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PMID: 

Pharmacol Res. 2019 Nov 16:104554. Epub 2019 Nov 16. PMID: 31743774

Abstract Title: 

Beneficial Effects of L-Carnitine Supplementation for Weight Management in Overweight and Obese Adults: An Updated Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.

Abstract: 

Despite preclinical studies demonstrating the efficacy of L-carnitine supplementation for weight management, findings in clinical setting are contradictory. Electronic bibliographical databases were systematically searched up to February 2019 with no limitation in language, including Scopus, PubMed, ISI Web of Science and Cochrane Library. Clinical trials registry platform were also searched. All randomized controlled trials (RCTs) which reported an effect of L-carnitine supplementation on obesity-related indices were included. Weighted mean difference (WMD) was estimated using a random-effect model (DerSimonian-Laird method). Eventually 43 eligible RCTs were included for quantitative analysis. Meta-analysis results revealed that L-carnitine supplementation significantly decreased weight (WMD: -1.129 kg, 95% CI: -1.590, -0.669; I: 63.4), body mass index (BMI) (WMD: -0.359 kg/m2, 95% CI: -0.552, -0.167; I:85.2) and fat mass (WMD: -1.158 kg, 95% CI: -1.763, -0.554, I:15.5). However, L-carnitine supplementation did not change body fat percentage (WMD: -0.874 %, 95% CI: -1.890, 0.142, I:98.2) or waist circumference (WMD: -0.883 mg/dl, 95% CI: -1.770, 0.004, I:74.8). L-carnitine supplementation changed weight (r = -0.98) and BMI (r = -0.67) in a non-linear fashion based on carnitine dosage and BMI according to trial duration (r = -0.04). Interestingly subgroup analysis revealed that L-carnitine showed anti-obesity effects only in overweight and obese subjects; L-carnitine decreased weight, and BMI alone when combined with other lifestyle modifications. Anthropometric indexes were not changed following L-carnitine supplementation among patients' undergoing hemodialysis. Our study revealed that L-carnitine supplementation might have a positive effects in achieving an improved body weight and BMI especially in overweight and obese subjects.

PMID: 

Dent Mater. 2015 May ;31(5):556-64. Epub 2015 Mar 6. PMID: 25749564

Abstract Title: 

Cytotoxic and genotoxic characterization of aluminum and silicon oxide nanoparticles in macrophages.

Abstract: 

OBJECTIVE: Although aluminum oxide and silicon oxide nanoparticles are currently available as dental materials, there is a lack of basic information concerning their biocompatibility. This study evaluates the biological responses of cultured macrophages (RAW264) to aluminum oxide (Al2O3NPs) and silicon oxide nanoparticles (SiO2NPs) by analyzing cytotoxicity and genotoxicity.METHODS: The nanoparticles are amorphous and spherical, with diameters of 13 nm for the Al2O3NPs and 12 nm for the SiO2NPs. The cultured RAW264 are exposed to the nanoparticles (NPs) and examined for cytotoxicity using the WST-8 cell viability and Hoechst/PI apoptosis assay, for genotoxicity by micronucleus analysis, for changes in nuclear shape (deformed nuclei) and for comet assay using confocal microscopy, and micromorphological analysis is done using scanning and transmission electron microscopes.RESULTS: Nuclei and DNA damage because of exposure to both types of NPs is observed by inmunostaining genotoxicity testing. The cytotoxicity and genotoxicity are well correlated in this study. Numerous NPs are observed as large aggregates in vesicles, but less or nonexistent NP internalization is seen in the nucleus or cytoplasm. These morphological results suggest that a primary cause of cell disruption is the chemical changes of the NPs in the low pH of vesicles (i.e., ionization of Al2O3 or SiO2) for both types of oxide NPs.SIGNIFICANCE: Although further research on the elution of NP concentrations on cell or tissue activity under simulated clinical conditions is required, NP concentrations over 200μg/mL are large enough to induce cytotoxic and genotoxic effects to cells.

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PMID: 

Int J Environ Res Public Health. 2018 05 3 ;15(5). Epub 2018 May 3. PMID: 29751492

Abstract Title: 

Aluminum Adjuvant-Containing Vaccines in the Context of the Hygiene Hypothesis: A Risk Factor for Eosinophilia and Allergy in a Genetically Susceptible Subpopulation?

