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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.
... Merck's clinical trial data indicate that the 4vHPV vaccine's systemic reactogenicity is largely driven by the AAHS adjuvant, since a similar percentage of systemic effects, including headache, fever, nausea and dizziness, have been observed in both Gardasil and AAHS-"placebo" recipients [29]. In various animal species injections of traditional less potent aluminum adjuvants at doses relevant to human exposure have resulted in neurophysiological impairments [30][31][32][33][34][35][36][37][38][39][40][41][42]. Moreover, gene expression analysis of spleen lymphocytes isolated from mice injected with either aluminum phosphate-adjuvanted tetanus vaccine or the adjuvant alone showed that the latter significantly upregulated many markers indicative of systemic toxicity, including inflammatory disease-related genes, oncogenes, and genes involved in cell stress and apoptosis [43]. ...
... For example, in a 2022 systematic review and meta-analysis of studies assessing biodistribution, clearance and neurotoxicology of aluminum adjuvants in animal models, Masson et al. identified 31 eligible studies, of which 17 focused on neurotoxicological impacts [30]. Of these 17 studies, 13 showed numerous detrimental effects [31][32][33][34][35][36][37][38][40][41][42]57,58], 12 of which mimicked human or veterinary levels of aluminum adjuvant exposure [31][32][33][34][35][36][37][40][41][42]57,58]. Notably, studies in sheep demonstrated that accumulation of aluminum in the spinal cord was higher after the injection of the adjuvant alone than after the injection of adjuvanted vaccines [59]. ...
... For example, in a 2022 systematic review and meta-analysis of studies assessing biodistribution, clearance and neurotoxicology of aluminum adjuvants in animal models, Masson et al. identified 31 eligible studies, of which 17 focused on neurotoxicological impacts [30]. Of these 17 studies, 13 showed numerous detrimental effects [31][32][33][34][35][36][37][38][40][41][42]57,58], 12 of which mimicked human or veterinary levels of aluminum adjuvant exposure [31][32][33][34][35][36][37][40][41][42]57,58]. Notably, studies in sheep demonstrated that accumulation of aluminum in the spinal cord was higher after the injection of the adjuvant alone than after the injection of adjuvanted vaccines [59]. ...
Background:
Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits.
Objective:
To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials.
Methods:
We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines.
Results:
It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group.
Conclusion:
In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.
... The remaining studies were specifically focused on adjuvant injections (see above). Berlyne et al. (1972) Aluminum toxicity in rats #2 Goto and Akama (1982) Histopathological studies of reactions in mice injected with aluminum-adsorbed tetanus toxoid #3 Flarend et al. (1997) In vivo absorption of aluminum-containing vaccine adjuvants using 26 Al #4 Valtulini et al. (2005) Aluminum hydroxide-induced granulomas in pigs #5 Verdier et al. (2005) Aluminum assay and evaluation of the local reaction at several time points after intramuscular administration of aluminum-containing vaccines in the Cynomolgus monkey #6 Authier et al. (2006) AlOH3-adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background #7 Petrik et al. (2007) AlOH3-adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background #8 Wise et al. (2008) Lack of effects on fertility and developmental toxicity of a quadrivalent HPV vaccine in Sprague-Dawley rats #9 Shaw and Petrik (2009) Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration #10 Segal et al. (2011) Evaluation of the intramuscular administration of Cervarix TM vaccine on fertility, pre-and post-natal development in rats #11 Khan et al. (2013) Slow CCL2-dependent translocation of biopersistent particles from muscle to brain #12 ...
... 13 of the 17 studies assessing neuromodulation pointed out CNS changes, directly or indirectly assessed, following ABAs exposure, including neuron apoptosis in the lumbar spinal cord (Petrik et al. 2007); increase of activated glial cells (Cr epeaux et al. 2017) or reactive astrocytes and hyper-phosphorylated tau protein (Shaw and Petrik 2009) in different cerebral areas, and a global brain pro-inflammatory response (Agmon-Levin et al. 2014). 11 of the 14 studies that performed behavioral evaluations also indicated a negative effect of ABAs in both adults and perinatally exposed animals. ...
... 11 of the 14 studies that performed behavioral evaluations also indicated a negative effect of ABAs in both adults and perinatally exposed animals. Behavioral abnormalities were uniformly found by different experiments and included an impact on anxiety/ depression-like behavior ( Inbar et al. 2017;Kivity et al. 2017); memory impairments (Shaw and Petrik 2009;Agmon-Levin et al. 2014;Eidi et al. 2020); social ability reduction (Sheth et al. 2018;As ın et al. 2020;Eidi et al. 2020); decreased muscular strength and endurance leading to a decrease of locomotor functions and activity (Petrik et al. 2007;Shaw and Petrik 2009;Cr epeaux et al. 2017;Inbar et al. 2017). ...
Aluminum (Al) salts are commonly used as adjuvants in human and veterinary vaccines for almost a century. Despite this long history of use and the very large number of exposed individuals, data in the literature concerning the fate of these molecules after injection and their potential effects on the nervous system is limited. In the context of (i) an increase of exposure to Al salts through vaccination; (ii) the absence of safety values determined by health regulators; (iii) the lack of robustness of the studies used as references to officially claim Al adjuvant innocuity; (iv) the publication of several animal studies investigating Al salts clearance/biopersistence and neurotoxicity; we have examined in this review all published studies performed on animals and assessing Al adjuvants kinetics, biodistribution, and neuro-modulation since the first work of A. Glenny in the 1920s. The diversity of methodological approaches, results, and potential weaknesses of the 31 collected studies are exposed. A large range of protocols has been used, including a variety of exposure schedule and analyses methods, making comparisons between studies uneasy. Nevertheless, published data highlight that when biopersistence, translocation, or neuromodulation were assessed, they were documented whatever the different in vivo models and methods used. Moreover, the studies pointed out the crucial importance of the different Al adjuvant physicochemical properties and host genetic background on their kinetics, biodistribution, and neuro-modulatory effects. Regarding the state of the art on this key public health topic, further studies are clearly needed to determine the exact safety level of Al salts.
... 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.
... 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.
... [1,[22][23][24][25] The mechanism of aluminum toxicity is extremely crucial as it has been linked to a number of neurodegenerative diseases, including oxidative brain damage and the generation of reactive oxygen species, altered neurotransmitter biosynthesis, inflammatory reactions (gliosis), reduced utilization of glucose, changes in the rate of transmembrane diffusion and the BBB transport system (BBB). [26,27] Aluminum hampered retrieval and acquisition of spatial recognition memory in the Y-maze, according to our findings. Toxicity-induced rats showed a decrease in the number of entries and less time spent in the novel arm, as well as an increase in the time it took to get to the novel arm; this reflects the impairment in spatial memory. ...
