Aluminium adjuvants versus placebo or no intervention in vaccine randomised clinical trials: a systematic review with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development. DESIGN: Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SOURCES: We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021. ELIGIBILITY CRITERIA: Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias with Cochrane's RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I2 statistic. We GRADE assessed the certainty of the evidence. RESULTS: We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants' seroprotection. CONCLUSIONS: Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.

A dose response effect of oral aluminum nanoparticle on novel object recognition memory, hippocampal caspase-3 and MAPKs signaling in mice.

The increasing use of aluminum nanoparticles (nano-Al) leads to increased human exposure and might affect human health. Considering the suggested connection between aluminum exposure and Alzheimer's disease (AD) pathogenesis, there is a concern about the effect of nano-Al on cognitive function and brain health. This study was aimed to assess the effect of a 5-day oral gavage of aluminum oxide nanoparticle (nano-Al) on memory and the phosphorylation levels of hippocampal p38, JNK (c-Jun N-terminal kinase), ERK (extracellular signal-regulated kinase) as well as cleaved caspase-3 in mice. Adult male NMRI mice were treated with nano-Al in doses 5 and 10 mg/kg/oral gavage for 5 days. The test session of novel object recognition (NOR) task was performed on day 5. Following the NOR test, the hippocampi were isolated for western blot analysis to determine the total and phosphorylated levels of p38, JNK, ERK as well as cleaved caspase-3 proteins. The results showed that nano-Al oral gavage in doses of 5 and 10 mg/kg impairs NOR memory in mice. Moreover, the memory impairing effect of nano-Al coincided with a dose dependent increase in phosphorylated p38 and cleaved caspase-3 in the hippocampus. It also increased the ratio of phosphorylated to total content of ERK in the hippocampus while JNK signaling was not affected by nano-Al. This study showed that nano-Al in doses as low as 5 and 10 mg/ kg ingested for 5 days impairs NOR memory and activates p38, ERK and cleaved caspase-3 in the hippocampus.

Investigation of TNFα Level and Metallothionein Gene Expression in Livers of Rats Exposed to Dietary Aluminum.

Aluminum chloride is a chemical compound widely used in both pharmaceutical and industrial sectors. The present study aimed to assess the effect of aluminum chloride on TNF levels and metallothionein gene expression in rat livers. A total of 16 Wistar rats were used as an experimental model and assigned to four groups (n=4). The treated groups received aluminum chloride (Sigma/USA) at a dose of 25g/kg body weight via a feeding tube as follows: group 1: Non-treated rats as the control group, group 2 were treated with aluminum chloride for 8 weeks, group 3 were treated with aluminum chloride for 12 weeks, and group 4 received aluminum chloride for 16 weeks. The TNF-α was measured in liver tissue using an enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry and real-time polymerase chain reaction (RT-PCR) were used to analyze metallothionein gene expression in rat liver. To estimate TNF levels, the results revealed that levels were considerably higher (P<0.01) in all experimental groups, especially in group 4 which underwent treatment for 16 weeks (401±22.1 ng/ml), as compared to that in the control group. For the immunohistochemistry assay, a gradient intensity of staining for liver tissue was observed, ranging from zero staining in the control group to moderate, medium, and high staining in the experimental groups after 8, 12, and 16 weeks of aluminum chloride treatment, respectively. The greatest amount of methylothionine expression was observed in the livers of group 4 which received aluminum chloride for 16 weeks (15.5-fold), with a significant difference (P<0.01) from the other experimental groups. In both immunohistochemical and RT-PCR experiments, aluminum administration had a substantial influence on TNFα levels and metallothionein expression in rat livers.

The Childhood Vaccination Schedule and the Lack of Association With Type 1 Diabetes.