Abstract: 

There are similarities between the immune response following immunization with aluminum adjuvants and the immune response elicited by some helminthic parasites, including stimulation of immunoglobulin E (IgE) and eosinophilia. Immunization with aluminum adjuvants, as with helminth infection, induces a Th2 type cell mediated immune response, including eosinophilia, but does not induce an environment conducive to the induction of regulatory mechanisms. Helminths play a role in what is known as the hygiene hypothesis, which proposes that decreased exposure to microbes during a critical time in early life has resulted in the increased prevalence and morbidity of asthma and atopic disorders over the past few decades, especially in Western countries. In addition, gut and lung microbiome composition and their interaction with the immune system plays an important role in a properly regulated immune system. Disturbances in microbiome composition are a risk factor for asthma and allergies. We propose that immunization with aluminum adjuvants in general is not favorable for induction of regulatory mechanisms and, in the context of the hygiene hypothesis and microbiome theory, can be viewed as an amplifying factor and significant contributing risk factor for allergic diseases, especially in a genetically susceptible subpopulation.

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PMID: 

J Biomed Mater Res B Appl Biomater. 2016 Feb ;104(2):241-52. Epub 2015 Feb 26. PMID: 25715832

Abstract Title: 

Investigation of the cytotoxicity of aluminum oxide nanoparticles and nanowires and their localization in L929 fibroblasts and RAW264 macrophages.

Abstract: 

The biological responses of aluminum oxide (Al2 O3 ) nanoparticles (NPs) and nanowires (NWs) in cultured fibroblasts (L929) and macrophages (RAW264) were evaluated from their cytotoxicities and micromorphologic properties. Cultured cells were exposed to Al2 O3 NPs (13 nm diameter) and Al2 O3 NWs (2-6× 200-400 nm). Cytotoxicity and genotoxicity were examined by immunostaining with fluorescence microscopy, and nanomaterial localization was studied by using scanning electron microscopy and transmission electron microscopy. The NPs were cytotoxic and genotoxic, whereas the NWs were not. The scanning electron microscopy images showed that the NPs aggregate more on the cell surface than do the NWs. The transmission electron microscopy images showed that the NPs were internalized into the vesicle and nuclei, for both cell types. In contrast, numerous solid NWs were observed as large aggregatesin vesicles, but not in nuclei. Nuclear damage was confirmed by measuring cell viability and by immunostaining for NPs. The chemical changes induced by the NPs in the vesicles or cells may cause cell damage because of their large surface area per volume. The extent of NW entrapment was not sufficient to lower the viability of either cell type.

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PMID: 

Vaccine. 2004 Aug 13 ;22(23-24):3127-35. PMID: 15297065

Abstract Title: 

Aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen-presenting cell type.

Abstract: 

Aluminum hydroxide (AlOOH) has been used for many years as a vaccine adjuvant, but little is known about its mechanism of action. We investigated in this study the in vitro effect of aluminum hydroxide adjuvant on isolated macrophages. We showed that AlOOH-stimulated macrophages contain large and persistent intracellular crystalline inclusions, a characteristic property of muscle infiltrated macrophages described in animal models of vaccine injection, as well as in the recently described macrophagic myofasciitis (MMF) histological reaction in humans. AlOOH-loaded macrophages exhibited phenotypical and functional modifications, as they expressed the classical markers of myeloid dendritic cells (HLA-DR(high)/CD86(high)/CD83(+)/CD1a(-)/CD14(-)) and displayed potent ability to induce MHC-II-restricted antigen specific memory responses, but kept a macrophage morphology. This suggests a key role of macrophages, in the reaction to AlOOH-adjuvanted vaccines and these mature antigen-presenting macrophages may therefore be of particular importance in the establishment of memory responses and in vaccination mechanisms leading to long-lasting protection.

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PMID: 

Vaccine. 1999 Oct 29 ;17 Suppl 3:S41-6. PMID: 10559533

Abstract Title: 

Vaccine risks: real, perceived and unknown.

Abstract: 

As immunizations successfully reduce the incidence of their target diseases, the vaccine community needs to evolve and recognize the increased relative prominence of vaccine safety. Just as the aviation community maintained public confidence by its continuous investment in a safety infrastructure as it evolved from propeller to jet and jumbo planes, modernization of the vaccine safety infrastructure commensurate with the current investment in vaccine development will be needed if the full promise of new vaccines made possible by the biotechnology revolution are likely to be fulfilled.

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PMID: 

J Neuropathol Exp Neurol. 2017 04 1 ;76(4):323-331. PMID: 28340105

Abstract Title: 

Morin Stain Detects Aluminum-Containing Macrophages in Macrophagic Myofasciitis and Vaccination Granuloma With High Sensitivity and Specificity.

