általános és specifikus hatásmechanizmusait. SUMMARY Adjuvants are used to induce increased immune responses of inactivated and subunit vaccines both in veterinary and human medicine. Vaccine producers must overcome serious challenges in order to develop safer and more efficient adjuvants without side effects. During the past decades the initial trial and error based approaches were gradually replaced by targeted developments. Most of the advances were due to the accumulation of detailed knowledge about the mechanisms of action of the adjuvants. In this review the authors describe the mechanisms of the most widely utilized adjuvants in the veterinary practice and that of the most promising ones under development.
... 37 An alternative mechanism is that vaccine constituents, such as aluminium, trigger a neuroinflammatory response after crossing the bloodbrain barrier. 38,39 Roszkiewicz and Shoenfeld, however, found that isolated ON was more common in vaccines not containing aluminium, whilst ON associated with other CNS demyelination (such as NMOSD or MS) was found more frequently following vaccination containing aluminium; they postulated that this may support the proposal of neurotoxicity from these components. 34 Of note, Mitkus et al. developed an up-to-date analysis on the role of aluminium, given public concern on aluminium in vaccines. ...
... As it follows from Table 1 Note: Here and in Table 2 data from reviews [14,33] were used as the basis. [20], chronic neurotoxicity [21,22], autoimmune/ inflammatory syndrome [23]. ...
The review is devoted to critical analysis of literature data, deal with effects and mechanisms of action of sulfated polysaccharides (PSs) – fucoidans from brown algae and products of their enzymatic transformation as potential adjuvants for enhancement of anti-infective and antitumor immune response. Numerous experimental data indicate that sulfated PSs demonstrate properties of vaccine adjuvants. Application perspectiveness of fucoidans as vaccine adjuvants is defined by their high biocompatibility, low-toxicity, safety and good tolerance by macroorganism, and also mechanisms of their immunomodulatory action. In particular, fucoidans are agonists of receptors of innate immunity and strong inducers of cellular and humoral immune response. At presenting the data of structural - functional interrelations, attention focused to the defining role of degree of sulfation, uronic acids and polyphenols contents, and also molecular mass in actions of fucoidans to innate and adaptive immunity cells. Insufficiency of literary data on studying of correlation of structure – physicochemical characteristics with adjuvanticities of the sulfated PSs, and also the problem of standardization of their active fractions are noted. Special attention is paid to the analysis of immunomodulatory and adjuvant activity of fucoidan oligosaccharides. Presented here results of experimental trial indicate that, despite the difficulties due to preparation of highly purified structurally characterized fractions and complex structure of fucoidans, these substances can be used as safe and effective adjuvants in vaccines against various pathogens including viruses, and also in antitumor vaccines.
... Des effets comportementaux ont par ailleurs été observés chez la souris [14,[23][24][25] et le mouton [17,26], à la suite d'injections d'oxy-hydroxyde d'Al ou de vaccins contenant cet adjuvant, avec parfois un effet dose-réponse non linéaire, qui semble lié à la taille des particules de sels d'Al [14,17]. ...
OBJECTIVES: Aluminum-containing vaccine adjuvants stimulate an adequate immune response to vaccination. The safety and rapid elimination of these molecules, a guarantee of their safe use for several decades, have been challenged by a growing number of studies over the last 20 years. Evaluation of exposure to aluminum adjuvants of an individual is thus essential. The current review answers the following questions: what is the exposure of aluminum adjuvants of an individual vaccinated in France? What are the factors of variation?.
METHODS: To evaluate the immunization exposure to aluminum for a vaccinee in France, we used the 2018 vaccination schedule and the Social Security database for vaccines reimbursed that year. French mandatory and recommended vaccines for an individual who does not travel abroad and has no particular professional obligations have been taken into account.
RESULTS: Our results show that an individual following the vaccination requirements and recommendations of 2018 receives between 2545 and 7735 ug of Al3+ during his lifetime, and at least 50 % before the age of 1 year. Exposure varies with age, weight, sex, and choice of administered vaccines.
CONCLUSION: Vaccines with higher doses of aluminum are mainly injected at the beginning of life. Women receive a proportionately larger dose than men. The most reimbursed vaccines are often those with the highest amount of aluminum salts.
... Animal studies show that injection of aluminum causes longterm neurological problems, motor deficits and social impairments [83][84][85]. Rates of autism were reported by some studies to not change after thimerosal was excluded from most childhood vaccines. ...
... The use of a single injection of FSH diluted in various degradable agents such as propylene glycol (PG), polyvinylpyrrolidone, aluminum hydroxide gel or hyaluronan (HA) was previously tested in cattle and ewes (Lopez-Sebastian et al. 1993;Dattena et al. 1994;Yamamoto et al. 1994;Takedomi et al. 1995;D'Alessandro et al. 2001;Kimura et al. 2007;Tribulo et al. 2012). Although these agents were effective at eliciting a slow release of FSH to induce a superovulatory response, in humans, PG and polyvinylpyrrolidone have caused allergic reactions (Catanzaro and Smith 1991;Gonzalo et al. 1999;Yoshida et al. 2007;Marques et al. 2011), while aluminum hydroxide induced neuropathological reactions and macrophagic myofascitis (Gherardi et al. 2001;Shaw and Petrik 2009). In contrast, there have been no reports of side effects from HA administered in mammals. ...
Superovulation is an important step in assisted reproductive technology. Due to its short half-life, follicle stimulating hormone is usually given twice daily to ewes for three to five days, which is both time- and labour-intensive. However, dissolving follicle stimulating hormone in degradable polymers to delay absorbtion has been effective in ruminants. Experiment 1 was performed to compare a split-single follicle stimulating hormone dissolved in hyaluronan (S group; 150 mg follicle stimulating hormone on the first day and 30 mg 48 h later; n = 21) and six decreasing doses of follicle stimulating hormone (M group; 50, 50, 30, 30, 10 and 10 mg; n = 22) at 12-h intervals. Ovarian responses and numbers of recovered ova/embryos did not differ significantly between groups. However, there tended to be more Grade 1 and 2 embryos in S vs M groups (mean ± SEM, 5.1 ± 4.9 vs 2.9 ± 2.9, respectively; P = 0.08). Experiment 2 tested the effectiveness of a simplified split-single follicle stimulating hormone in purebred sheep on a commercial farm. The numbers of recovered good-grade embryos (day 2) were 4.8 ± 5.0 and 4.0 ± 2.5 per donors in Corriedale and Bond sheep breeds, respectively. We conclude that this modified technique for ewe superovulation improved animal welfare, reduced animal handling and labour and yielded results similar to or better than conventional twice-daily follicle stimulating hormone treatments.
... This selection is inadequate at least for the first study [7] which included no clinical evaluation because it was designed to explore and understand systemic translocation of aluminum and other biopersitent particles injected in muscle. In contrast, Ameratunga et al. omitted a number of mouse studies documenting neurologic effects of aluminum adjuvant administration [18][19][20]. ...
... Such treatment leads to motor deficits and motor neuron degeneration. [10,219] Al 3+ has no known beneficial physiological action in the human body. Al 3+ induced events likewise include oxidative stress, disruptions of energy metabolism, inflammation, glutamate excitotoxicity and effects on Ca 2+ homeostasis, and therefore might participate in etio-pathology of ASD. ...
Our review suggests that most autism spectrum disorder (ASD) risk factors are connected, either directly or indirectly, to immunoexcitotoxicity. Chronic brain inflammation is known to enhance the sensitivity of glutamate receptors and interfere with glutamate removal from the extraneuronal space, where it can trigger excitotoxicity over a prolonged period. Neuroscience studies have clearly shown that sequential systemic immune stimulation can activate the brain’s immune system, microglia and astrocytes, and that with initial immune stimulation, there occurs CNS microglial priming. Children are exposed to such sequential immune stimulation via a growing number of environmental excitotoxins, vaccines, and persistent viral infections. We demonstrate that fluoride and aluminum (Al3+) can exacerbate the pathological problems by worsening excitotoxicity and inflammation. While Al3+ appears among the key suspicious factors of ASD, fluoride is rarely recognized as a causative culprit. A long-term burden of these ubiquitous toxins has several health effects with a striking resemblance to the symptoms of ASD. In addition, their synergistic action in molecules of aluminofluoride complexes can affect cell signaling, neurodevelopment, and CNS functions at several times lower concentrations than either Al3+ or fluoride acting alone. Our review opens the door to a number of new treatment modes that naturally reduce excitotoxicity and microglial priming.
... In mice, it has been reported that 6 times subcutaneous injections of Al hydroxide used in vaccines during 2-3 weeks, even at a low dose (total 0.1 or 0.55 mg Al/kg, corresponding to the clinical doses), induced decreased locomotor activity, increased anxiety-like behavior, and induced a spatial memory deficit. 78,79 However, there seems to be little possibility that such a short-term and low-dose Al exposure produces substantial behavioral changes, as suggested by the findings of this study, although there were differences in the form of the Al, the administration route, the exposure duration, and the behavioral testing between the studies. These findings indicate the necessity of further investigations on the effects of long-term Al exposure from early life at relatively low doses in future animal and human studies. ...
Background
Aluminum (Al) is considered to be a neurotoxic metal, and excessive exposure to Al has been reported to be a potential risk factor for neurodegenerative diseases. Al ammonium sulfate is one of the Al compounds that is widely used as a food additive. However, the effects of the oral administration of Al ammonium sulfate on physical development and behavior remain to be examined.
Methods
In this study, we investigated the effects of the administration of Al ammonium sulfate 12‐water dissolved in drinking water (0.075 mg/mL) beginning in adolescence on various types of behavior in adult female C57BL/6J mice through a battery of behavioral tests (low‐dose experiment; Experiment 1). We further examined the behavioral effects of the oral administration of a higher dose of the Al compound in drinking water (1 mg/mL) beginning in the prenatal period on behavior in adult male and female mice (high‐dose experiment; Experiment 2).
Results
In the low‐dose experiment, in which females’ oral intake of Al was estimated to be 0.97 mg Al/kg/d as adults, Al‐treated females exhibited an increase in total arm entries in the elevated plus maze test, an initial decrease and subsequent increase in immobility in the forced swim test, and reduced freezing in the fear conditioning test approximately 1 month after the conditioning session compared with vehicle‐treated females (uncorrected P < .05). However, the behavioral differences did not reach a statistically significant level after correction for multiple testing. In the high‐dose experiment, in which animals’ oral intakes were estimated to be about ten times higher than those in the low‐dose experiment, behavioral differences found in the low‐dose experiment were not observed in high‐dose Al‐treated mice, suggesting that the results of the low‐dose experiment might be false positives. Additionally, although high‐dose Al‐treated females exhibited increased social contacts with unfamiliar conspecifics and impaired reference memory performance, and high‐dose Al‐treated mice exhibited decreases in prepulse inhibition and in correct responses in the working memory task (uncorrected P < .05), the differences in any of the behavioral measures did not reach the significance level after correction for multiple testing.