... AlCl 3 buildup in the brain can disrupt the neuronal signal transduction system that is linked to glutamate receptor that can causes excitotoxicity in neuronal cells [36,37] by altering glutamine synthase and availability of glutamate. [27] In this study, there was a considerable increase in glutamate concentration in brain region might be due to deposition of aluminum that enhances adenylate cyclase induced cAMP activity in brain. Rivastigmine and SECD effectively decreased the glutamate and aspartate levels by attenuating the Al-glutamate complex due to increase in glutamate decarboxylase release in neuronal cells. ...
... The Danio rerio is a species of tropical fish that has been used as an alternative animal model for research due to its genetic similarity with human genes (70%) [27]. Because of this, several studies involving numerous toxic agents are being developed to define genetic and toxicity mechanisms and neurobehavioral effects using this experimental model [28,29] Since several studies have explored the toxicity of aluminum hydroxide [30][31][32][33] and isolated thimerosal [21,[34][35][36][37] and these compounds are found together in the formulation of some multidose vaccines applied in developing countries, such as Brazil [4], it is relevant to study their toxicological effects in combination. Thus, this study aimed to analyze the toxic effects of metal-containing molecules used as adjuvants and preservatives (aluminum hydroxide and thimerosal, respectively) in the formulation of vaccines using D. rerio as an experimental model. ...
... No results were found in the literature that corroborate our findings. However, one study showed an accumulation of Al in the hair of children who had been immunized with hepatitis B, triple bacterial vaccine, and meningococcal vaccines [31]. Interestingly, in our study, Hg accumulated more in the head of the fish and Al in the body. ...
Vaccination programs in the first years of a child’s life are effective and extremely important strategies for the successful eradication of diseases. However, as no intervention is without risks, the metal-based components of some vaccines, such as thimerosal (TMS), a preservative composed of ethylmercury, and aluminum (Al), have begun to generate distrust on the part of the population. Therefore, this study evaluated the effects of exposure to thimerosal and aluminum hydroxide (alone or in mixture) on Danio rerio (zebrafish) specimens. The fish were exposed to thimerosal and/or aluminum hydroxide intraperitoneally. The liver, kidney, and brain were removed for a biochemical biomarker analysis, histopathological analysis, and metal quantification. As a result, we observed changes in the activity of the analyzed enzymes (SOD, GST, GPx) in the kidney and brain of the zebrafish, a reduction in GSH levels in all analyzed tissues, and a reduction in MT levels in the kidney and liver as well as in the brain. Changes in AChE enzyme activity were observed. The biochemical results corroborate the changes observed in the lesion index and histomorphology sections. We emphasize the importance of joint research on these compounds to increase the population’s safety against their possible toxic effects.
... Finally, in all in vivo studies, physico-chemical properties of these particles are never explored in their entirety. For example, sometimes Al adjuvants are diluted before injections, without checking the effect of the dilution on particle size and thus risk biasing the conclusions drawn from the observations made, especially when the injection schedule is thought to represent a human exposure [25][26][27]. ...
... This point is of utmost importance for the studies of vaccine effect, because dilution, by reducing the size of the particles, will have a real effect on the particles toxicity, which is a wellconfirmed fact. However, most of the in vivo published studies diluted the vaccines before animal injection, thus modifying the size of particles, which they did not check, and then cannot estimate the possible mechanisms induced [11,21,[25][26][27]. Indeed, in their discussion, Crépeaux et al., mentioned the importance of controlling the size in the future studies [21]. ...
Aluminum salts have been used as adjuvants in human vaccines since 1932. The most used adjuvants are Al oxyhydroxide (AlOOH) and Al hydroxyphosphate (AlOHPO 4). Al adjuvants have different physico-chemical properties. The differences in these properties are not well documented and not considered by the Food and Drug Administration (FDA), though they can largely influence biological effects of the adjuvants which are particulate components. In this study, different physico-chemical properties including the shape, size and charge of particles have been evaluated under different conditions in three Al adjuvants containing-vaccines and two corresponding commercial adjuvants suspensions. The results showed that the two Al adjuvants have different shapes, sizes and charges but both form aggregates. In addition, a clear effect of dilution on the size of the aggregates was observed. Moreover, different sizes of Al particles were measured for both Al oxyhydroxide adjuvant alone or in the vaccine, at identical concentrations , displaying the impact of adsorbed proteins on the size of aggregates in the case of the vaccine. Taken together, this paper suggests the importance to evaluate, before any biological and especially toxicological impact study, the whole physico-chemical properties of Al particle without restricting to the sole evaluation of the injected concentration. Furthermore, any modification of these mentioned parameters during manipulation, before animal or cell exposure, should be considered. In a more global way, the fixed ''safe dose" of Al adjuvants should be specific for each type of Al adjuvant independently or for a mix of the two compounds, due to their different properties.
... 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.
... In un recente studio sperimentale del 2013, Roos et al., già autori di studi sul Manganese presente nelle matrici biologiche dei pazienti affetti da SLA, hanno effettuato una valutazione dei metalli all'interno del liquor cefalorachi-diano di tali pazienti trovando alte concentrazioni degli stessi, tra cui ll'Alluminio (124). Altri studi sono dedicati alla valutazione di 'varianti di SLA' come la degenerazione motoneuronale osservata in un disordine multisistemico di cui sono affetti i veterani della Guerra del Golfo: uno studio osservazionale ha messo in relazione lo sviluppo di tale degenerazione motoneuronale e la somministrazione di vaccini contro l'antrace in cui era presente, tra gli eccipienti, l'idrossido di Alluminio (125). Ancora, lavori di ricerca di biologia molecolare condotti negli ultimi anni, hanno prodotto svariate speculazioni scientifiche circa i fini meccanismi d'azione del metallo nella genesi e nello sviluppo della patologia neurodegenerativa (126). ...
In recent years, scientific literature has been giving more and more importance to the study of the occupational/environmental exposure to risk agents related to the onset of Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex. Aim of this work is to verify the state of art about the eventual role of occupationall environmental exposure to risk agents. Selected articles, on the basis of keywords, year of publication and topics, are related to occupational and environmental exposure to xenobiotics, and, in particular, to the exposure to heavy metals that could lead to neuronal damage mechanisms involved in ALS onset. The review shows that although the scientific production has increased the interest in the evaluation of extra-genetic causes of ALS onset, there are still few studies concerning the careful study of the work activities of the individual patient, and the inferences that can be drawn to date about the possible connection between occupational exposure to risk factors and the onset of ALS are still lacking.
... He responded, "Always. " [93,94] We are now seeing ALS occurring at a much younger age, yet it also occurs in the older age groups as before. I am convinced that the aluminum from the grossly expanded vaccine schedule is responsible for this horrifying disease's appearance in the younger population. ...
Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain’s innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal’s toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum’s neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.