OBJECTIVES: Safety studies assessing the association between the entire recommended childhood immunization schedule and autoimmune diseases, such as type 1 diabetes mellitus (T1DM), are lacking. To examine the association between the recommended immunization schedule and T1DM, we conducted a retrospective cohort study of children born between 2004 and 2014 in 8 US health care organizations that participate in the Vaccine Safety Datalink. METHODS: Three measures of the immunization schedule were assessed: average days undervaccinated (ADU), cumulative antigen exposure, and cumulative aluminum exposure. T1DM incidence was identified by International Classification of Disease codes. Cox proportional hazards models were used to analyze associations between the 3 exposure measures and T1DM incidence. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated. Models were adjusted for sex, race and ethnicity, birth year, mother's age, birth weight, gestational age, number of well-child visits, and study site. RESULTS: In a cohort of 584 171 children, the mean ADU was 38 days, the mean cumulative antigen exposure was 263 antigens (SD = 54), and the mean cumulative aluminum exposure was 4.11 mg (SD = 0.73). There were 1132 incident cases of T1DM. ADU (aHR = 1.01; 95% CI, 0.99-1.02) and cumulative antigen exposure (aHR = 0.98; 95% CI, 0.97-1.00) were not associated with T1DM. Cumulative aluminum exposure >3.00 mg was inversely associated with T1DM (aHR = 0.77; 95% CI, 0.60-0.99). CONCLUSIONS: The recommended schedule is not positively associated with the incidence of T1DM in children. These results support the safety of the recommended childhood immunization schedule.

Using chemical speciation modelling to discuss variations in patch test reactions to different aluminium and chromium salts.

BACKGROUND: Allergic contact dermatitis to metals is diagnosed by applying a metal salt in a patch test. The bioavailability of the metal salt might depend on the choice of metal salt, the concentration, sweat composition, and pH. OBJECTIVES: The main purpose of this study was to apply chemical speciation modelling, which is based on experimentally derived input data and calculates the concentrations of chemical forms (species) in solutions, to reproduce and discuss clinical patch test results of aluminium and chromium. METHODS: Joint Expert Speciation System (JESS), Hydra/Medusa, and Visual MINTEQ were employed to study the bioavailable fraction and chemical form of clinically applied aluminium and chromium salts as a function of salt type, applied concentration, sweat composition, and pH. RESULTS: Investigated aluminium and chromium salts can have a very low bioavailability with a large dependency on sweat composition, pH, metal salt, and concentration. Both aluminium and chromium ions could shift the pH towards acidic or basic values based on their chemical form. CONCLUSIONS: Reported seasonal and interpatient variability in positive reactions to aluminium is likely related to sweat pH and composition. Potassium dichromate increases the pH, whereas aluminium and trivalent chromium chloride strongly decrease the pH, possibly increasing skin diffusion.

EBER in situ hybridization in subcutaneous aluminum granulomas/lymphoid hyperplasia: A diagnostic clue to differentiate injection-associated lymphoid hyperplasia from other forms of pseudolymphomas and cutaneous lymphomas.

BACKGROUND: Subcutaneous vaccination or desensitization may induce persistent nodules at the injection sites. Without the knowledge of prior injection, histopathological work-up may be challenging. OBJECTIVE: Aim of this study was to contribute to the histopathological work-up of unclear subcutaneous nodules, especially their differentiation from cutaneous lymphoma. METHODS: We retrospectively reviewed clinical data and histopathological slides of four patients with subcutaneous nodules, which were suspected to suffer from cutaneous T- or B-cell lymphoma. Sections of these cases and 12 negative controls were stained with hematoxylin and eosin and a standardized immunohistochemical panel of B- and T-cell markers including EBER in situ hybridization as well as electron microscopy. RESULTS: In all cases, large histiocytes with granular cytoplasm compatible with intracellular aluminum hydroxide were present. EBER in situ hybridization revealed positive staining of these granular histiocytes while staining was absent in negative controls. LIMITATIONS: Post hoc completion of medical history revealed that vaccination or specific immunotherapy had been applied before at the biopsy site in only three out of four patients; one patient was lost to follow-up. CONCLUSION: EBER in situ hybridization is an adjunctive tool to differentiate aluminum-induced granuloma/lymphoid hyperplasia from other forms of pseudolymphoma and cutaneous B- or T-cell lymphomas.