Conclusion
Our results show that long‐term oral exposure to Al ammonium sulfate at the doses used in this study may have the potential to induce some behavioral changes in C57BL/6J mice. However, the behavioral effects of Al were small and statistically weak, as indicated by the fact that the results failed to reach the study‐wide significance level. Thus, further study will be needed to replicate the results and reevaluate the behavioral outcomes of oral intake of Al ammonium sulfate.
... Another additive still present in many vaccines and shown to cause neurological pathologies is Aluminum. Inbar and colleagues noted; "…contrary to popular assumptions of inherent safety of Al in vaccines, there is now compelling data from both human and animal studies which implicates this most widely used adjuvant in the pathogenesis of disabling neuroimmuno-inflammatory conditions" [16] Aluminum has been linked to several disorders of the nervous system and GI tract including but not limited to multiple sclerosis, Crohn's disease [17], Gulf War Syndrome, Alzheimer's disease [18], autism and ALS [19]. The effects caused by vaccine additives has been given a name by the scientific community, ASIA-"autoimmune/inflammatory syndrome induced by adjuvants". ...
The mere mention of a possible link between vaccines and disorders such as autism will instantly elicit a visceral response from many pediatricians. In most cases the response is to point out that the paper linking the MMR vaccine to autism authored by Dr. Andrew Wakefield and colleagues has been discredited, with Wakefield, vaccine advocates whipping boy losing his license to practice medicine in the UK. The implication being that anti-vaccine groups are relying on flawed or fraudulent data or that this is only study to ever make a connection between vaccines and autism, so the issue has been put to rest. Medicine has a history of exercising its cultural authority to suppress opposition opinion. These include Dr. William Coley, who observed one of his patients began recovering from cancer after he was infected with Streptococcus pyogenes. This led Coley to theorize that post-surgical infections helped defeat cancer by mobilizing the immune system, but almost all his scientific peers rejected the idea, writing it off as "crazy and dangerous". Coley died in 1936, and with his death his theory and work which were looked down on as "quack medicine" died too. Coley's theory of immune system stimulation to fight cancer was "surpassed" by "scientific" chemotherapy and radiation. Francis Peyton Rous was a pathologist who discovered that certain viruses were linked to the development of certain cancers was ostracized by his peers and both he and his findings were largely discredited. However, in 1966, over 50 years after his initial findings, he was awarded the Nobel Prize in Physiology or Medicine. This paper is not about Wakefield nor is it a defense of him or his research, it is however intended to point out that there has been an organized attempt to silence vaccine opponents, both professionals and parents who, backed with valid research as defined by pro-vaccine's definition of "real science" have raised legitimate concerns as to the safety and efficacy of certain vaccines. Before latching onto the Wakefield case as the holy grail to prove that vaccine opposition groups rely on fraudulent or weak data to advance their agenda, vaccine advocates need to examine their own science and those who are supplying it. "It is dangerous to be right in matters on which the established authorities are wrong."-Voltaire
... Animal studies show that injection of aluminum causes longterm neurological problems, motor deficits and social impairments [83][84][85]. Rates of autism were reported by some studies to not change after thimerosal was excluded from most childhood vaccines. ...
Neurodevelopmental disorders, including Autism Spectrum Disorders, have a complex biological and medical basis involving diverse genetic risk and myriad environmental exposures. Teasing apart the role of specific stressors is made challenging due to the large number of apparently contributing associations, gene X environment interactions and phenomimicry [1]. Historically, these conditions have been rare, making causality assessment at the population level infeasible. Only a few vaccines have been tested for association with autism, and it has been shown that improved diagnosis only explains a percentage of the increase in diagnosis. Now, the rates are so high in some countries that public school programs cannot handle the large numbers of special needs students, and professionals are quitting their jobs due to security concerns. Here, I review evidence of the pathophysiology of autism that reconciles the apparent paradox between the high degree of causal heterogeneity in environmental toxins, the absence of common "autism gene," and the high degree of genetic concordance (heritability) of ASD and ASD-like traits. In brief, the sampling of environmental toxins, and thus the environmental toxin sampling liability for ASD varies among families involving different local exposures following injury to normal cellular endoplasmic detoxification and mitochondrial processes from toxic metals. The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, run-away cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload (ER hyper stress), contributing to neuronal and glial apoptosis via the unfolded-protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal retoxification in neurons and glial cells accompanied by chronic UPR is key. This model explains the aberrant protein disorder observed in ASD; the great diversity of genes that are found to have low, but real contributions to ASD risk and the sensitivity of individuals with ASD to environmental toxins. The hindrance of detoxification and loss of cellular energetics leads to apoptosis, release of cytokines and chronic neuroinflammation and microglial activation, all observed hallmarks of ASD. Interference with the development of normal complex (redundant) synapses leads to a pathological variation in neuronal differentiation, axon and dendrite outgrowth, and synaptic protein expression. The most general outcomes are overall simplification of gross synaptic anatomy and, neurofunctionally, a loss of inhibitory feedback and aberrations in long-term connections between distant regions of the brain. Failed resolution of the ER stress response leads to re-distribution of neurotoxic metals, and the impaired neurocellular processes lead to subsequent accumulation of a variety of additional types of toxins with secondary, sometime life-threatening comorbidities such as seizures, with overlapping (not mutually exclusive) causality. Reduction of exposure to toxins known to cause mitopathy (mercury) and endoplasmic reticulum dysfunction (mercury and aluminum) during pregnancy and during the early years of development will reduce the risk of ER overload and ER hyper stress, and of ASD diagnosis. This knowledge has immediate clinical translational relevance: post-vaccination symptoms should be heeded as a sign of susceptibility to toxin; Vitamin D can be increased to drive the healthy early phases of the UPR, and mutations in ASD genes encoding proteins with high intrinsic disorder may contraindicate the use of aluminum and mercury for carriers of risk alleles. Clinicians should be alert to a patient’s Vitamin D receptor (BSM) mutational status prior to recommending increased doses. Approaches to improving overall brain health in autistics must be de-stigmatized and given high priority. Reduction of lifetime exposures of industrial and agricultural toxins will improve brain health for the entire human population. Purely genetic studies of ASD, and studies that do not include vaccination as an environmental exposure with potential liability and interactions with genes, are unethical. To qualify as science, studies must test plausible hypotheses, and the absence of association from poorly designed, unethically executed, and underpowered and unsound whole-population association studies have been harmful distractions in the quest for understanding. Skilled paediatricians and ob/gyns will seek evidence of genetic predisposition to environmental susceptibility in the form of non-synonymous substitutions in brain proteins that require ER-folding, and they will provide informed cautions on exposures (from all sources) to environmental toxins to patients and parents of patients with signs of metal and chemical sensitivity. To aid in this, a list of ASD environmental susceptibility protein-encoded genes is presented. A clinical Exome sequence test, followed by loss of function prediction analysis, would point to individuals most susceptible to vaccine metal-induced ER hyper stress leading to failed cellular detoxification.
... Another hypothesis that follows directly from TNRtheory is that all morbid conditions affecting human beings from stress "disorders" [123], [124] to lifethreatening infectious diseases [125], to poisoning events [81], [83], [126], or traumatic injuries of any kind [127], must involve the disruption of the body's biosignaling systems in some way. The biosemiotic depth hypothesis is framed in relation to what is known of the body's biosignaling systems and the many ways they can be disrupted. ...
At their most abstract level, according to a certain generalized paradigm in biosemiotic philosophy grounded in well-established mathematical proofs, valid communications from molecules upward must be formally isomorphic to the dynamic true narrative representations (TNRs) of natural language systems that vest those meaningful signs with their functional (pragmatic) content. TNRs, in DNA, RNA, proteins, and higher constructions, therefore, are requisite to health in the individual, in interactions with the larger environment, and with other organisms. In homo sapiens, the generalized biosemiotic paradigm proves that morbidities in general must always, in some manner, involve degradation of internal and external communications through TNRs in DNA, RNA, protein language, organelles, cells, tissues, and organ systems. The mathematically grounded paradigm shows that any given TNR can be superveniently degenerated, by very coarse or very fine degrees, to many distinct fictions, errors, lies, and nonsense strings out to the absolute limit of a complete erasure. The depth hypothesis asserts that if the timing and breadth of any degenerative disruption can be held equal, in fact or in principle, the depth of penetration of any disruptive factor into biosignaling representations must in theory be pathognomonic of severity in the supervened morbidities. From meiosis through conception to maturity, ceteris paribus, corruptions deeper in the developmental hierarchy must be more harmful in the morbidities they supervene. The depth hypothesis suggests a differentiation of autoimmune disorders as deeper than allergies, but less so than prion diseases, tumorigenesis, and metastatic cancers in that order. It suggests, therefore, a potentially useful generalized ranking of morbidities.
... Aluminioak erantzun immunean dituen onurak frogatzen dituzten ikerketez gain, badira horren aurka egiten dutenak eta aluminioa bezalako konposatuen erabilerak dituen eragin negatiboak azpimarratzen dituztenak ere [15]. Eragin negatibo horien artean gaixotasun autoimmuneak, eta muskulu eta nerbio-sistemako kalteak daude, segurtasun handiagoko laguntzaileen beharra nabarmendu dutenak [16]. ...
Hamarkadak dira aluminio konposatuak txertoen laguntzaile gisa erabiltzen direla albaitaritzan eta giza-txertoetan. Laguntzaile hauen erabilera oso hedatua egon arren, ez da ongi ezagutzen zein mekanismoren bidez eragiten dituzten ondorio onuragarriak eta, aldizka, kontrako erreakzioak eragin ditzakete. Sistemen biologiako tekniken bidez laguntzaile hauen sinadura molekularra ikertu egin da, gizakietan zein etxabereetan. Hainbat eragin mekanismo proposatu dira aluminioaren sistema immunea pizteko ahalmena azaltzeko eta analisi transkriptomikoetan erlazionatuako geneak aurkitu dira. Batzuetan emaitzak kontraesankorrak dira, aktibatzen den erantzun immunea desberdina izan daitekeelako egoeraren arabera. Aluminio-gatzen tamainak, formak, propietate fisiko-kimikoek eta antigenoen absortzioak eragina dutela ematen du ere. Laguntzaile hauek ez dira antigeno-garraiatzaile soilak, sistema immunea kitzikatzen duten arrisku seinale endogenoak pizten baitituzte. Argitzeke dago oraindik euren eragin mekanismo zehatza eta epe luzeko aktibazio immunitarioak sistema immunitarioaren gainestimulazioa eragin dezakeen.