... However, these industrial alloys turned out to be unfriendly to humans; this is mainly related to the composition of the strengthening elements in these magnesium alloys, such as manganese (Mn), aluminum (Al), zirconium (Zr), and rare earth elements [9][10][11]. For example, the high concentration of Mn has been confirmed to cause neuro-toxicity and lead to Parkinson's disease [12]; an excess of ionic Al would induce dementia [13]; and a large amount of rare earth elements such as Zr and Y has been tested to be associated with liver, lung, breast, and nasopharyngeal cancers [14]. Moreover, Mg alloy used as a degradable material is, mainly, by its own characteristic, easily corrodible. ...
To further improve the mechanical properties and corrosion resistance of the biodegradable magnesium (Mg) alloy, the Mg-4Zn-0.5Sr-xAg alloy (x = 0.2 wt.%, 0.5 wt.%, 1.0 wt.%, and 2.0 wt.%) was smelted in vacuum under the protection of inert gas. The effect of the Ag content on the microstructure and mechanical properties of Mg-4Zn-0.5Sr was tested. The results show that the comprehensive properties of Mg-4Zn-0.5Sr-0.5Ag are best. The grain size of the Mg-4Zn-0.5Sr-0.5Ag alloy is minimal, that is, 83.28 μm. The average tensile strength (σb), yield strength (σs), elongation (ε), and hardness for the Mg-4Zn-0.5Sr-0.5Ag alloy is 168.00 MPa, 88.00 MPa, 12.20%, and 59.90 HV, respectively. To further improve the properties of cast Mg-4Zn-0.5Sr-0.5Ag alloy, extruding treatment was conducted. After extrusion deformation, the grain size of the alloy was significantly refined to 9 μm; at the same time, fine second phases were formed and evenly distributed in the matrix. And then, the mechanical properties of the alloy are significantly enhanced due to the effect of fine crystal strengthening and dispersion strengthening. The σb, σs, ε, and hardness value for the extruded Mg-4Zn-0.5Sr-0.5Ag alloy are 236.00 MPa, 212.00 MPa, 18.97%, and 65.42 HV, respectively. Under the synergistic action of adding the Ag element and extrusion treatment, the grain size of the alloy was significantly refined and the coarse second phase in the alloy became refined to disperse in the matrix, which benefits the formation of electric couples characterized as small cathode–large anode between the second phase and Mg matrix. During full immersion, corrosion products covered on the large anode surface could reduce the galvanic corrosion tendency.
... Therefore, it can influence energy metabolism. Al has been linked to several neurodegenerative diseases, including AD, PD, and ALS [157][158][159][160]. ...
Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical features, such as Alzheimer’s and Parkinson’s diseases. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies, and most probably, each metal has its specific pathway to trigger cell death. As a result, exposure to essential metals, such as manganese, iron, copper, zinc, and cobalt, and nonessential metals, including lead, aluminum, and cadmium, perturbs metal homeostasis at the cellular and organism levels leading to neurodegeneration. In this contribution, a comprehensive review of the molecular mechanisms by which metals affect microglia physiology and signaling properties is presented. Furthermore, studies that validate the disruption of microglia activation pathways as an essential mechanism of metal toxicity that can contribute to neurodegenerative disease are also presented and discussed.
... The document 8 listed several publications (see Table 2) on the pathogenicity of HPV vaccines that have been used as scientific evidence to support the causative roles of HPV vaccines for plaintiffs' "diverse symptoms." [9][10][11][12][13][14][15][16][17][18] The manuscripts that the attorneys' group has used as evidence in the document can be categorized into the following three findings/hypotheses ( Table 2). Hypothesis I: Molecular mimicry between HPV L1 protein contained in vaccines and human proteins results in the production of cross-reactive antibodies that attack host organs. ...
Cervical cancer is caused by human papillomavirus (HPV) infection, which is preventable by HPV vaccines. In Japan, the HPV vaccination rate has remained extremely low due to the concerns for alleged neuropsychological symptoms or "diverse symptoms" following injections of two HPV vaccines, Cervarix and Gardasil, in HPV vaccine lawsuits. In the lawsuits, the attorneys' group has used several manuscripts proposing that aluminum (Al) adjuvant contained in HPV vaccines causes immune-mediated disease, called macrophagic myofasciitis (MMF), as well as pathology in the central nervous system (CNS). We scientifically evaluated these manuscripts describing the "Al adjuvant-induced pathologies", particularly MMF. Although MMF patients have been reported to develop clinical symptoms/signs in various organs, including the CNS, muscle biopsy of the patients and animal experiments demonstrated that MMF pathology was localized only at the injected muscle. No muscle pathology which characterizes MMF was observed in any other muscles; thus, the systemic and neurological signs of MMF cases were irrelevant to localized MMF pathology. We evaluated that MMF-like pathology was induced as a local inflammatory response following vaccinations; MMF pathology was not the cause of systemic inflammation or "diverse symptoms." Lastly, MMF cases have been reported after vaccinations with Al-hydroxide-containing vaccines exclusively. Since Al-hydroxide is a component of Cervarix, but not Gardasil, "diverse symptoms" following two HPV vaccinations in Japan cannot be explained by MMF. Our evaluation would help readers understand the validity of the manuscripts on the role of Al adjuvants or MMF for the alleged "diverse symptoms."
... In some cases, it can lead to neurotoxicity and cause several diseases related to kidney, breast cancer and digestive disorders [16]. From observations on mice, their capacity of spatial memory was reduced and motor functioning quality were reduced after an injection of aluminum hydroxide [67]. Large local concentrations of aluminum in the body can lead to Alzheimer disease [49,66]. ...
Developing biomaterials with appropriate physiochemical and mechanical properties as per the requirements set by biomedical applications remains a challenge. This challenge has pushed research in the direction of biomaterials development and the surface modification of existing materials that could be useful for biomedical applications. Keeping this demand in focus, this paper intends to conduct an in-depth review, which includes, first, the requirements of biomedical surfaces associated with the growth of cells on biomedical alloys, such as the bone formation, adhesion, increased wear resistance and biofilm formation; second, possible biomaterials candidates for such applications; and third, possible surface modification techniques. Both subtractive and additive methods of surface modification are discussed, along with their pros and cons. Hence, this study gives an excellent compendium of scientific works conducted on surface modification techniques and the development of biocompatible surface alloys, along with research trends.
... Of the eight elements we evaluated, Al showed the highest concentrations, results in keeping with Al's high levels in the Earth's crust generally and particularly in areas where acid soils predominate. Al is also a known toxin, particularly a neurotoxin, and Al-induced neurodegeneration can be seen in in vivo models of neurological disease, notably Alzheimer's disease and ALS [25][26][27][28][29]. The second most abundant metal or metalloid in our samples was Se. ...