The bioavailability of ingested 26Al-labelled aluminium and aluminium compounds in the rat.

The fractional uptake of ingested aluminium and aluminium compounds (aluminium citrate, aluminium nitrate, aluminium chloride, aluminium sulphate, aluminium hydroxide, aluminium oxide, aluminium metal, powdered aluminium pot electrolyte, acidic sodium aluminium phosphate (SALP), basic sodium aluminium phosphate (Kasal), sodium aluminium silicate and FD&C red 40 aluminium lake) from the gastro-intestinal tract of adult female rats was measured. This was determined by comparing retained body burden of 26Al at seven days post-admistration of an i.v. injection of 26Al-labelled aluminium citrate with that retained following the gastric admistration of 26Al-labelled test compounds as either solutions or suspended solid. The calculated percentage uptake of 26Al for all the aluminium solutions was similar: aluminium citrate 0.08%, aluminium chloride 0.05%, aluminium nitrate 0.05% and aluminium sulphate 0.21%. The uptake of 26Al administered as insoluble particulates was lower: 0.03% for aluminium hydroxide; 0.02% for aluminium oxide; 0.04% for powdered pot electrolyte; 0.12% for sodium aluminium silicate; and 0.09% for FD&C red 40 aluminium lake. For aluminium metal, SALP and Kasal the amount of 26Al present in the rats was insufficient to determine uptake and was less than 0.03%. The results produced for aluminium citrate, aluminium hydroxide and aluminium sulphate are close to those published for man.

Calcium, magnesium and aluminium ions as decontaminating agents against dermal fluoride absorption following hydrofluoric acid exposure.

The fluoride ions of the industrially largely irreplaceable, locally corrosive hydrofluoric acid (HF) can scavenge cations in biological tissues, which explains their high toxic potential, and also leads to local acidification through proton release. The influence of three complexing agents, calcium (Ca2+) gluconate (as 2.5% Ca2+gel and individually (2.84%) or commercially (10%) formulated Ca2+solution), magnesium (Mg2+) gluconate (2.84%) solution and aluminium (Al3+) solution (Hexafluorine®, pure and diluted) on the absorption of fluoride following HF exposure (1-3 min, 100 µl, 30%/0.64 cm2) through human skin was investigated in an ex-vivo diffusion cell model. Fluoride absorption was assessed over 6-24 h and analysed with a fluoride electrode. Decreasing the contamination time reduced the fluoride absorption distinctly which was further reduced by the application of fluoride-binding decontamination agents (Ca2+, Mg2+, Al3+) or water alone without being significantly different. Ca2+ appeared slightly more effective than Mg2+ in reducing fluoride absorption. Moreover, the addition of pH adjusting buffer promoted the decontamination efficacy. Fluoride-binding agents can facilitate the decontamination of dermal HF exposure. However, prompt decontamination appeared to be the key to successful limitation of fluoride absorption and pushes the choice of decontamination agent almost into the background.

Exposure to Aluminum, Cadmium, and Mercury and Autism Spectrum Disorder in Children: A Systematic Review and Meta-Analysis.