... 133 This ingredient's action mechanism is yet to be understood but seems to increase the immune response, antibody titer, 134,135 and autoimmune side effects. 136,137 It remains widely used because of its low cost, adsorptive capacity, and effectiveness as an adjuvant. [138][139][140][141] 0.78 mg of L-histidine: L-Histidine is a semi-essential amino-acid for humans, indicating a potential slight risk of toxicity as a vaccine ingredient. ...
Human papillomavirus (HPV) was labeled a cause of cervical cancer, and nationwide decisions are taken regarding HPV-vaccines and the prevention of such cancer. Healthcare providers and the public depend on recommendations of national, state, or provincial authorities. Risk-benefit evaluations and robust critical analysis of the data is crucial to reach consensus. Despite numerous studies on this topic, vaccine effectiveness has been established while omitting major confounders. Numerous factors can influence the studied outcomes such as societal changes, subjects characteristics, culture and ethnicity, subject behaviors, type of medication, diet, alcohol and cigarette consumption, genetic factors, mother to infant transmission, screening recommendations, socioeconomic status, parity, sexual behavior, number of partners, condom usage, and vaginal flora, to mention only a few discussed in this review. The omission of these influential factors when studying a vaccine effectiveness can lead to incorrect results and misleading conclusions. While addressing potential confounders, the author reviews the efficacy, cost-effectiveness and safety of Gardasil®9. To date, the immune response to human papillomaviruses is not yet fully understood, and antibodies are not always present following a cleared HPV-infection. Are antibodies essential to the elimination of human papillomaviruses? Geometric mean titer (GMT) levels have been used to assess efficacy, while the clinical relevance of such information is unknown. Despite the lack of evidence, a 3-dose Gardasil®9 regimen was accepted. There is growing evidence on the possible non-inferior effectiveness of a one-dose vaccine compared to a two or three-dose regimen. When assessing the risk-benefits of a vaccination program, an assessment of the benefits should equally weigh its risks and safety. However, most reports share effectiveness information based on studies and briefly describe its safety. The author reviews the ingredients and potential consequences of Gardasil®9 in parallel with other evidence. This literature review does not express that the HPV vaccine is ineffective, but raises the concern about numerous omitted confounders that could have led to biased conclusions. The effectiveness and efficacy of HPV vaccine cannot seem to be concluded until all confounders are accounted for.
... Mice exposed to aluminum sulfate in drinking water developed Aβ deposits in their cerebral cortex (16) while IP injection of AlCl 3 resulted in cortical atrophy, neuronal shrinkage, and amyloid deposition in the rat brain (17). Mice receiving subcutaneous injections of AlOH 3 showed evidence of increased apoptosis of motor neurons and reactive astrocytes and microglia in the spinal cord and cerebral cortex (18). Studies also showed a significant increase in acetylcholinesterase (AChE) activity in the brain (19) and serum (20) of AlCl 3 -treated rodents. ...
Objectives:
To investigate the potential therapeutic effect of Bougainvillea spectabilis flower decoction on aluminum chloride (AlCl3)-induced neurotoxicity.
Materials and methods:
Rats received daily intraperitoneal injections of AlCl3 at 10 mg/kg for two months and were treated with B. spectabilis decoction at 50 or 100 mg/kg or saline during the 2nd month of the study. The control group received saline. Brain malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), acetylcholinesterase (AChE), amyloid Aβ peptide, and interleukin-6 (IL-6) concentrations and paraoxonase-1 (PON-1) activity were determined and brain histology was done. Behavioral and neurological testing included Morris water maze (WMZ), Y maze, and wire hanging.
Results:
Compared with saline controls, AlCl3 significantly increased brain MDA and NO along with decreased GSH and PON-1 activity. It also increased AChE, IL-6, and amyloid Aβ concentrations. AlCl3 impaired motor strength and memory performance and caused brain neurodegeneration. B. spectabilis decoction given at 50 or 100 mg/kg protected against the biochemical and histopathological alterations evoked by AlCl3 by alleviating the increase in MDA and NO, and decrease in GSH and PON-1 activity. B. spectabilis decoction showed no significant effect on AChE but markedly decreased IL-6 and amyloid Aβ in the brain of AlCl3-treated rats. It also restored memory performance and motor strength, and protected against AlCl3-induced neurodegeneration.
Conclusion:
These results suggest that B. spectabilis flower decoction might prove of value in the treatment of Alzheimer's disease.
... Brain showed hypermic blood vessel, vacuolation and degenerative changes in cell body. These fi ndings are in accordance with the observations of earlier workers in rodents 20,21 , in aluminium chloride in rats 22 , in mice 23 and in nanoalumina fed rats 14 . They reported signifi cant inflammatory changes, deranged and degenerated neurons, vacuolization around the neuron, disruption of nucleus and congestion in the blood vessels. ...
... Therefore, VLPs have been a reliable and safe tool for the development of new vaccines. In the context of vaccine adjuvants, the use of aluminium salts as an adjuvant is currently licensed in most vaccine preparations [20], however, its use is related to episodes of severe local adverse reactions, such as pruritic subcutaneous nodules and hypersensitivity [21] and motor neuron degeneration [22]. Given these limitations, this study contributes to the characterization and evaluation of the immunostimulatory action of TrV-VLPs for their ability to induce antibodies, in the absence of aluminium adjuvant. ...
Background
The infection caused by the protozoan Trypanosoma cruzi affects humans and is called as Chagas disease. Currently, the main measures available to reduce the incidence of this disease are drug treatment and vector control. Traditionally, the development of vaccines occurs mainly through the use of antigenic candidates of the etiologic agent in the form of a vaccine preparation. Virus-like particles (VLPs) are structures analogous to viral capsids composed essentially of structural proteins and are widely used in vaccination protocols because of their immunostimulatory properties. In this context, the objective of this study was to use strategies in a murine immunization model to characterize the immunostimulatory capacity of VLPs from Triatoma virus (TrV-VLPs), analysed in the presence or absence of the aluminium vaccine adjuvant. In parallel, to characterize the immunogenic behaviour of four T. cruzi chimeric recombinant proteins (mix-IBMP) associated with TrV-VLPs or aluminium vaccine adjuvant.
Method
We immunized BALB/c mice once or twice, depending on the strategy, and collected serum samples at 15, 30 and 45 days after the immunization. Subsequently, serum samples from animals immunized with TrV-VLPs were used to determine total IgG, IgG1, IgG2a, IgG2b and IgG3 anti-TrV-VLPs by enzyme-linked immunosorbent assay (ELISA).
Results
Data obtained demonstrate the ability of TrV-VLPs to preferably induce IgG2b and IgG3 type antibodies in the absence of aluminium adjuvant. In fact, the use of aluminium did not interfere with the total IgG profile of anti-TrV-VLPs. Interestingly, mix-IBMP had a better profile of total IgG, IgG1 and IgG3 subclasses when mixed with TrV-VLPs.
Conclusion
In conclusion, these results suggest the potential of TrV-VLPs as a vaccine adjuvant and the use of T. cruzi chimeric antigens as a rational strategy for the development of vaccines against the experimental model of Chagas disease.
... In addition, female mice treated with Al during pregnancy and lactation produced offspring that had a decline in physical development, motor activity behavior, cognitive response, and brain neurotransmitter levels (Abu-Ta weel et al., 2012). Aluminum exposure generates decreases in motor function and spatial memory capability in juvenile mice (Shaw and Petrik, 2009) and rats (Fernandes et al., 2020). Morphological changes and a decline in mitochondrial function were found in three regions of Fig. 1. ...
Background
Aluminum is a neurotoxic element that can accumulate in the brain and cause neurodegenerative disorders. In addition, the antioxidants found in pomegranate juice (PJ) are much more than those existing in other fruits. It was proven to provide protection against neurodegenerative diseases.
Objectives
This experiment aimed to clarify the amelioration efficiency of PJ against aluminum chloride-induced neurobehavioral and biochemical disorders in female mice.
Methods
The female mice were given oral administrations for 35 days as follows. The control group received tap water, the PJ groups received 20% and 40% pomegranate juice, the aluminum chloride (AlCl3) group was treated with 400 mg/kg AlCl3, and the last two groups received AlCl3 + 20% PJ and AlCl3 + 40% PJ, respectively. The neurobehavioral features were assessed by shuttle box, T-maze, and Morris water maze devices. Furthermore, the neurotransmitters and oxidative indicators in the brains of the female mice were determined at the end of experiment.
Results
Significant effects of AlCl3 were observed on female mice in the body weight, during the behavioral tasks (shuttle box, T-maze, and Morris water maze), and in neurotransmitters and oxidative stress parameters. Pomegranate juice, especially at low concentrations, induced remarkable improvements in body weight, spatial memory and learning during T-maze, Morris water maze and shuttle box tasks, as well as in neurotransmitters and oxidative biomarkers in the AlCl3-treated female mice.
Conclusion
PJ reversed AlCl3-induced neurotoxicity and improved learning and memory in female mice. However, PJ contains a group of antioxidants that may be considered double-edged swords in the cellular redox status especially at high doses.
... However, aluminum is potentially harmful to the CNS and may be associated with neurodegenerative diseases [85]. Mice injected with aluminum hydroxide can induce motor dysfunction and loss of motor neurons, which is similar to ALS [86]. Interestingly, the incidence of ALS among Gulf War veterans may be related to the anthrax vaccine containing aluminum hydroxide, which increases the incidence of ALS and causes a younger onset age [84,87]. ...
Introduction
Coronavirus Disease 2019 (COVID-19) poses a substantial threat to the lives of the elderly, especially those with neurodegenerative diseases, and vaccination against viral infections is recognized as an effective measure to reduce mortality. However, elderly patients with neurodegenerative diseases often suffer from abnormal immune function and take multiple medications, which may complicate the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Currently, there is no expert consensus on whether SARS-CoV-2 vaccines are suitable for patients with neurodegenerative diseases.