Exposure to environmental toxins may be partly responsible for mammal neurodegenerative disorders. Consumption of seeds from Guam’s cycad tree has been linked to the disorder known as amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC). The unambiguous identification of causal agents of ALS-PDC has been elusive. We have examined the levels of eight metals and metalloids in cycad seeds as a function of the ambient shade in which the plants were grown. Of these metals, the data strongly suggest that aluminum (Al) and selenium (Se) are present in washed flour prepared from southern Guam’s cycad seed tissues at elevated levels, especially when the trees are grown in shade. Previous authors have speculated that Al and Se are involved in various ALS outcomes, and our results support this interpretation.
... Finally, experimental studies focused on the biopersistence and neurotoxic effects of these compounds addressed in different animal models (mainly rodents, rabbits and sheep) showed that ABAs (mainly Al oxyhydroxide) or Al-containing vaccines (i) are capable of inducing behavioral alterations [157,[160][161][162][163][164][165][166][167][168][169], (ii) remain in the organism [143,[145][146][147]158,[170][171][172][173][174][175][176][177][178], and (iii) can leave the injection area to reach remote organs such as the nervous system [146,157,163,164,173,179,180]. Of these thirty-one studies, only six evaluated perinatal period exposure: two studies on gestational exposure on rats [181,182], three studies on newborn mice [163,167,169], and one on newborn rats [183] (for a review, see [148]). ...
Autism spectrum disorder (ASD), schizophrenia, and bipolar disorder are genetically complex and heterogeneous neurodevelopmental disorders (NDDs) resulting from genetic factors and gene-environment (GxE) interactions for which onset occurs in early brain development. Recent progress highlights the link between ASD and (i) immunogenetics, neurodevelopment, and inflammation, and (ii) impairments of autophagy, a crucial neurodevelopmental process involved in synaptic pruning. Among various environmental factors causing risk for ASD, aluminum (Al)-containing vaccines injected during critical periods have received special attention and triggered relevant scientific questions. The aim of this review is to discuss the current knowledge on the role of early inflammation, immune and autophagy dysfunction in ASD as well as preclinical studies which question Al adjuvant impacts on brain and immune maturation. We highlight the most recent breakthroughs and the lack of epidemiological, pharmacokinetic and pharmacodynamic data constituting a “scientific gap”. We propose additional research, such as genetic studies that could contribute to identify populations at genetic risk, improving diagnosis, and potentially the development of new therapeutic tools.
... The development of sheep production in many countries where the industrial of sheep is useful, mainly depends on reproductive performance like twins ratio and fecundity that regarding as vital economic feature [1]. Many factors had been influenced on fertility like management, nutrition and genetics, so for enhancing the fertility performance the various hormonal techniques have followed to increase number of lambs born per year, but that usage can be effected on ewes and lambs health causing different problems when repeated usage with progress [2,3]. Therefore authors attempted to find another methods for improving the fecundity like immunization with steroid free follicular fluid antiserum [4,5], As well as, an addition some natural matters and plants such as coriander (Coriandrum sativum), porpolis, Thyme, Ceylon cinnamon, fenugreek, mulberry, Nigella sativa can augment the health, support production and fecundity characters in an animals with no or fewer deleterious effects [6][7][8][9][10][11]. ...
The fecundity efficacy of ewes depends on reproductive hormones, ovarian activity so the current research was designed to improve the fecundity of Iraqi anestrous ewes by mulberry leaves ( Morus alba ) powder extract supplementation. 30th healthy non-pregnant ewes aged 2-3.5 year outbreeding season were divided into equal three groups, 1st group represent a (control) had fed the standard diet, second and third group represent T1 and T2 supplemented 15 and 30 mg/kg mulberry powder extract, respectively, for 40 day before sponge insertion. At day 28th of beginning supplementation the intra-vaginal sponge were inserted for 12 days. After sponges eliminated, estrous onset reported and blood collected before 20 and after 23 & 40 hrs of VSPR to estimate FSH, LH, progesterone and Estradiol concentration. Also, the fecundity, lambing and prolificacy rates had manifested. The results recorded a significant elevation in FSH, estradiol and LH while progesterone registered significant decreased in T1 &T2 comparing with C at 23 & 40 hr after VSPR. Also the fecundity, lambing rates were significantly higher in T1 &T2 in comparing with C. In concluded, that the mulberry leaves powder extract can augment the fecundity in anestrus Iraqi ewes by enhancing the fecundity profile and prolificacy rate.
... 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. ...
A 71-year-old woman presented 2 weeks after vaccination with the first dose of Vaxzevria (AstraZeneca, Oxford) for COVID-19 with a left lower motor neuron facial nerve palsy, which progressed to bilateral involvement. This was accompanied by bilateral proximal leg weakness. She was diagnosed with the ‘facial diplegia with paraesthesia’ variant of Guillain-Barré syndrome. Seven weeks post vaccination she developed painless loss of vision in the right eye. The visual acuity in that eye was light perception only with a right relative afferent pupillary defect and right optic disc swelling. A diagnosis of optic neuritis was made and she received pulsed intravenous methylprednisolone for 3 days, followed by oral prednisolone. The optic neuritis recurred following initial cessation of steroids requiring an extended course of steroids. Despite this, she made a good visual recovery to 6/6 in the affected eye. We present this case and a review of the literature surrounding vaccination and the development of these conditions.
... 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.
... 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.
... Vanadium (V) and aluminum (Al) are common alloying elements for Ti (seen in Ti6Al4V alloy). Individually each element has shown potential adverse effects in high concentrations, causing carcinogenicity and neurotoxicity [10][11][12]. However, reports on V also demonstrate antidiabetic effects and resulted in reduced weight gain and gastrointestinal discomfort [1,13]. ...
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.
Significance Statement
Biomaterials have become essential for modern implants. A suitable implant biomaterial integrates into the body to perform a key function, whilst minimizing negative immune response. Focusing on dentistry, the use of dental implants for tooth replacement requires a balance between bodily response, mechanical structure and performance, and aesthetics. This mini-review addresses the use of biomaterials in dental implants with significant comparisons drawn between Ti and zirconia. Attention is drawn to optimizing surface modification processes and the additional use of coatings. Alternatives and novel developments are addressed, providing potential implications of combining biomaterials to form novel composites that combine and synergize the benefits of each material.
... 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.
... 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.
... 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.
... 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.
... 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.
日本におけるHPVワクチンの実情を紹介するとともに、ワクチンに含まれるアルミニウム・アジュバントと副反応の仮説の科学的欠陥について概説する。
This book explains and evidences the toxic content of the COVID vaccines, causing, among others, excess mortality. It acknowledges the cover up of official entities and put the total picture into a context of society we are living in. This book may change your worldview and belief system.