Autism spectrum disorder (ASD) is a complex neurobehavioral disorder that is believed to be multifactorial in origin. As the incidence of ASD is rising along with industrialization, and because certain metals have been linked to neurological problems, it is important to consider whether such metals may play a role in the development of ASD. Previously, we performed a meta-analysis of existing literature to examine the potential link between inorganic arsenic and lead exposure and ASD. This is a continuation of that study investigating the association of the exposure to aluminum (Al), cadmium (Cd), and mercury (Hg) and ASD. These metals were chosen because they are abundant in our environment, are known to cause neurological problems in humans, and have multiple published studies examining their potential links with ASD. Following the same approach as our previous paper, we conducted a systematic review of the existing literature and performed a meta-analysis to evaluate the current evidence regarding these metals and their potential relationship with autism. We reviewed 18 studies on Al, 18 on Cd, and 23 on Hg, and the individual studies showed inconsistent results. When the measurements were integrated into the meta-analysis, we found significant associations between all the metals and ASD, but the associations were not always in the same direction. Levels of Hg in hair, urine, and blood were all positively associated with ASD. Levels of Al in hair and urine were positively associated with ASD, while levels of Al in blood were negatively associated. In comparison, levels of Cd in hair and urine were negatively associated with ASD. These results imply that, while these metals are all neurotoxic, their impact on the development of ASD and their modes of action could be different. Further research is warranted to examine the longitudinal effects of these toxic metals on the risk of ASD, to assess the critical period when exposure may affect development, and to investigate potential factors that may enhance or ameliorate the effect of metals. Overall, these findings support policies that advocate limiting exposure to neurotoxic metals, particularly for pregnant women and young children, in order to help reduce the rising incidence of ASD.

Preclinical evidences of aluminum-induced neurotoxicity in hippocampus and pre-frontal cortex of rats exposed to low doses.

Aluminum (Al) is a neurotoxicant agent implicated in several behavioral, neuropathological and neurochemical changes associated with cognitive impairments. Nevertheless, mechanisms of damage and safety concentrations are still very discussed. Thus, the main purpose of this study was to investigate whether two aluminum low doses were able to produce deleterious effects on cognition of adult rats, including oxidative stress in hippocampus and prefrontal cortex, two important areas for cognition. For this, thirty adult Wistar rats were divided into three groups: Al1 (8.3 mg/kg/day), Al2 (32 mg/kg/day) and Control (Ultrapure Water), in which all three groups received their solutions containing or not AlCl3 by intragastric gavage for 60 days. After the experimental period, the short- and long-term memories were assessed by the object recognition test and step-down inhibitory avoidance. After euthanizing, prefrontal cortex and hippocampus samples were dissected for Al levels measurement and evaluation of oxidative biochemistry. Only Al2 increased Al levels in hippocampal parenchyma significantly; both concentrations did not impair short-term memory, while long-term memory was affected in Al1 and Al2. In addition, oxidative stress was observed in prefrontal and hippocampus in Al1 and Al2. Our results indicate that, in a translational perspective, humans are subjected to deleterious effects of Al over cognition even when exposed to low concentrations, by triggering oxidative stress and poor long-term memory performance.

Al centre-powered graphitic nanozyme with high catalytic efficiency for pH-independent chemodynamic therapy of cancer.

An Al centre-powered graphitic nanozyme derived from a metal organic framework was first developed for a chemodynamic tumor treatment. By virtue of the rapid and efficient generation of ˙OH in the slightly acidic tumor microenvironment, this nanozyme afforded high anti-tumor efficacy both in living cells and in vivo.

Genome-wide identification and expression analysis of the NAC transcription factor family in tomato (Solanum lycopersicum) during aluminum stress.

BACKGROUND: The family of NAC proteins (NAM, ATAF1/2, and CUC2) represent a class of large plant-specific transcription factors. However, identification and functional surveys of NAC genes of tomato (Solanum lycopersicum) remain unstudied, despite the tomato genome being decoded for several years. This study aims to identify the NAC gene family and investigate their potential roles in responding to Al stress. RESULTS: Ninety-three NAC genes were identified and named in accordance with their chromosome location. Phylogenetic analysis found SlNACs are broadly distributed in 5 groups. Gene expression analysis showed that SlNACs had different expression levels in various tissues and at different fruit development stages. Cycloheximide treatment and qRT-PCR analysis indicated that SlNACs may aid regulation of tomato in response to Al stress, 19 of which were significantly up- or down-regulated in roots of tomato following Al stress. CONCLUSION: This work establishes a knowledge base for further studies on biological functions of SlNACs in tomato and will aid in improving agricultural traits of tomato in the future.