Areas covered
We searched Pubmed to conduct a systematic review of published studies, case reports, reviews, meta-analyses, and expert guidelines on the impact of SARS-CoV-2 on neurodegenerative diseases and the latest developments in COVID-19 vaccines. We also summarized the interaction between vaccines and age-related neurodegenerative diseases. The compatibility of future SARS-CoV-2 vaccines with neurodegenerative diseases is discussed.
Expert opinion
Vaccines enable the body to produce immunity by activating the body’s immune response. The pathogenesis and treatment of neurodegenerative diseases is complex, and these diseases often involve abnormal immune function, which can substantially affect the safety and effectiveness of vaccines. In short, this article provides recommendations for the use of vaccine candidates in patients with neurodegenerative diseases.
... Our results do not agree with a large body of research which has showed that aluminum exposure at different concentrations leads an hypokinesia [23,5,24]. Exposure to aluminum causes significant impairments in a number of motor functions and increased apoptosis of motor neurons [25]. In addition to the motor dysfunction, an increase in immobility time was observed in animals exposed to Al. ...
Aluminum (Al) is an element with ubiquitous presence on the earth crust that may cause neuropathological, neurobehavioral, neurophysical, and neurochemical changes linked to its bioavailability. The purpose of the present study was to determine the neuroprotective potential of pomegranate juice on Al induced neurotoxicity. Three groups of 7 female albino Swiss mice were used: the control group received only drinking water; the positive control group was exposed daily to 500 mg/kg of AlCl3 orally; and the third treated group received pomegranate juice (v/v in water) supplied in dark bottles for 4 h/day followed by AlCl3 at a dose of 500 mg/kg orally for 20 h/day for 90 days. After 90 days, the mice were subjected to behavioral and memory tests. Cortex cerebral and hippocampus injuries were determined with hematoxylin and eosin staining and Al accumulation was measured by graphite furnace atomic absorption with Zeeman correction. The Al deposition in the brain caused neural degeneration and decreased cell density inducing a state of anxiety, depression, and a deficit of learning and memory. Pomegranate juice treatment attenuated neurobehavioral alterations, decreased Al in the brain and restored the histological structure. High-performance liquid chromatography with a diode-array detector (HPLC-DAD) revealed a range of bioactive molecules (i.e., gallic acid, quercetine, luteolin) in the pomegranate juice that may have neuroprotective value for the nervous disorders caused by Al intoxication.
... In this process, small amounts of aluminum ingested over the years accumulate in the brain tissue and form deposits that activate apoptosis and promote degeneration that leads to neuron loss. This toxic effect has been described with injected and ingested aluminum in animal models by different authors [14,[28][29][30][31][32] and some factors have being described to determine the grade of neurotoxicity, such as age and renal function [33]. Furthermore, there are groups already testing ways to protect neuronal tissue from the effects of aluminum [34,35]. ...
... Many studies in vitro and in vivo are related to the accumulation of this metal in the encephalon with neurodegenerative diseases, like Alzheimer's disease and amyotrophic lateral aclerosis, once this metal can modify the metabolism and influence several SNC functions [59][60][61]. From the studies which portray that kind of association between Al and SNC, there are only a few that deals with evaluating motor parameters aimed at investigating the effects of safe and representative doses of human consumption [62][63][64]. ...
High amounts of aluminum (Al) are found in soil and water. It is highly bioavailable, which makes it an important agent of environmental imbalance. Moreover, Al is considered a neurotoxic agent that is associated with several neurodegenerative diseases. Thus, this study investigated the effects of long-term Al chloride (AlCl3) exposure on motor behavior, oxidative biochemistry, and cerebellar tissue parameters. For this, adult Wistar rats were divided into three groups: Al-D1 (8.3 mg kg−1 day−1), Al-D2 (5.2 mg kg−1 day−1), and control (distilled water); all groups were orally exposed for 60 days by intragastric gavage. After the exposure period, animals performed the open field, elevated plus maze, rotarod, and beam walking tests. Then, the blood and cerebellum were collected to evaluate Al levels and biochemical and morphological analyses, respectively. Our results demonstrate that animals exposed to Al doses presented a higher Al level in the blood. In the spontaneous locomotor activity, Al exposure groups had traveled a lower total distance when compared with the control group. There was no statistically significant difference (p > 0.05) between exposed and control groups when anxiogenic profile, forced locomotion, fine motor coordination/balance, pro-oxidative parameter, and density Purkinje cells were compared. Thus, aluminum exposure in equivalent doses to human consumption in urban regions did not promote significant changes in the cerebellum or motor parameters.
Aluminium hydroxide adjuvants are crucial for livestock and human vaccines. Few studies have analysed their effect on the central nervous system in vivo. In this work, lambs received three different treatments of parallel subcutaneous inoculations during 16 months with aluminium-containing commercial vaccines, an equivalent dose of aluminium hydroxide or mock injections. Brain samples were sequenced by RNA-seq and miRNA-seq for the expression analysis of mRNAs, long non-coding RNAs and microRNAs and three expression comparisons were made. Although few differentially expressed genes were identified, some dysregulated genes by aluminium hydroxide alone were linked to neurological functions, the lncRNA TUNA among them, or were enriched in mitochondrial energy metabolism related functions. In the same way, the miRNA expression was mainly disrupted by the adjuvant alone treatment. Some differentially expressed miRNAs had been previously linked to neurological diseases, oxidative stress and apoptosis. In brief, in this study aluminium hydroxide alone altered the transcriptome of the encephalon to a higher degree than commercial vaccines that present a milder effect. The expression changes in the animals inoculated with aluminium hydroxide suggest mitochondrial disfunction. Further research is needed to elucidate to which extent these changes could have pathological consequences.
Immunotherapy (e.g., checkpoint blockade, adoptive T cell therapy, cancer vaccine) has emerged as one of the most important treatment modalities for cancer in the past two decades. While these approaches are promising, the response rates observed in clinical trials are less than 30% due to tumor heterogeneity and complexity of the tumor microenvironment. Smart nanosystems have the potential to address some of the limitations associated with immunotherapy. Herein, we review applications of nanosystem-mediated immunotherapy for functional T cell activation, including formation of artificial antigen presenting cells, cancer nanovaccination, tumor microenvironment modulation, and combination therapy. Finally, we propose areas of research for the future development of nanosystem-mediated cancer immunotherapy.
Background:
Our group has shown that significant correlations exist between rates of Autism Spectrum Disorder (ASD) and total aluminum adjuvants given to children through vaccines in several Western countries. These correlations satisfied eight out of nine Hill criteria for causality. Experimental studies have demonstrated a range of behavioural abnormalities in young mice after postnatal exposure to aluminium. To build on our previous work, the current study will investigate the effect of aluminium adjuvants on social behaviour in mice. Anomalies in social interaction are a key characteristic of those with ASD.
Methods:
Neonatal CD-1 mice pups were injected with either a total of 550μg of aluminum hydroxide gel (experimental group) or saline (control) spread out during the first two weeks of postnatal life. The mice were then subjected to behavioural tests for social interest and social novelty at postnatal week 8, 17 and 29. p-Values were calculated using the Mann-Whitney and Kruskal Wallis tests.
Results:
Aluminum injected mice showed diminished social interest compared to controls at week 8 (p=0.016) and 17 (p=0.012). They also demonstrated abnormal social novelty from controls at week 8 (p=0.002) and week 29 (p=0.042).
Conclusion:
This is the first experimental study, to our knowledge, to demonstrate that aluminum adjuvants can impair social behaviour if applied in the early period of postnatal development. The study, however, is insufficient to make any assertive claims about the link between aluminium adjuvants and ASD in humans.
The efficient study of human disease requires the proper tools, one of the most crucial of which is an accurate animal model that faithfully recapitulates the human condition. The study of amyotrophic lateral sclerosis (ALS) is no exception. Although the majority of ALS cases are considered sporadic, most animal models of this disease rely on genetic mutations identified in familial cases. Over the past decade, the number of genes associated with ALS has risen dramatically and, with each new genetic variant, there is a drive to develop associated animal models. Rodent models are of particular importance as they allow for the study of ALS in the context of a living mammal with a comparable CNS. Such models not only help to verify the pathogenicity of novel mutations but also provide critical insight into disease mechanisms and are crucial for the testing of new therapeutics. In this Review, we aim to summarize the full spectrum of ALS rodent models developed to date. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motor neurons. Various genes have been linked to ALS, leading to the generation of many rodent models of this disease. In this Review, Todd and Petrucelli provide a broad overview of these models.
Aluminum (Al), a common light metal, affects the developing nervous system. Developmental exposure to Al chloride (AlCl3 ) induces aberrant neurogenesis by targeting neural stem cells (NSCs) and/or neural progenitor cells (NPCs) in the dentate gyrus (DG) of rats and mice. To investigate whether hippocampal neurogenesis is similarly affected by AlCl3 exposure in a general toxicity study, AlCl3 was orally administered to 5-week-old Sprague Dawley rats at dosages of 0, 4000, or 8000 ppm in drinking water for 28 days. AlCl3 downregulated Sox2 transcript levels in the DG at the highest dosage and produced a dose-dependent decrease of SOX2+ cells without altering numbers of GFAP+ or TBR2+ cells in the subgranular zone, suggesting that AlCl3 decreases Type 2a NPCs. High-dose exposure downregulated Pcna, upregulated Pvalb, and altered expression of genes suggestive of oxidative stress induction (upregulation of Nos2 and downregulation of antioxidant enzyme genes), indicating suppressed proliferation and differentiation of Type 1 NSCs. AlCl3 doses also increased mature granule cells in the DG. Upregulation of Reln may have contributed to an increase of granule cells to compensate for the decrease of Type 2a NPCs. Moreover, upregulation of Calb2, Gria2, Mapk3, and Tgfb3, as well as increased numbers of activated astrocytes in the DG hilus, may represent ameliorating responses against suppressed neurogenesis. These results suggest that 28-day exposure of young-adult rats to AlCl3 differentially targeted NPCs and mature granule cells in hippocampal neurogenesis, yielding a different pattern of disrupted neurogenesis from developmental exposure.