La vaccination est une avancée majeure de la médecine moderne ayant permis d’éradiquer certaines maladies et d’endiguer la propagation de nombreuses autres. Malgré une bonne tolérance par la population générale, certains individus présentent des difficultés d’élimination des particules aluminiques utilisées comme adjuvant vaccinaux. Ces patients présentent une lésion histopathologique musculaire caractéristique, biopersistante sur le long terme et composée de cellules immunitaires présentant des inclusions intracellulaires de cristaux aluminiques. Cette lésion, associée à un ensemble d'arthromyalgie, de fatigue chronique et de troubles cognitifs, est appelée myofasciite à macrophages (MFM).Les vaccins à base d’aluminium sont des particules pseudo-infectieuses gérées comme des agents pathogènes par des cellules présentatrices d'antigènes via endocytose et élimination ultérieure par l'intermédiaire de la machinerie xéno/autophagique. Par ailleurs, la littérature scientifique a montré que l’oxy-hydroxyde d'aluminium, l’un des principaux adjuvants, peut perturber la réponse autophagique. Cela conforte l’idée que l’intolérance aux adjuvants aluminiques pourrait être la conséquence d’une interaction de type « gènes x environnement » reposant sur une déficience de l’autophagie dans les cellules de l’immunité comme facteur de susceptibilité individuelle aux particules d’aluminium d’origine vaccinale.Les réponses autophagiques et inflammatoires des cellules immunitaires isolées en réponse aux particules aluminiques n’étant pas totalement caractérisées parmi la population globale. Le travail de thèse présenté dans ce manuscrit a donc eu pour premier objectif d’étudier ces réponses chez des individus sains avant de comparer les résultats avec ceux obtenus chez des individus atteint de MFM. Les données ont démontré que de nombreuses interactions entre les mécanismes d’endocytose, d’autophagie et d’inflammation sont mises en œuvre par les cellules de l’immunité en réponse à la présence de particules d’aluminium. Des expérimentations complémentaires seront nécessaires afin de caractériser finement les différentes intrications entre ces mécanismes. Cependant, certaines observations ont laissé entrevoir de subtiles variations de réponse au sein des cellules immunitaires des patients MFM exposées à des particules aluminiques. Ces cellules ont ainsi présenté un équilibre entre autophagie et endocytose penchant en faveur de l’endocytose et associé à une réponse inflammatoire réduite par rapport aux individus sains. Ces observations sont en accord avec la littérature scientifique actuelle et pourraient être principalement la conséquence plus que la cause de l’état de santé des patients MFM.Suite aux observations in vitro, des analyses exploratoires in vivo ont été menées afin de développer un modèle murin avec des perturbations de l’autophagie pour étudier l’importance de ce mécanisme dans la prise en charge et le devenir des particules aluminiques. Une étude longue a été réalisée pour tester l’efficacité d’un traitement pharmacologique (hydroxychloroquine) à perturber l’autophagie sans induire de toxicité. Nos résultats montrent que, bien qu’apparemment non toxique pour les animaux, le traitement utilisé n’a pas été en mesure de perturber l’autophagie sur le long terme. Par conséquent, l’étude de l’importance du mécanisme autophagique dans la translocation des particules d’aluminium a été réalisée en privilégiant un modèle de KO génétique. Les données ont confirmé les précédentes observations faites sans mettre en avant de rôle majeur de l’autophagie dans le déplacement des particules d’aluminium depuis le site d’injection initial, au regard du faible effectif d’animaux disponibles pour cette étude.En conclusion, ce travail a permis de mettre en évidence une prise en charge des particules aluminiques d’origine vaccinale d’une grande complexité, nécessitant une approche pluridisciplinaire pour être finement décrite.
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.KeywordsAluminum bioavailabilityCentral nervous systemImmune systemAutoimmunityAutism spectrum disorder
The current study was designed to assess the possible neuroprotective effect of borax (BX) against the toxicity of aluminum hydroxide [AH, Al (OH)3] on brain of rainbow trout (Oncorhynchus mykiss) with multibiomarker approaches. For this purpose, the presence of the neuroprotective action by BX against the AH exposure was assessed by the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), myeloperoxidase (MPO), acetylcholinesterase (AChE). In addition, we evaluated glutathione (GSH), malondialdehyde (MDA), DNA damage (8-OHdG), apoptosis (caspase 3), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), nuclear factor erythroid-2 (Nrf-2), and brain-derived neurotrophic factor (BDNF) levels in 96 hours semi-static treatment. In the 48th and 96th hour samplings, apoptosis induced by AH in the Nrf-2/BDNF/AChE pathways in rainbow trout brain tissue was revealed by DNA damage, enzyme inhibitions and lipid peroxidations. On the contrary applications of BX supported antioxidant capacity without leading apoptosis, lipid peroxidation, inflammatory response and DNA damage. BX also increased the BDNF levels and AChE activity. Moreover, BX exerted a neuroprotective effect against AH-induced neurotoxicity via down-regulating cytokine-related pathways, minimising DNA damage, apoptosis as well as up-regulating GSH, AChE, BDNF and antioxidant enzyme levels. It can be concluded that the combination of borax with AH modulated the toxic effects of AH.
A new set of triazoles(5a-5e) has been designed in this paper utilizing a Cu(I) catalyzed click reaction, and their characterizations have been carried out using different spectroscopic methods such as ¹H and ¹³C NMR, TGA, and mass spectrometry. UV-Vis and fluorescence spectroscopy validated the compound5a's outstanding selectivity and sensitivity toward Al³⁺ ions with no appreciable interference from other metal ions.The compound 5a binds to Al³⁺ in 1:1 stoichiometry, as determined by Job's plot. The high value of binding constants were 2.878 × 10⁶ M⁻¹and 4.101 × 10⁷ M⁻¹, as determined by the B-H plot and the Stern-Volmer plot, respectively. The LOD values obtained from absorption and emission spectroscopy are 0.04 × 10⁻⁸ M and 0.012 × 10⁻⁹ M, respectively. MOLINSPIRATION and ADMET studies were used to determine the pharmacokinetic characteristics of the synthesized compounds. The transferase protein of the protozoan Entamoeba histolytica was used in molecular docking in-silico experiments to investigate the use of compound5a in biological areas. A high binding energy of -7.59 Kcal mol⁻¹ and a low value of inhibition constant of 2.75µM demonstrated that the ligand may operate as a good inhibitor for this parasite and might be employed as an anti- parasitic agent in the future.
Cervical cancer is caused by infections of the human papillomavirus (HPV), which can be preventable by vaccinations. In Japan, although about 3,000 people died of cervical cancer annually, the HPV vaccination rate has remained extremely low in the eligible population, since many Japanese have been concerned that "diverse symptoms," such as chronic pain, movement disorders, and cognitive impairment, may occur as adverse reactions after HPV vaccination. The concern has been raised by media coverage of the ongoing HPV vaccine lawsuits, in which the plaintiffs complained of their symptoms caused by HPV vaccination. The claims have been based on the alleged pathogenic findings in research articles on HPV vaccines, summarized in the document prepared by the plaintiffs' attorneys. We critically evaluated these articles, in which the authors proposed the following findings/hypothesis: (i) molecular mimicry between HPV L1 and human proteins leads to the production of cross-reactive antibodies; and (ii) HPV vaccine injection in mice causes damage in the brain, a mouse model for "HPV vaccine associated neuro-immunopathic syndrome (HANS)." We found that they were based mainly on the findings from a few research groups and that all the articles had flaws in the method, result, or discussion sections. Our current evaluation would help better understand the validity of the findings, which have been often misunderstood as the truth by the general public. We propose to accumulate high-quality data on potential adverse events following HPV vaccination and to continue critically evaluating them.