The effect of dealuminated jellyfish in mitigating toxicity on mice exposed to aluminum.

In the present study, the removal effect of dealuminated jellyfish on Aluminum (Al) in mice was evaluated. The results showed that the consumption of dealuminated jellyfish significantly decreased Al accumulation in the liver of mice, indicating an Al-removing effect of dealuminated jellyfish on Al-enriched mice. In addition, the effect of dealuminated jellyfish consumption on an Al-overload model was further evaluated. The result showed that the Al content in different tissues and organs of mice was significantly reduced, but it had no significant effect on the other metallic element content. These results indicated that the samples from oral administration have a certain Al-removing effect in Al-overloaded mice. Moreover, the cluster analysis of differentially expressed proteins in blood and liver showed that a high dose of dealuminated jellyfish improve the expression of amine oxidase B and enhance the effect of Al discharge.

Characterization of bone aluminum, a potential biomarker of cumulative exposure, within an occupational population from Zunyi, China.

OBJECTIVES: Aluminum (Al) is a neurotoxicant; however, efforts to understand Al toxicity are limited by the lack of a quantitative biomarker of cumulative exposure. Bone Al measurements may address this need. Here, we describe and compare non-invasive bone Al measurements with fingernail Al and Al cumulative exposure indices (CEIs). METHODS: We completed a cross-sectional study of 43 factory workers in Zunyi, China. Bone Al measurements were taken with a compact in-vivo neutron activation analysis system (IVNAA). Fingernail samples were analyzed using inductively coupled plasma mass spectrometry. CEIs, based on self-reported work history and prior literature, were calculated for the prior 5, 10, 15, 20 years and lifetime work history. Linear regressions adjusted for age and education compared fingernail Al and Al CEIs with bone Al. RESULTS: Median (interquartile range (IQR)) Al measurements were: 15 µg/g dry bone (IQR = 28) for bone Al; 34.9 µg/g (43.3) for fingernail; and 24 (20) for lifetime CEI. In adjusted regression models, an increase in 15-year CEI was significantly associated with increased bone Al (ß = 0.91, 95% confidence interval (CI): 0.16, 1.66). Associations of bone Al with 10- and 20-year CEI were approaching statistical significance (ß = 0.98, 95% CI: -0.14, 2.1; ß = 0.59, 95% CI: -0.01, 1.18, respectively). Other models were not statistically significant. CONCLUSIONS: Bone Al was significantly associated with 15-year Al CEI, but not other Al CEIs or fingernail Al. Bone Al may be a useful measure of cumulative, rather than short-term, Al exposure. Additional refinement of this method is ongoing.

Metal Ions Activate the Human Taste Receptor TAS2R7.

Divalent and trivalent salts exhibit a complex taste profile. They are perceived as being astringent/drying, sour, bitter, and metallic. We hypothesized that human bitter-taste receptors may mediate some taste attributes of these salts. Using a cell-based functional assay, we found that TAS2R7 responds to a broad range of divalent and trivalent salts, including zinc, calcium, magnesium, copper, manganese, and aluminum, but not to potassium, suggesting TAS2R7 may act as a metal cation receptor mediating bitterness of divalent and trivalent salts. Molecular modeling and mutagenesis analysis identified 2 residues, H943.37 and E2647.32, in TAS2R7 that appear to be responsible for the interaction of TAS2R7 with metallic ions. Taste receptors are found in both oral and extraoral tissues. The responsiveness of TAS2R7 to various mineral salts suggests it may act as a broad sensor, similar to the calcium-sensing receptor, for biologically relevant metal cations in both oral and extraoral tissues.

Assessment of dietary exposure of young Chinese children to aluminium residues.