L'aluminium est un métal très abondant dans la nature. Pourtant, il n'est pas présentchez l'Homme de manière naturelle et ne participe à aucune fonction essentielleconnue à ce jour. Il entre dans la composition de divers produits vendus en officine,tels que les vaccins, certains médicaments oraux (anti-acides principalement), lesanti-transpirants et d'autres cosmétiques.Depuis plusieurs années, ses effets sur la santé sont au centre des préoccupations dela population, des professionnels de santé, et des scientifiques. De nombreusesétudes ont été réalisées à ce sujet.Les études indiquent que l'aluminium peut entraîner des effets indésirablesneurologiques (autisme, encéphalopathie, maladie d'Alzheimer), hématologiques(anémie) et au niveau osseux (ostéodystrophie, ostéomalacie) suite à un passagedans le sang quelle que soit sa voie d'administration. Par ailleurs, il semble êtreresponsable d'effets locaux, tels que des nodules cutanés et la myofasciite àmacrophages suite à la vaccination. D'autres effets indésirables, tels que desirritations, de l'eczéma, et des réactions allergiques sont observés lorsqu'il estprésent dans les cosmétiques.Il a été supprimé de la composition du liquide de dialyse. Cependant, il reste présentdans les autres produits étudiés malgré les efforts pour le retirer, car il y joue un rôleimportant pour leur efficacité.L'utilisation des médicaments contenant de l'aluminium peut toutefois être évitée enles remplaçant par des médicaments qui en sont dépourvus. Quant à l'usage d'antitranspirantou de cosmétique, il n'est pas une nécessité et peut sans problème êtreévité. La notion de rapport bénéfices-risques est tout de même à garder en mémoire,notamment pour les vaccins, qui restent nécessaires pour éviter certaines maladies,malgré le risque faible d'entraîner une myofasciite à macrophages.
SÍNTESIS
Los adyuvantes son componentes esenciales en las vacunas, sin embargo, debido a la toxicidad, desde 1926 sólo las sales de aluminio y más recientemente otros pocos se han autorizado para emplearse en vacunas humanas. Hoy se necesitan nuevas técnicas para mejorar los estudios inmunotoxicológicos preclínicos de los adyuvantes. En esta tesis se evalúan tres métodos alternativos para este fin: 1) el HET-CAM, un método in vitro para la detección de irritabilidad directa y su inserción en un estudio preclínico de balance eficacia-toxicidad; 2) herramientas bioinformáticas (in sílíco) para la detección de mimetismo molecular entre antígenos vacunales y proteínas humanas, evaluándose la capacidad de predicción de autoinmunidad a nivel preclínico; 3) se desarrolla un biomodelo cinético de teofilina plasmática en ratas, para evaluar el efecto de la inmunoestimulación por adyuvantes sobre medicamentos que se metabolizan por vía citocromo P450. Para estos ensayos se emplearon adyuvantes en desarrollo como: AFCo1, Cliptox, Montanide IMS 1313 y 1314, así como los ya establecidos adyuvantes de Freund e hidróxido de aluminio. Se evidenció la utilidad del HET-CAM para estudios de irritabilidad directa de los adyuvantes y como parte de los ensayos preclínicos; también se demostró que la detección del mimetismo molecular entre antígenos vacunales y proteínas humanas es de gran valor, pero su alcance para la predicción de autoinmunidad a nivel preclínico es limitada y finalmente, se pudo demostrar que un biomodelo cinético de teofilina es potencialmente útil para estudiar el efecto de la inmunoestimulación por adyuvantes sobre la concentración plasmática de este fármaco.
Background:
Mesial temporal lobe epilepsy (mTLE) is the most common type of refractory epilepsy, and non-human primate (NHP) models are important to investigate its mechanism and therapy. However, previous mTLE-NHP models have some defects.
Methods:
Thirteen rhesus monkeys were randomly assigned to a control group and epilepsy group. Kainic acid (KA) was injected into the left hippocampus and amygdala assisted by a neurosurgical robot system, while the control group received normal saline injection. Stereoelectroencephalography (SEEG) electrodes were implanted into the hippocampus in the acute and chronic stages to monitor epileptic discharges, with continuous behavior monitoring. The changes in hippocampal volume were evaluated by magnetic resonance imaging. Transmission electron microscopy, western blotting and immunofluorescence were performed 3 months after injection to investigate neuronal ultrastructural alteration, blood-brain barrier (BBB) disruption, neuronal loss and gliosis in multiple brain regions.
Results:
In the epilepsy group, status epilepticus (SE) and spontaneously recurrent seizures (SRSs) were detected in the acute and chronic stages via video monitoring. SEEG confirmed that the epileptic zone was focused on the injection area. The hippocampal volume was significantly decreased in the chronic stage compared with baseline. Neuronal ultrastructure and BBB integrity deteriorated in the hippocampus and amygdala of epileptic monkeys. The obvious neuronal loss and gliosis in the CA1-CA4 hippocampal regions were confirmed by western blotting and immunofluorescence; however, the temporal cortex was not affected. Moreover, the neuronal ultrastructural deterioration was detected in other limbic system regions (orbitofrontal cortex and posterior cingulate cortex).
Conclusion:
A novel mTLE-NHP model was induced by one-time intra-hippocampal and intra-amygdalar KA injection, with detectable SE and SRS. Severe hippocampal atrophy, neuronal ultrastructural damage, BBB disruption, neuronal loss and gliosis were confirmed in this model, with widespread limbic system damage, which are similar to the pathology of mTLE patients.
The present study was designed to evaluate the possible effects of the paediatric vaccination schedule in the United States on the central nervous system in a murine model. We compared the impact of treatment with the whole vaccines versus true placebo control. Seventy-six pups were divided into three groups: two vaccinated groups and unvaccinated control. The two vaccinated groups were treated between 7 and 21 post-natal days either with one or three times of the vaccine doses per body weight as used in children between newborn and eighteen months of age. The post-vaccination development, neuromotor behaviours and neurobehavioural abnormalities (NBAs) were evaluated in all mouse groups during the 67 post-natal weeks of mouse age. Mouse body weight was affected only in the vaccinated females compared to males and control. Some NBAs such as decreased sociability, increased anxiety-like behaviours, and alteration of visual-spatial learning and memory were observed in vaccinated male and female mice compared to controls. The present study also shows a slower acquisition of some neonatal reflexes in vaccinated female mice compared to vaccinated males and controls. The observed neurodevelopmental alterations did not show a linear relationship with vaccine dose, suggesting that the single dose gave a saturated response. The outcomes seemed to be sex-dependent and transient with age.
Aluminum‐containing adjuvants used in vaccine formulations suffer from low cellular immunity, severe aggregation and cerebral accumulation problems. Conventional aluminosilicates widely used in chemical industry focus mainly on acidic sites for catalytic applications, but are rarely used as adjuvants. We report an innovative “ligand‐assisted steric hindrance” strategy to create a high density of six‐coordinate VI Al‐OH groups with basicity on dendritic mesoporous silica nanoparticles as new nanoadjuvants to address the challenges. Compared to four‐coordinate IV Al modified counter‐parts, VI Al‐OH rich aluminosilicate nanoadjuvants enhance cellular delivery of antigens and provoke stronger cellular immunity. Moreover, the aluminum accumulation in brain is reduced than a commercial adjuvant. Our results have shown that coordination chemistry can be used to control the adjuvanticity, providing new understandings in the development of next‐generation vaccine adjuvants.
In this short review, we summarize much of the past and current data on the neurological disease spectrum of ALS‐parkinsonism dementia complex (ALS‐PDC) of Guam and the Western Pacific. Once highly prevalent on Guam, ALS‐PDC comprises two overlapping neurological conditions. The first described appeared to be a classical form of ALS first described by US Navy doctors in 1949. Later, a parkinsonism with dementia disorder arose. Some individuals developed both disorders. Overall, the incidence of ALS‐PDC vastly exceeded that of ALS or Parkinson's disease in North America or Europe. Various etiological factors were considered for this disease spectrum, with an eventual conclusion that the causal factor was some environmental toxin, most likely one contained in the seed of the local cycad tree, a food in the diet of the local population. While ALS‐PDC has almost disappeared, the unique features of this spectrum disorder may have lessons for us today as we seek etiologies for ALS in the rest of the world.
A new class of mesoporous aluminosilicate adjuvants is created by controlling the surface coordination chemistry, which further adjusts the adjuvanticity. Nanoadjuvants modified with a binuclear octahedral aluminum‐acetate complex, with a high density of six‐coordinate VIAl−OH species and Brønsted basicity, show superior performance compared to counterparts modified with four‐coordinate IVAl species with Brønsted acidity and a commercial product.
Abstract
Aluminum‐containing adjuvants used in vaccine formulations suffer from low cellular immunity, severe aggregation, and accumulation in the brain. Conventional aluminosilicates widely used in the chemical industry focus mainly on acidic sites for catalytic applications, but they are rarely used as adjuvants. Reported here is an innovative “ligand‐assisted steric hindrance” strategy to create a high density of six‐coordinate VIAl−OH groups with basicity on dendritic mesoporous silica nanoparticles as new nanoadjuvants. Compared to four‐coordinate IVAl‐modified counterparts, VIAl−OH‐rich aluminosilicate nanoadjuvants enhance cellular delivery of antigens and provoke stronger cellular immunity. Moreover, the aluminum accumulation in the brain is more reduced than that with a commercial adjuvant. These results show that coordination chemistry can be used to control the adjuvanticity, providing new understanding in the development of next‐generation vaccine adjuvants.
Variety of implant materials have been employed in various disciplines of medical science depending on the requirement of a particular application. Metals, alloys, ceramics, and polymers are the commonly used biomaterials. The main focus of this study is to review the various structural and microstructural properties of titanium and titanium based alloys used as orthopaedic implants. Orthopaedic implants need to possess certain important qualities to ensure their safe and effective use. These properties like the biocompatibility, relevant mechanical properties, high corrosion and wear resistance and osseointegration are summarized in this review. Various attempts to improve upon these properties like different processing routes, surface modifications have also been inculcated in the paper to provide an insight into the extent of research and effort that has been put into developing a highly superior titanium orthopaedic implant.
In the following, I will consider the impact of aluminum on two major systems, the central nervous system (CNS) and the immune system, across the life span. The article will discuss the presence of aluminum in the biosphere, its history, and the sources of the element. These include food, water cosmetics, some vaccines, and a range of other sources. I will also consider aluminum’s unique chemistry. Finally, in humans and animals, I will consider how aluminum may impact the CNS at various levels of organization and how it may be involved in various neurological disease states across the life span. These disorders include those of infancy and childhood, such as autism spectrum disorder (ASD), as well as those in adulthood, such as in Alzheimer’s disease. The bidirectional nature of CNS–immune system interactions will be considered and put into the context of neurological disorders that have an autoimmune component. I will argue that the exposure to humans and animals to this element needs to be reduced if we are to diminish some CNS and immune system disorders.