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.
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.
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.
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.
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.
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.
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.
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.
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, developmental 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 (M r ) neurofilament (NF) subunits, both acidic and basic cytokeratin (CK) proteins; three different micro tubule 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 (LC b ); 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).
The major findings derived from these studies may be summarized as follows: (1) the most primitive neuroepithelial cells only expressed VFP and MAP5; (2) postmitotic, postmigratory neurons transiently expressed NGFR in the earliest developmental stages, while NF‐H, NF‐M, NF‐L, MAP2, MAP5, clathrin LC b , and SYP were expressed throughout development although the time of initial onset of each of these proteins differed; for example, NF‐M isoforms generally appeared before NF‐L and NF‐H isoforms, and the most highly phosphorylated NF‐H variants emerged much later than NF‐M; moreover, the induction of SYP in anterior horn cells followed the induction of proteins that are thought to determine neuronal polarity (e.g., NF‐L, NF‐M, NF‐H, MAP2, tau); (3) GFAP positive astrocytes became evident after the appearance of many neuron specific proteins although radial glia transiently expressed VFP earlier in development; (4) MBP appeared in the cell bodies of glial cells contemporaneously with GFAP, and in the myelin sheaths of white matter well before axons acquired a fully mature complement of cytoskeletal proteins; and (5) although programmed neuron death undoubtedly occurred during the GAs examined here, this process was not associated with the presence of debris containing any of the developmentally regulated polypeptides examined in this stud.
We conclude that human neurogenesis and gliogenesis in the developing spinal cord is a highly orchestrated process in which neuron specific and specific genes are induced manner quite similar to that described in previous studies of other experimental animals. However, unlike some reports on neurogenesis in rodents and birds, the acquisition of the molecular neuronal phenotype in the human spinal cord was exclusively a postmitotic, postmigratory series of events. Nevertheless, as in these other species, the induction of neuron specific gene products in human spinal cord neurons occurred in a step‐wise, asynchronous manner. Finally, the absence of cellular debris containing any of the developmentally regulated antigens we studied here, at a time during which massive neuron death is likely to be in progress, suggests that the induction of these neuron specific genes may identify subsets of neurons destined to survive into maturit.
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.
Recent epidemiological, neuropathological, and biochemical studies have suggested a possible link between the neurotoxicity of aluminum and the pathogenesis of Alzheimer's disease. However, this relationship remains controversial. To investigate detailed characteristics of neurotoxicity of aluminum, we used primary cultured neurons of rat cerebral cortex as an in vitro model system for the observation of morphological changes induced by chronic exposure to aluminum. Although the exposure to aluminum chloride (10-100 microM) for 1 week did not cause marked neuronal death, degeneration of neuritic processes and accumulation of tau protein and beta-amyloid protein appeared after chronic exposure to 50 microM aluminum chloride for more than 3 weeks. We also investigated the polymerization of beta-amyloid protein in vitro using the immunoblotting technique. We thus found that aluminum induced conformational changes in beta-amyloid protein and enhanced its aggregation in vitro. The aggregated beta-amyloid protein was dissolved by the addition of desferrioxamine, a chelator of aluminum. The aggregated beta-amyloid protein pre-incubated with aluminum formed fibrillar deposits on the surface of cultured neurons.
It has been postulated that the neurotoxic effects of aluminium could be mediated through glutamate, an excitatory amino acid. Hence the effects of aluminium administration (at a dose of 4.2mg/kg body weight daily as aluminium chloride, hexahydrate, intraperitoneally, for 4 weeks) on glutamate and gamma-amino butyrate (GABA), an inhibitory amino acid, and related enzyme activities in different regions of the brain were studied in albino rats. The glutamate level increased significantly in the cerebrum, thalamic area, midbrain-hippocampal region and cerebellum in response to in vivo aluminium exposure. The aluminium insult also caused significant increases in glutamate alpha-decarboxylase activity in all the brain regions. However, on aluminium insult, the GABA content was not significantly changed except in the thalamic area, where it was elevated. On the contrary, the GABA-T activities of all the regions were reduced significantly in all regions except the midbrain-hippocampal region. However, the succinic semi-aldehyde content of all brain regions increased, often significantly. The aluminium-induced modification of the enzyme activities may be either due to the direct impact of aluminium or due to aluminium-induced changes in the cellular environment. The aluminium-induced differential regional accumulation of glutamate or other alterations in enzymes of the glutamate-GABA system may be one of the causes of aluminium-induced neurotoxicity.
US secretary of veterans affairs Anthony Principi has declared that motor neurone disease is connected with service in the Gulf war.
He is the first to connect a specific illness with service in the Gulf war, and his decision will lead to full disability and survivor benefits for those with the disease, the cause of which is unknown.
Last month the Department of Veterans Affairs described preliminary results of a government sponsored study involving 2.5 million US servicemen and servicewomen. The study was carried out at Duke University and the Veterans Administration Hospital in Durham, North Carolina, and was directed by Dr Ronald Horner, director of epidemiological research at the Veterans Administration Center in Durham. It found that of 700 000 US veterans who served in the Gulf from August 1990 to July 1991, 40 had motor neurone disease (known in the United States as amyotrophic lateral sclerosis), a case rate of 6.7 per million. Of 1.8 million US veterans in the same period who were not deployed, 67 developed motor neurone disease, a case rate of 3.5 per million.
Dr Horner said, “We hope to have the manuscript describing the study and its findings published sooner rather than later. However, I cannot provide details as to a journal or publication date.”
Since the Gulf war, more than 100 000 US veterans have complained of a wide range of symptoms that have collectively been labelled the “Gulf war syndrome” (BMJ 2001;323:473). The government has so far spent $155m (£111m; €173m) on 193 research projects to investigate their complaints. The studies have found no definitive links, although several have suggested that stress, exposure to chemicals, or prophylactic medicines given to soldiers may be factors. Motor neurone disease usually affects people in middle age, but the cases among Gulf war veterans have affected a much younger population. The cause is unknown, and no curative treatment exists.
A spokeswoman for the UK Ministry of Defence said that they were aware of the study but await peer review of the findings. About 40 000 British troops served in the Gulf war.
Aluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been commonly used as an adjuvant in many vaccines licensed by the US Food and Drug Administration. Chapter 21 of the US Code of Federal Regulations [610.15(a)] limits the amount of aluminum in biological products, including vaccines, to 0.85 mg/dose. The amount of aluminum in vaccines currently licensed in the US ranges from 0.85-0.125 mg/dose. Clinical studies have demonstrated that aluminum enhances the antigenicity of some vaccines such as diphtheria and tetanus toxoids. Moreover, aluminum-adsorbed diphtheria and tetanus toxoids are distinctly more effective than plain fluid toxoids for primary immunization of children. There is little difference between plain and adsorbed toxoids for booster immunization. Aluminum adjuvants have a demonstrated safety profile of over six decades; however, these adjuvants have been associated with severe local reactions such as erythema, subcutaneous nodules and contact hypersensitivity.
Cholinesterases are a large family of enzymatic proteins widely distributed throughout both neuronal and non-neuronal tissues. In Alzheimer's disease (AD), analytical as well as epidemiological studies suggest an implication of an abnormal focal accumulation of aluminum in the brain. In this devastating disease, aluminum may interfere with various biochemical processes including acetylcholine metabolism, and can thus act as a possible etiopathogenic cofactor. Acetylcholinesterase (AChE) exists in several molecular forms that differ in solubility and mode of membrane attachment rather than in catalytic activity. Mice were treated orally with aluminum chloride or aluminum lactate (Al(lac)(3)), and AChE activity in their brain homogenates was then assayed. Results showed that this in vivo treatment augmented the activity of the enzyme. An activating effect was also observed in vitro, when the aluminum compounds were added directly to mouse brain homogenates. However, the activating effect observed in vivo was much more marked than that observed in vitro. In addition, the activation produced by Al(lac)(3) was higher than that obtained after aluminum chloride treatment. Kinetics measurements of AChE activity in the absence and presence of treatment with aluminum both in vivo and in vitro are reported. The influence of the metal speciation on enzymatic activity is discussed in relation to a possible implication of aluminum in some neurodegenerative diseases.
The etiology of human neurodegenerative diseases including Alzheimer's disease (AD) is exceedingly complex and our understanding of the mechanisms involved is far from complete. The experimental neurotoxicology of aluminum has been shown to recapitulate many of the pathophysiological features of AD and therefore represents a useful model to study the mechanisms involved in neurodegeneration. The present study investigated the effects of aluminum maltolate (Al-maltol) on the delicate balance that exists between pro-inflammatory cytokines and neurotrophins using primary brain rotation-mediated aggregate cultures. Aggregates were treated with Al-maltol (5-150 microM) on day 15 in vitro for 72 h. Cell death increased in a time- and concentration-dependent manner reaching significance in aggregates treated with 150 microM Al-maltol in 48 h and 50 microM by 72 h. Analysis of gene expression at 72 h revealed a concentration-dependent increase in tumor necrosis factor alpha (TNFalpha) and macrophage inflammatory protein-1alpha (MIP-1alpha) suggestive of a state of inflammation. In contrast, a dramatic concentration-dependent decrease in the expression of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) was observed. In fact, NGF expression could not be detected in aggregates treated with 50 and 150 microM Al-maltol. These changes in gene expression correlated with a decrease in aggregate size and an increase in neurodegeneration as indicated by Fluoro-Jade B staining. The results indicated a differential regulation of pro-inflammatory cytokines and neurotrophins in brain tissue following treatment with Al-maltol. Such findings provide insight into the possible involvement of deregulation of the cytokine/neurotrophin balance in the etiology of neurodegeneration.
We examined the effect of aluminum on the permeability of the blood-brain barrier (BBB) during nitric oxide-blockade-induced chronic hypertension in rats. Animals were given the inhibitor of nitric oxide synthase, l-NAME (N
ω-nitro-l-arginine methyl ester), for 4 wk to induce chronic hypertension. Two groups of rats were given an intraperitoneal injection of aluminum chloride. The integrity of the BBB was assessed by a quantitative measurement for Evans blue (EB) dye. The arterial blood pressure in l-NAME- and l-NAME plus aluminum-treated animals was significantly elevated from 115±2.8 and 110±1.7 mm Hg to 174±5.2 and 175±4.8 mm Hg, respectively (p<0.01). The EB dye content in the brain regions of the rats in the l-NAME group was increased, but there was no statistical significance compared to the saline group. The extravasation of EB dye was significantly increased in the brain regions of the animals treated with aluminum compared to the rats treated with saline (p<0.05). A significantly higher EB dye content in the brain regions was observed in the l-NAME plus aluminium group compared to l-NAME, aluminum, and saline groups (p<0.01). These findings indicate that exposure to a high level of aluminum leads to an additional increase in BBB permeability where nitric oxide-blockade-induced chronic hypertension potentiates the effect of aluminum to enhance BBB permeability to EB dye.
Reported cases of ALS in young veterans of the 1991 Gulf War have suggested excess incidence.
To compare observed and expected incidence of ALS in Gulf War veterans diagnosed before age 45 years (young veterans).
Cases of ALS diagnosed from 1991 through 1998 were collected from military registries and a publicity campaign in late 1998. Diagnoses were established from neurologists' medical records using El Escorial criteria. Expected incidence was estimated from the age distribution of the Gulf War veteran population, weighted by age-specific death rates of the US population. Secular changes in nationwide ALS rates were assessed using calculations of the age-specific US population death rates from vital statistics data of 1979 to 1998.
During 8 postwar years, 20 ALS cases were confirmed in approximately 690,000 Gulf War veterans, and 17 were diagnosed before age 45 years. All developed bulbar and spinal involvement, and 11 have died. In young veterans, the expected incidence increased from 0.93 cases/year in 1991 to 1.57 cases/year in 1998, but the observed incidence increased from 1 to 5 cases/year. The observed incidence was 0.94 (95% CI, 0.26 to 2.41) times that expected in the baseline period from 1991 to 1994 (4 vs 4.25 cases; p = 0.6); it increased to 2.27 (95% CI, 1.27 to 3.88) times that expected during the 4-year period from 1995 to 1998 (13 vs 5.72 cases; p = 0.006); and it peaked at 3.19 (95% CI, 1.03 to 7.43) times that expected in 1998 (5 vs 1.57 cases; p = 0.02). The magnitude of the excess of ALS cases over the expected incidence increased during the 8-year period (Poisson trend test, p = 0.05), and the increase was not explained by a change in the interval from onset to diagnosis or by a change in the US population death rate of ALS in those aged <45 years.
The observed incidence of ALS in young Gulf War veterans exceeded the expected, suggesting a war-related environmental trigger.
In response to Gulf War veterans' concerns of high rates of ALS, this investigation sought to determine if Gulf War veterans have an elevated rate of ALS.
A nationwide epidemiologic case ascertainment study design was used to ascertain all occurrences of ALS for the 10-year period since August 1990 among active duty military and mobilized Reserves, including National Guard, who served during the Gulf War (August 2, 1990, through July 31, 1991). The diagnosis of ALS was confirmed by medical record review. Risk was assessed by the age-adjusted, average, annual 10-year cumulative incidence rate.