The aim of this study was to assess the Al dietary exposure of young Chinese children aged 0-3 years via formulae, complementary foods and wheat-based foods. Al residue data were obtained from the national food contamination monitoring programme from 2013 to 2016, encompassing 13,833 samples of 12 food items with a detection rate of 76.0%. Food consumption data were gathered from the China National Food Consumption Survey conducted in 2015, comprising 20,172 children aged 0-3 years old. The mean dietary exposure to Al for the general population of young Chinese children was estimated at 0.76 mg/kg bw/week, which does not exceed the PTWI. The 97.5th percentile intakes of Al reached 3.42 mg/kg bw/week, more than 1.7 times the PTWI. Wheat-based foods contributed 80.5% of the Al intake for the general population of young Chinese children, while formulae and complementary foods accounted for 19.5% of the total intake. The dietary intake of Al from formulae and complementary foods accounted for 6.0% and 1.6% of PTWI, respectively. These findings suggested that dietary exposure to Al among the general population of young Chinese children was lower than the PTWI and that there are no health concerns related to this level of Al intake. However, more attention should be placed on the health risks associated with Al exposure from wheat-based foods for young consumers with high food consumption in China (97.5th percentile).

Effect of Er:YAG Laser for Women with Stress Urinary Incontinence.

PURPOSE: The aim of our study is to assess efficacy of noninvasive erbium-doped yttrium aluminium garnet laser (Er:YAG laser) for female stress urinary incontinence (SUI). MATERIALS AND METHODS: Forty-one women with SUI were included in the study and scheduled for vaginal Er:YAG laser treatment. The procedure was performed with a 2940 nm, Er:YAG laser (Fotona Smooth ™ XS, Fotona, Ljubljana, Slovenia), designed to heat up the vaginal mucosa to around 60°C. All subjects had a baseline and 6 months' posttreatment assessment that included perineal sonography and lower urinary tract symptoms. RESULTS: Significant improvements in both urinary frequency and incontinence were found 6 months after Er:YAG laser treatment when compared to the baseline results (p<0.001). The battery of questionnaires administered to patients, including the UDI-6, IIQ-7, OABSS, and POPDI-6, all showed significant improvement posttreatment (P < 0.001). The treatment efficacy for the vaginal Er:YAG laser for SUI at 6 months posttreatment was 75.5% (31/41). Bladder neck mobility by perineal ultrasonography decreased significantly (16.1 ± 6.4 mm to 10.5 ± 4.6 mm) after treatment (p=0.039). No permanent adverse events were found. CONCLUSIONS: The Er:YAG vaginal laser seems to be a safe and efficacious treatment for women with mild to moderate SUI, this being partly related to the decrease of bladder neck mobility following laser treatment.

Aluminum granuloma in a child secondary to DTaP-IPV vaccination: A case report.

Reports detailing the acute formation of aluminum granulomas, which can cause persistent, intensely pruritic nodules secondary to the administration of aluminum-containing vaccines, are infrequently described in medical literature. To our knowledge, this is the first report describing the development of an aluminum granuloma causing a persistent, pruritic nodule at the injection site following the administration of the DTaP-IPV vaccine. We present the case of a 6-year-old girl who developed a severely pruritic subcutaneous nodule on her anterior right thigh at the injection site three weeks after the administration of the aluminum-containing DTaP-IPV (Kinrix) vaccine. The nodule was eventually excised 14 months after its initial appearance, after which her symptoms resolved. Histologic inspection demonstrated a dense, deep dermal and subcutaneous nodular mixed infiltrate of lymphocytes, histiocytes, and eosinophils, with germinal center formation. The bluish, amphophilic granular cytoplasm found in most of the histiocytes is a characteristic feature of "aluminum granulomas." This adverse reaction should be considered in any patient presenting with similar findings in the weeks following a DTaP-IPV vaccination or other aluminum-containing vaccines. Furthermore, the self-limiting tendency of these nodules should not preclude affected patients from any future vaccinations, though vaccines without aluminum should be preferentially selected when possible.