Nanotechnology has a vital role in vaccine development. Nano-adjuvants, as robust delivery systems, could stimulate immune responses. Using nanoparticles (NPs) in vaccine formulations enhances the target delivery, immunogenicity, and stability of the antigens. Herein, silk fibroin nanoparticles (SFNPs) were used as a nano-adjuvant for delivering recombinant hepatitis B surface antigen (HBsAg). HBsAg was loaded physically and chemically on the surface of SFNPs. The HBsAg-loaded SFNPs had a spherical morphology. The in vitro release studies showed that HBsAg had a continuous and slow release from SFNPs during 56 days. During this time, ∼45.6% and 34.1% HBsAg was released from physical-SFNPs and chemical-SFNPs, respectively. HBsAg-loaded SFNPs were also stable for six months with slight changes in the size, surface charge, and morphology. The results of circular dichroism (CD) and fluorescence spectroscopy indicated that the released HBsAg preserved the native secondary and tertiary structures. The quantitative cellular uptake study also showed that physical-SFNPs were taken up more into J774A.1 macrophage cells than chemical-SFNPs. After 28 and 56 days post-injection, the immunogenicity studies showed that the specific total IgG, IgG1, and IgG2a levels against HBsAg were significantly higher in the physically loaded group than in the chemically loaded group and commercial hepatitis B vaccine. IgG2a levels were detected only in mice immunized with physical-SFNPs. However, the low levels of IL-4 and IFN-γ were produced in all vaccinated groups and differences in mean values were not significant compared with control groups. Results indicated an improvement in the levels of anti-HBsAg IgG in mice immunized with the physical-SFNPs group compared to other groups.
Dental implants have been used as far back as 2000BC, and since then have developed into highly sophisticated solutions for tooth replacement. It is becoming increasingly important for the materials used in dental implants to exhibit and maintain favorable long-term mechanical, biological and more recently, aesthetic properties. This review aims to assess the biomaterials used in modern dental implants, introducing their properties, and concentrating on modifications to improve these biomaterials. Focus is drawn to the prominent biomaterials, titanium (Ti) and zirconia due to their prevalence in implant dentistry. Additionally, novel coatings and materials with potential use as viable improvements or alternatives are reviewed. An effective dental biomaterial should osseointegrate, maintain structural integrity, resist corrosion and infection, and not cause systemic toxicity or cytotoxicity. Current materials such as bioactive glass offer protection against biofilm formation, and when combined with a titanium–zirconium (TiZr) alloy, provide a reliable combination of properties to represent a competitive alternative. Further long-term clinical studies are needed to inform the development of next-generation materials.
Administration of aluminum (Al) produces accumulation of neurofilaments (NF), called neurofibrillary tangles (NFT), in neuronal cell bodies and proximal axonal segments. This study was undertaken to investigate whether these changes are associated with impairment of the slow axonal transport. Local administration of AlCl3 induced the formation of NFT in 90 to 100% of the rabbit hypoglossal neurons. [35S]Methionine was then administered to the hypoglossal nerve nuclei. The hypoglossal nerves were processed 18 or 28 days later for one- and two-dimensional SDS-polyacrylamide gel electrophoresis and fluorography. Labeled NF polypeptides and a polypeptide of 57 kilodaltons (Kd) were not detectable beyond the proximal 9-mm segment of the hypoglossal nerve in Al-treated rabbits 18 days after labeling, whereas they were present up to 27 mm from the medulla in controls. Tubulin and polypeptides migrating with slow component b were not significantly affected. In rabbits sacrificed 28 days after labeling, accumulation of NF subunits within the proximal 9 mm of hypoglossal nerve was less dramatic, and labeled NF were present up to 30 mm from the medulla whereas they were detectable up to 45 mm in controls. Morphological studies demonstrated the presence of enlarged axons filled with NF in the proximal 9 mm of the hypoglossal nerve. In nerve segments immediately distal, axons were markedly reduced in size and contained no NF but an apparently normal number of microtubules and other organelles. Transport of NF and of a 57-Kd polypeptide is markedly but reversibly slowed down or blocked within the proximal 9-mm segments of the hypoglossal nerve following Al administration to the hypoglossal nucleus. It is suggested that NF transport is maintained distally, resulting in lack of NF in axonal segments immediately distal to the block. Local Al intoxication provides a novel model of impairment of NF transport.
The effects of the trivalent cation aluminum (Al3+) on voltage activated calcium channel currents were examined. Al3+ blocks sustained and transient components of voltage activated calcium channel currents of cultured rat dorsal root ganglion (DRG) cells. Currents were elicited by voltage jumps from -80 to 0 mV. The channel block was use dependent. Steady state blockade occurred after 1 to 5 min, when opening the channel every 10 s. There was little or no recovery after washing. Threshold concentration was about 20 microM Al3+ and total blockade (> 80%) was obtained at 200 microM Al3+; the IC50 was 83 microM and the Hill number was around 3. The degree of blockade was pH dependent, and increased with H+ concentration. The current-voltage relation frequently shifted to depolarised voltages after applying Al3+. The degree of the shift was a function of Al3+ concentration, but the magnitude differed from cell to cell. In the effective concentration range (< 200 microM Al3+) the effect was quite specific to voltage activated calcium channel currents. Voltage activated potassium and sodium channels were reduced less than 15% by 200 microM Al3+. We conclude that Al3+ is a potent and irreversible blocker of voltage activated calcium channel currents in mammalian neurons.
Previous studies demonstrate that aluminium hydroxide adjuvant (alum) produces increased Th1 responses in IL-4-deficient mice compared with wild-type animals, although the continued production of IL-5 by spleen cells from these mice also indicates that Th2 responses are induced. In the present study, we demonstrate that alum can induce Th2-associated IL-4 and IL-5 production in the absence of IL-4 signaling in mice deficient in either IL-4Ralpha or Stat6. The Th2 responses observed could not be due to IL-13 as IL-13 responses are also impaired in IL-4Ralpha- and Stat6-deficient mice. We also detected higher levels of IL-4 in IL-4Ralpha gene-deficient, though not Stat6-deficient, mice compared with their wild-type counterparts. The increased levels of IL-4 could be explained by the IL-4R being unavailable to neutralize this cytokine in IL-4Ralpha-deficient mice. While levels of IL-5 production in IL-4Ralpha- or Stat6-deficient mice were similar to IL-4-deficient and wild-type mice, other type 2-associated responses, which are largely or wholly IL-4 dependent, such as the production of IgG1 or IgE Abs, were either reduced or absent. We conclude that alum adjuvants can induce IL-4 production and Th2 responses independently of IL-4 or IL-13, negating the requirement for an early source of IL-4 in the Th2 response induced by this adjuvant.
The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM197 (Hib-CRM197) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO4).
The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Gülveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days.
Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO4 vaccine (19, 10, 11% in Chiron Hib/AlPO4, VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 micro g/mL, respectively (P < 0.05).
The use of aluminum compounds adjuvants in Hib-CRM197 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.
Aluminium compounds have been used as adjuvants in practical vaccination for more than 60 years to induce an early, an efficient and a long lasting protective immunity and are at present the most widely used adjuvants in both veterinary and human vaccines. Although the last two decades of systematic research into the nature of these adjuvants has contributed significantly to understanding their nature and their limitations as Th2 stimulators the more detailed mode of action of these adjuvants is still not completely understood. We have a comprehensive record of their behaviour and performance in practical vaccination, but an empirical approach to optimising their use in new vaccine formulations is still to some extent a necessity. The aim of the present review is to put the recent findings into a broader perspective to facilitate the application of these adjuvants in general and experimental vaccinology.
We successfully isolated a rat cDNA clone encoding a novel EF hand protein with a molecular weight of about 17 kDa and designated this geneiba1(ionized calcium binding adapter molecule 1). The genomic copy of theiba1gene was located within a segment of the major histocompatibility complex class III region between theBat2andTNFαgenes. Theiba1gene was shown to be highly expressed in testis and spleen, but weakly expressed in brain, lung, and kidney. Among brain cells, theiba1gene was specifically expressed in microglia. A screening of hemopoietic cell lines showed that the Iba1 protein was clearly expressed in monoblastic cell lines but only very weakly expressed in myeloid cell lines. Iba1 protein is therefore suggested to act as an adapter molecule, mediating calcium signals that may function in a monocytic lineage including microglia.
This is a review of the literature on the use of cycads as food and medicine, with special attention to their toxic properties.
In the tropics and subtropics, where the plants are indigenous, their toxicity has long been known. Both gastrointestinal
and neurological effects have been reported. Although several toxic components of the plants have been investigated, none
has yet been shown to be responsible for specific effects. No lesion has been demonstrated to account for the progressive
and apparently irreversible posterior paralysis which reputedly follows consumption of the plants by cattle. Current interest
in the toxicity of the cycads has been stimulated by recognition of the high incidence of neurological diseases in an area
of the world where they are used as food.
Although the neurotoxic actions of aluminium (Al) have been well documented, its contribution to neurodegenerative diseases such as Alzheimer’s disease remains controversial. In the present study, we applied histochemical techniques to identify changes induced by intracerebroventricular Al injections (5.4 μg in 5.5 μl, daily over a period of 5 successive days) in the adult rat brain after survival periods of either 1 or 6 weeks. For both Al- and saline-infused controls, no major signs of gross histological changes were evident in cresyl violet-stained sections. Al (as indicated by the fluorescent Morin staining) was concentrated in white matter of the medial striatum, corpus callosum, and cingulate bundle. Immunoreactivity of astrocytes and phagocytic microglia based on glial fibrillary acidic protein and ED1 markers, respectively, revealed a greater inflammatory response in Al-injected animals compared to controls. Damage of the cingulate bundle in Al-treated animals led to a severe anterograde degeneration of cholinergic terminals in cortex and hippocampus, as indicated by acetylcholinesterase labelling. Our data suggest that the enhancement of inflammation and the interference with cholinergic projections may be the modes of action through which Al may cause learning and memory deficits, and contribute to pathological processes in Alzheimer’s disease.
Macrophagic myofasciitis and chronic fatigue syndrome are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual. This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including chronic fatigue syndrome and macrophagic myofasciitis.
Aluminium is widely used as an adjuvant in human vaccines, and children can often receive up to 3.75 mg of parenteral aluminium during the first six months of life. We show that intraperitoneal injection of aluminium adsorbed vaccines into mice causes a transient rise in brain tissue aluminium levels peaking around the second and third day after injection. This rise is not seen in the saline control group of animals or with vaccine not containing aluminium. It is likely that aluminium is transported to the brain by the iron-binding protein transferrin and enters the brain via specific transferrin receptors.