Among approximately 2.5 million eligible military personnel, 107 confirmed cases of ALS were identified for an overall occurrence of 0.43 per 100,000 persons per year. A significant elevated risk of ALS occurred among all deployed personnel (RR = 1.92; 95% CL = 1.29, 2.84), deployed active duty military (RR = 2.15, 95% CL = 1.38, 3.36), deployed Air Force (RR = 2.68, 95% CL = 1.24, 5.78), and deployed Army (RR = 2.04; 95% CL = 1.10, 3.77) personnel. Elevated, but nonsignificant, risks were observed for deployed Reserves and National Guard (RR = 2.50; 95% CL = 0.88, 7.07), deployed Navy (RR = 1.48, 95% CL = 0.62, 3.57), and deployed Marine Corps (RR = 1.13; 95% CL = 0.27, 4.79) personnel. Overall, the attributable risk associated with deployment was 18% (95% CL = 4.9%, 29.4%).
Military personnel who were deployed to the Gulf Region during the Gulf War period experienced a greater post-war risk of ALS than those who were not deployed to the Gulf.
The gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in vertebrate CNS. At GABAergic synapses, a high-affinity transporter exists, which is responsible for GABA reuptake and release during neurotransmission. GABA transporter activity depends on the phosphorylation/dephosphorylation state, being modulated by Ca(2+)/calmodulin-dependent protein phosphatase 2B (calcineurin). Aluminium is known to interfere with the Ca(2+)/calmodulin signalling pathway. In this work, we investigate the action of aluminium on GABA translocation mediated by the high-affinity transporter, using synaptic plasma membrane (SPM) vesicles and synaptosomes isolated from brain cortex. Aluminium completely relieved Ca(2+) downregulation of GABA transporter, when mediating uptake or release. Accordingly, aluminium inhibited Ca(2+)/calmodulin-dependent calcineurin activity present in SPM, in a concentration-dependent manner. The deleterious action of aluminium on the modulation of GABA transport was ascertained by comparative analysis of the aluminium effect on GABA uptake and release, under conditions favouring SPM dephosphorylation (presence of intracellular micromolar Ca(2+)) or phosphorylation (absence of Ca(2+) and/or presence of W-7, a selective calmodulin antagonist). In conclusion, aluminium-induced relief of Ca(2+) modulatory action on GABA transporter may contribute significantly to modify GABAergic signalling during neurotoxic events in response to aluminium exposure.
We have reviewed evidence of adverse events after exposure to aluminium-containing vaccines against diphtheria, tetanus, and pertussis (DTP), alone or in combination, compared with identical vaccines, either without aluminium or containing aluminium in different concentrations. The study is a systematic review with meta-analysis. We searched the Cochrane Vaccines Field Register, the Cochrane Library, Medline, Embase, Biological Abstracts, Science Citation Index, and the Vaccine Adverse Event Reporting System website for relevant studies. Reference lists of retrieved articles were scanned for further studies. We included randomised and semi-randomised trials and comparative cohort studies if the report gave sufficient information for us to extract aluminium concentration, vaccine composition, and safety outcomes. Two reviewers extracted data in a standard way from all included studies and assessed the methodological quality of the studies. We identified 35 reports of studies and included three randomised trials, four semi-randomised trials, and one cohort study. We did a meta-analysis of data from five studies around two main comparisons (vaccines containing aluminium hydroxide vs no adjuvant in children aged up to 18 months and vaccines containing different types of aluminium vs no adjuvants in children aged 10-16 years). In young children, vaccines with aluminium hydroxide caused significantly more erythema and induration than plain vaccines (odds ratio 1.87 [95% CI 1.57-2.24]) and significantly fewer reactions of all types (0.21 [0.15-0.28]). The frequencies of local reactions of all types, collapse or convulsions, and persistent crying or screaming did not differ between the two cohorts of the trials. In older children, there was no association between exposure to aluminium-containing vaccines and onset of (local) induration, swelling, or a raised temperature, but there was an association with local pain lasting up to 14 days (2.05 [1.25-3.38]). We found no evidence that aluminium salts in vaccines cause any serious or long-lasting adverse events. Despite a lack of good-quality evidence we do not recommend that any further research on this topic is undertaken.
Some evidence suggests that aluminum is one of the risk factors in Alzheimer's disease (AD); however, there is no study on the relationship between the synaptic configuration changes and aluminum uptake. In the present study, 40 rats were fed with water solution aluminum for 3 months and the effects of aluminum on the Gray's type I synapses in hippocampus and frontal cortex of rats were quantitatively investigated by electron microscopy. The effects of aluminum on the ability to learn and memorize were tested by a Morris water maze. Length of synaptic active zone, width of synaptic cleft, curvature of synapse, and thickness of postsynaptic density (PSD) were measured in the interface of synapses by the IBM-PC microimage processing system. The flat synapse, positive and negative curvature synapses, as well as the perforated synapse were classified and counted according to the type of the interfacial structure of a synapse. The amounts of aluminum deposited in brain were measured with an atomic absorption spectrophotometer. Our results show that the time and the distance taken by the rats to find the water maze increased after the rats were fed aluminum for 3 months. As compared with control, the synapses in aluminum-induced rats exhibited the following significant changes: decreased thickness of PSD (P < 0.01), increased width of synaptic cleft (P < 0.05), increased numbers of flat synapse, decreased numbers of positive curvature synapse and perforated synapse, and significantly increased aluminum deposits in hippocampus and frontal cortex (P < 0.01). Our study indicates that aluminum can decrease the ability of rats to learn and memorize and induce their synaptic configuration changes. These changes may be related to synaptic efficacy and may be one of the mechanisms for AL to induce AD.
We have investigated the expression of Hsp25, a heat shock protein constitutively expressed in motoneurons, in amyotrophic lateral sclerosis (ALS) mice that express G93A mutant SOD1 (G93A mice). Immunocytochemistry and Western blotting showed that a decrease of Hsp25 protein expression occurred in motoneurons of G93A mice prior to the onset of motoneuron death and muscle weakness. This decrease in Hsp25 expression also preceded the appearance of SOD1 aggregates as identified by cellulose acetate filtration and Western blot analysis. In contrast to Hsp25 protein levels, Hsp25 mRNA as determined by in situ hybridization and RT-PCR, remained unchanged. This suggests that the decrease in Hsp25 protein levels occurs post-transcriptionally. In view of the cytoprotective properties of Hsp25 and the temporal relationship between decreased Hsp25 expression and the onset of motoneuron death, it is feasible that reduced Hsp25 concentration contributes to the degeneration of motoneurons in G93A mice. These data are consistent with the idea that mutant SOD1 may reduce the availability of the protein quality control machinery in motoneurons.