Insights into the programmatic induction of neuronal and glial genes during human embryogenesis have depended largely on extrapolations of data derived from experimental mammals. However, the assumptions upon which these extrapolations are based have not been rigorously tested. Indeed, practically no information is available even on the human counterparts of the relatively small subset of well-characterized, developmentally regulated neuron and glial specific genes of the mammalian CNS. Thus, the developmental programs upon which human neural embryogenesis are based remain largely undeciphered. We have addressed this problem in immunohistochemical studies conducted on 22 human fetal spinal cords with gestational ages (GAs) that ranged from 6 to 40 weeks by using monoclonal antibodies to several classes of neuron or glial specific polypeptides. These polypeptides included: representatives of four different types (Types I-IV) of intermediate filament proteins, i.e., vimentin filament protein (VFP), glial fibrillary acidic protein (GFAP), different phospho-isoforms of the high (NF-H), middle (NF-M), and low (NF-L) molecular weight (Mr) neurofilament (NF) subunits, both acidic and basic cytokeratin (CK) proteins; three different microtubule associated proteins (MAPs), i.e., MAP2, MAP5, and tau; two different synaptic or coated vesicle proteins, i.e., synaptophysin (SYP) and clathrin light chain B (LCb); an oligodendroglial specific protein, i.e., myelin basic protein (MBP); and a receptor for a CNS trophic factor, i.e., the nerve growth factor receptor (NGFR).(ABSTRACT TRUNCATED AT 400 WORDS)
Inclusion of 1.1% elemental tellurium in the diet of postweanling rats produces a peripheral neuropathy due to a highly synchronous primary demyelination of sciatic nerve; this demyelination is followed closely by remyelination. Sciatic nerves from animals fed tellurium for various times were removed and incubated ex vivo for 1 h with [14C]acetate, and radioactivity incorporated into individual lipid classes was determined. In nerves from rats exposed to tellurium, there was a profound and selective block in the conversion of radioactive acetate to cholesterol. Another radioactive precursor, [3H]water, gave similar results. We suggest that tellurium feeding inhibits squalene epoxidase activity and that the consequent lack of cholesterol destabilizes myelin, thereby causing destruction of the larger internodes. Ex vivo incubation experiments were also carried out with liver slices. As with nerve, tellurium feeding caused accumulation in squalene of label from radioactive acetate, whereas labeling of cholesterol was greatly inhibited. Unexpectedly, however, incorporation of label from [3H]water into both squalene and cholesterol was increased. Relevant is the demonstration that liver was the primary site of bulk accumulation of squalene, which accounted for 10% of liver dry weight at 5 days. Thus, accumulation of squalene (and other mechanisms, possibly including up-regulation of cholesterol biosynthetic pathways) drives squalene epoxidase activity at normal levels in liver even in the presence of inhibitors of this enzyme. This is reflected by continuing incorporation of [3H]water into cholesterol; incorporation of this precursor takes place at many of the postsqualene biosynthetic steps for sterol formation. [14C]Acetate entering the sterol pathway before squalene in liver is greatly diluted in specific activity when it reaches the large squalene pool, and thus increased squalene epoxidase activity does not transfer significant 14C label to sterols. In contrast to the situation with liver, synthesis of sterols is markedly depressed in sciatic nerve, and squalene does not accumulate to high levels.
Experimental evidence is summarized to support the hypothesis that chronic exposure to low levels of aluminum may lead to neurological disorders. These disorders result from defective phosphorylation--dephosphorylation reactions, reduced glucose utilization and site-specific damage inflicted by free radicals produced by altered iron metabolism. The brain is a highly compartmentalized organ. Therefore, a co-localization of critical mass of metabolic errors rather than a single event may be essential to precipitate a neural disease. Aluminum appears to participate in formulating this critical mass. Patients with dialysis dementia get partial relief by desferroxamine which chelates aluminum. However, it also chelates iron and therefore limits its applicability. While the specific chelator for aluminum is yet to be made available, exercising a caution in aluminum intake appears prudent.
Aluminum was observed in the nucleolus, interchromatin granules, rough endoplasmic reticulum, free ribosomes, euchromatin, and the heterochromatin of the neuron. The association of aluminum with the first four r-RNA-containing cellular components and with the last two DNA-containing chromatins suggests the association of aluminum with the nucleic acids. The aluminum may interfere with the normal mechanism of the protein synthesis of r-RNA and of the transcription or gene modulation of DNA. Aluminum was also observed in the astrocytic process and in the nuclei of endothelial cells, pericytes, and the muscle cells of the blood vessels. The detection of aluminum in the pyrimidal cells of the cerebral cortex and hippocampus and in the spinal cord neurons, was observed 1 h after i.v. injection, indicating a rapid entry of aluminum from the injection site through the blood-brain barrier (BBB) to the neurons. Using Morin stain, pyramidal neurons of the cerebral cortex and hippocampus, motoneurons of spinal cord, ganglion cells, and bipolar cells of retina and Purkinje cells of cerebellum, exhibited yellow fluorescence, with peak intensity at 560 nm. Tangles were observed in these six types of neurons. The granule cells of hippocampus and cerebellum and the photoreceptors of the retina exhibited green fluorescence with the peak intensity at 490-500 nm. Tangles were not observed in these three types of neurons.
The view that ‘degenerative’ neurological conditions such as amyotrophic sclerosis (ALS), Parkinson's disease and Alzheimer's dementia may be caused by environmental toxins has been strengthened by a recent report by Spencer et al. in Science1. Male cynomolgus monkeys developed cortico-neuronal dysfunction, parkinsonian features and behavioral changes with chromatolysis and degeneration of motor neurons following daily oral doses of (BMAA), a ‘free excitatory’ neurotoxic amino acid present in the seeds of Cycas circinalis.
Aluminum is established as a neurotoxin, although the basis for its toxicity is unknown. It recently has been shown to alter the function of the blood-brain barrier (BBB), which regulates exchanges between the central nervous system (CNS) and peripheral circulation. The BBB owes its unique properties to the integrity of the cell membranes that comprise it. Aluminum affects some of the membrane-like functions of the BBB. It increases the rate of transmembrane diffusion and selectively changes saturable transport systems without disrupting the integrity of the membranes or altering CNS hemodynamics. Such alterations in the access to the brain of nutrients, hormones, toxins, and drugs could be the basis of CNS dysfunction. Aluminum is capable of altering membrane function at the BBB; many of its effects on the CNS as well as peripheral tissues can be explained by its actions as a membrane toxin.
Long-term epidemiological studies indicate that environmental factors play a causative role in high-incidence amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) in the western Pacific. An increased risk for disease is acquired in youth and remains for life. The low concentrations of calcium and magnesium and high levels of aluminum in the soil and drinking water, along with the relative isolation of these populations, constitute an unusual environmental feature common to all three high-incidence foci. Studies of mineral deposition in brain tissue of Guamanian ALS and PD patients, as well as of neurologically normal Guamanians with neurofibrillary degeneration, demonstrate accumulations of calcium, aluminum and silicon in neurofibrillary tangle-bearing neurons. In an attempt to duplicate the low calcium and high aluminum and manganese in soil and drinking water in these foci, we maintained juvenile cynomolgus monkeys for 41 to 46 months on a low-calcium diet with or without supplemental aluminum and manganese. Experimental animals exhibited mild calcium and aluminum deposition and degenerative changes, compatible with those of early ALS and PD, in motor neurons of the spinal cord, brain stem, substantia nigra and cerebrum. Neuropathological findings included chromatolysis, aberrant perikaryal accumulation of phosphorylated neurofilament, neurofibrillary tangles, axonal spheroids, and basophilic and hyaline-like inclusions consisting of abnormal cytoskeletal elements by electron microscopy. The magnitude and extent of these lesions far exceeded those found in normal aged monkeys.
Information transfer across an isolated cholinergic synapse exposed to aluminum was investigated using conventional electrophysiological techniques and computer-assisted analysis. Spontaneous and stimulation-induced release of neurotransmitter from frog motor nerve endings was augmented in the presence of aluminum (6-200 micrograms/ml). The release-enhancing effect of aluminum was dose-dependent and it was independent of the concentration of calcium ions in the extracellular solution. These results indicate that aluminum at concentrations similar to those found in the diseased brain of demented patients modulates synaptic transmission.
Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by the development of large numbers of neurofibrillary tangles in certain neuronal populations of affected brains. This paper presents a review of the available evidence which suggests that aluminum is associated with Alzheimer's disease and specifically with the development of the neurofibrillary tangle. Aluminum salts inoculated into experimental animals produce neurofilamentous lesions which are similar, though not identical, to the neurofibrillary tangle of man. Although a few reports have suggested evidence of increased amounts of aluminum in the brains of Alzheimer's disease victims, such bulk analysis studies have been difficult to replicate. Using scanning electron microscopy with x-ray spectrometry, we have identified accumulations of aluminum in neurofibrillary tangle-bearing neurons of Alzheimer's disease. Similar accumulations have been identified in the neurofibrillary tangle-bearing neurons found in the brains of indigenous natives of Guam who suffer from parkinsonism with dementia and amyotrophic lateral sclerosis. This ongoing research still cannot ascribe a causal role of aluminum in the pathogenesis of neurofibrillary tangle formation; however, it does suggest that environmental factors may play an important part in the formation of this abnormality.
The high incidence rates of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) occurring among the Chamorros of Guam have declined to rates only slightly higher than those observed in the continental United States. This decline has occurred principally among males, especially those born after 1920 and living in areas where calcium and magnesium levels are low in soil and water. The male-to-female ratio among affected patients now approaches unity, compared with ratios of 2 to 1 for ALS and 3 to 1 for PD three decades ago. These changes are consistent with the hypothesis that the previously high incidence resulted from defects in mineral metabolism and secondary hyperparathyroidism, provoked by nutritional deficiencies of calcium and magnesium, with resultant deposition of calcium and aluminum in neurons.
Although aluminum is neurotoxic, the mechanisms and sites of action are unknown. Using the histochemical stains, morin and Solochrome Azurine, intracellular binding of aluminum was examined in brain tissues of animals with an aluminum induced encephalopathy, in human lymphocytes and in cells of plant meristems. Accumulation of aluminum occurred on chromatin of interphase nuclei and on chromosomes of mitotic cells. These findings suggest that neurofibrillary degeneration following the intracerebral injection of aluminum salts in experimental animals may be the results of interactions between aluminum and chromatin.
Neurofibrillary degeneration is an important pathological finding in senile and presenile dementia of the Alzheimer type.
Experimentally, aluminum induces neurofibrillary degeneration in neurons of higher mammals. Aluminum concentrations approaching
those used experimentally have been found in some regions of the brains of patients with Alzheimer's disease.
Nine dialysis patients with significantly increased serum-aluminum levels due to chronic ingestion of aluminum hydroxide gels and eleven dialysis patients with normal serum-aluminum levels were tested neuropsychologically for generalized functions (intelligence, reasoning, memory) and for more specific abilities (visual memory, verbal and reading fluency, manual dexterity). All tests did not reveal any significant difference in neurophyscholigical functioning between the two groups. This finding seems to indicate that oral aluminum is not neurotoxic for man, even under circumstances of renal failure. This contradicts the idea that oral aluminum plays a role in etiology of dialysis dementia. However, the possibility cannot be excluded that aluminum overload in the present sample was not sufficient to induce changes in CNS functioning. Thus, until the importance of oral aluminum has been decided, it seems wise to keep all sorces of aluminum overload as low as possible.
A series of 14 monoclonal antibodies (MAs) has been obtained from a single rat-mouse fusion using gel-excised bovine glial filament (GF) proteins as immunogens. These MAs were characterized by two separate immunochemical assays and by two different immunohistochemical methods. Nine MAs demonstrated specificity for GF proteins. One MA also recognized an epitope shared by intermediate filaments (IF) of the vimentin class (VF). Using the enzyme-linked immunosorbent assay, four of the MAs recognized 200,000, 150,000, and 51,000 dalton proteins, suggesting that these MAs were specific for GF proteins (the 51,000 dalton protein) and neurofilament (NF) proteins (the two high-molecular-weight proteins). However, in both of the immunohistochemical assay systems, these MAs stained neurons and their processes but not astroglial cells. These observations strongly suggest that the 51,000-dalton protein recognized by these four MAs was not derived from GF proteins but instead represents derivatives of NF protein subunits comigrating in gels with GF proteins. These data provide additional information concerning the unique and shared antigenic determinants of the three classes of IF (NF, GF, and VF) of the CNS. In addition, they draw attention to the fact that proteins of certain IF may undergo degradation and comigrate in gels with the proteins of unrelated IF. This emphasizes the need for the use of independent immunochemical and immunohistochemical assays in the characterization of the specificity of MAs.
Scanning electron microscopy with energy-dispersive x-ray spectrometry was used to analyze the elemental content of neurofibrillary
tangle (NFT)-bearing and NFT-free neurons within the Sommer's sector (H1 region) of the hippocampus in Guamanian Chamorros
with amyotrophic lateral sclerosis and parkinsonism-dementia and in neurologically normal controls. Preliminary data indicate
prominent accumulation of aluminum within the nuclear region and perikaryal cytoplasm of NFT-bearing hippocampal neurons,
regardless of the underlying neurological diagnosis. These findings further extend the association between intraneuronal aluminum
and NFT formation and support the hypothesis that environmental factors are related to the neurodegenerative changes seen
in the Chamorro population.
We have studied serum cytokine profiles in BALB/c mice after immunization with influenza vaccine alone or combined with the following adjuvants: alum; MF59 emulsion; MF59 containing the muramyl peptide N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2- dipalmitoyl-sn-glycero-3-(hydroxyphosphoryloxy)) ethylamide (MTP-PE); MF59 plus the lipid A analogue monophosphoryl lipid A; MF59 plus the Quil A saponin fraction LTC; or LTC alone. Pooled mouse sera were analyzed by ELISA at various times after immunization for IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-gamma, and TNF-alpha. In naive mice, vaccine alone induced low levels of IL-3 and IL-5 only; vaccine plus alum induced a low IL-6 response as well. The MF59-based adjuvants significantly increased the IL-5 and IL-6 levels, whereas Quil A LTC induced strong IFN-gamma and measurable IL-2 responses, in addition to moderate IL-5 and IL-6. In previously infected mice, MF59 and MF59/MTP-PE were capable of generating IFN-gamma responses, as well as IL-5 and IL-6. All of the cytokine responses were rapid (peaking 3 to 12 h postimmunization) and short lived. In naive mice, the MF59 adjuvants induced serum cytokine profiles that are consistent with a primarily Th2-type response, whereas the Quil A LTC induced cytokines associated with both Th1 and Th2 responses. Ab analyses indicated that, although the adjuvants strongly affected the magnitude of the humoral response, there was no obvious correlation between the cytokine profile observed and the subclasses of Ab induced.
In the present study, aluminum (Al) accumulation has been examined after aluminum loading in mice. The kidney, liver, and brain aluminum levels for mice that had been treated orally with aluminum hydroxide for 105 d and for the control group were determined using graphite furnace atomic absorption spectrophotometry (GFAAS) following an acid digestion. Matrix modifier consisted of 2% Triton X-100 and 2% Mg (NO3)2. Al loaded mice showed a significant increase in tissue aluminum levels, relative to the control group.
The effect of aluminum on the metabolism of glutamate and glutamine in astrocytes was studied to provide information about a possible biochemical mechanism for aluminum neurotoxicity and its potential contribution to neurodegenerative disease. Exposure of cultured rat brain astrocytes for 3-4 d to 5-7.5 mM aluminum lactate increased glutamine synthetase activity by 100-300% and diminished glutaminase activity by 50-85%. Increased glutamine synthetase enzyme activity was accompanied by an elevated level of glutamine synthetase mRNA. Alterations in glutaminase and glutamine synthetase following aluminum exposure caused increased intracellular glutamine levels, decreased intracellular glutamate levels, and increased conversion of glutamate to glutamine and the release of the latter into the extracellular space. The results of these changes may alter the availability of neurotransmitter glutamate in vivo and may be a mechanism for the aluminum neurotoxicity observed in individuals exposed to the metal during dialysis procedures and other situations.
Long Evans rats were treated for 90 days with water-soluble, insoluble or chelated aluminium compounds. The daily treatments given were as follows: controls, NaCl (100 mg/kg body weight) plus citric acid (30 mg/kg); AlCl3 (30 or 100 mg/kg); Al(OH)3 (100 mg/kg) plus citric acid (30 mg/kg); Al(OH)3 (300 mg/kg). Their learning ability was determined in the labyrinth test at day 90, and the choline-acetyltransferase, acetylcholinesterase activity and aluminium content of the brains were measured. Soluble and chelated aluminium compounds seriously worsened the learning ability, and the aluminium content of the brain was elevated. Acetylcholinesterase activity increased and choline-acetyltransferase activity decreased, resulting in a diminished cholinergic activity, which is a characteristic of Alzheimer's disease.
The primary objective of this study was to determine the pattern of motor neuron loss in thoracic spinal cord from amyotrophic lateral sclerosis (ALS) patients. A prerequisite to this objective was to examine control human spinal cord with the techniques to be used for ALS specimens. Combined choline acetyltransferase (ChAT) immunocytochemistry and NADPH diaphorase histochemistry (a marker for nitric oxide synthase) revealed a staining pattern very similar to that seen in other mammals. Stained cell groups were present in the superficial dorsal horn (labeled only by diaphorase), the deep dorsal horn (double-labeled), the intermediate region (double-labeled), around the central canal (mostly double-labeled), autonomic motor neurons (AMNs; either double-labeled or ChAT-positive only), and somatic motor neurons (SMNs; ChAT-positive only). These similarities indicated that most cell types previously described in other mammals are present in human spinal cord. However, the percentage of AMNs that were double-labeled was much higher in humans (94%) than in rodents (approximately 66%) or in nonmammalian vertebrates (essentially 0%). In ALS, extensive loss of SMNs is known to occur in cervical and lumbar enlargements, and similarly, our specimens revealed a degeneration of nearly all SMNs in thoracic spinal cord. In contrast, the average number of AMNs in ALS specimens was not significantly different from that in controls, directly confirming clinical observations suggesting that AMNs do not degenerate in ALS. Most importantly, the percentage of AMNs that were diaphorase-negative was not decreased in ALS, indicating that AMN resistance in this degenerative neurological disorder probably is independent of nitric oxide synthase expression.
The symptoms of Gulf War syndrome are compatible with the hypothesis that the immune system of affected individuals is biased towards a Th2-cytokine pattern. Factors that could lead to a Th2 shift among Gulf War veterans include exposure to multiple Th2-inducing vaccinations under stressful circumstances and the way in which such vaccinations were administered, which would be expected to maximise Th2 immunogenicity. These factors may have led to a long-term systemic shift towards a Th2-cytokine balance and to mood changes related to the immunoendocrine state. Other vaccines that lead to similar long-term, non-specific shifts in cytokine balance are well-established. If our hypothesis is proven, treatment may be possible with regimens that induce a systemic Th1 bias.
Alzheimer's disease has a complex pathogenesis and is a devastating neurologic disorder, predominantly of the elderly human population. Neuronal cell loss and neuritic pathology are a major neuropathologic feature of Alzheimer's disease, but there is no established mechanism to explain the degenerative process. The development of suitable animal systems would be of great value in helping to understand the basic mechanisms underlying the disease. We propose that the aluminum maltolate-treated elderly rabbit is a potentially useful animal system to model Alzheimer's disease neurofibrillary pathology. Details of such an experimental aluminum encephalopathy produced in the rabbit are discussed, along with other aspects of aluminum-induced neurodegeneration.
Parkinsonism-dementia complex (PDC) is the second most common neurodegenerative disorder in Guam, after amyotrophic lateral sclerosis (ALS). PDC was first described by Hirano 1961. A familial appearance is seen among some PDC cases, which may also include ALS, and vice versa, but subsequent research including pedigree analysis, prospective case control registries, and the search for specific gene markers has failed to yield a satisfactory genetic explanation. Important diagnostic indicators of the illness include rigido-akinetic type Parkinsonism and severe dementia.
In PDC, rigidity is so marked that postural deformities such as a generally flexed posture become rather prominent. Gait disturbances are a common initial symptom. Hyperreflexia and spinal muscular atrophy, developing mainly in the distal extremities, are frequently observed. These mixedsyndrome patients can be seen as clear support for the view that Guam ALS and PDC constitute a single mixed disease entity with a spectrum of clinical expression.
The present paper offers an overview and description of the clinical features of PDC.