Abstract: 

Macrophagic myofasciitis (MMF) is an inflammatory condition associated with the intramuscular (i.m.) injection of aluminum adjuvant-containing vaccines. It is clinically characterized by myalgia, weakness, and chronic fatigue and histologically by aggregates of cohesive macrophages with abundant basophilic, periodic acid-Schiff (PAS)-positive, diastase-resistant granules that percolate through the peri- and endomysium without eliciting substantial myofiber damage. The definitive diagnosis of MMF requires demonstration of aluminum within these macrophages. We evaluated the Morin stain, a simple, 2-step histochemical stain for aluminum, as a confirmatory diagnostic tool for MMF. Among 2270 muscle biopsies processed at UTSW between 2010 and 2015, a total of 12 MMF cases and 1 subcutaneous vaccination granuloma case were identified (11 pediatric, 2 adults). With the Morin stain, all 13 cases showed strong granular reactivity within the cytoplasm of macrophages but not in myofibers or connective tissue. Three cases of inflammatory myopathy with abundant macrophages (IMAM), 8 cases of granulomatous inflammation and 23 other deltoid muscle biopsies used as controls were all negative. Morin stain could be used in both formalin-fixed paraffin-embedded and cryostat sections. Thus, Morin stain detects aluminum with high sensitivity and specificity in human muscle and soft tissue and may improve the diagnostic yield of MMF and vaccination granuloma.

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PMID: 

J Inorg Biochem. 2018 04 ;181:87-95. Epub 2017 Dec 28. PMID: 29307441

Abstract Title: 

Critical analysis of reference studies on the toxicokinetics of aluminum-based adjuvants.

Abstract: 

We reviewed the three toxicokinetic reference studies commonly used to suggest that aluminum (Al)-based adjuvants are innocuous. A single experimental study was carried out using isotopic 26Al (Flarend et al., Vaccine, 1997). This study used aluminum salts resembling those used in vaccines but ignored adjuvant uptake by cells that was not fully documented at the time. It was conducted over a short period of time (28days) and used only two rabbits per adjuvant. At the endpoint, Al elimination in the urine accounted for 6% for Al hydroxide and 22% for Al phosphate, both results being incompatible with rapid elimination of vaccine-derived Al in urine. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to an oral"minimal risk level"(MRL) extrapolated from animal studies. Keith et al. (Vaccine, 2002) used a high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (Vaccine, 2011) only considered solubilized Al, with erroneous calculations of absorption duration. Systemic Al particle diffusion and neuro-inflammatory potential were omitted. The MRL they used was both inappropriate (oral Al vs. injected adjuvant) and still too high (1mg/kg/d) regarding recent animal studies. Both paucity and serious weaknesses of reference studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including both neonatal and adult exposures, to ensure their safety and restore population confidence in Al-containing vaccines.

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PMID: 

Front Immunol. 2018 ;9:2406. Epub 2018 Oct 23. PMID: 30405610

Abstract Title: 

Molecular Signature of Aluminum Hydroxide Adjuvant in Ovine PBMCs by Integrated mRNA and microRNA Transcriptome Sequencing.

Abstract: 

There have been fewstudies on the effect of aluminum hydroxide adjuvant and its influence on the immune response to vaccination. In this study, lambs received a parallel subcutaneous treatment with either commercial vaccines containing aluminum hydroxide or an equivalent dose of this compound only with the aim of identifying the activated molecular signature. Blood samples were taken from each animal at the beginning and at the end of the experiment and PBMCs isolated. Total RNA and miRNA libraries were prepared and sequenced. After alignment to the Oar3.1 reference genome and differential expression with 3 programs, gene enrichment modeling was performed. For miRNAs, miRBase and RNAcentral databases were used for detection and characterization. Three expression comparisons were made: vaccinated animals at the beginning and at the end of the treatment, adjuvanted animals at the same times, and animals of both treatments at the end of the experiment. After exposure to both treatments, a total of 2,473; 2,980 and 429 differentially expressed genes were identified in vaccinated animals, adjuvanted animals and animals at the end of both treatments, respectively. In both adjuvant and vaccine treated animals theκsignaling pathway was enriched. On the other hand, it can be observed a downregulation of cytokines and cytokine receptors in the adjuvanted group compared to the vaccinated group at the final time, suggesting a milder induction of the immune response when the adjuvant is alone. As for the miRNA analysis, 95 miRNAs were detected: 64 previously annotated in, 11 annotated inand 20 newly described. Interestingly, 6 miRNAs were differentially expressed in adjuvant treated animals, and 3 and 1 in the other two comparisons. Lastly, an integrated miRNA-mRNA expression profile was developed, in which a miRNA-mediated regulation of genes related to DNA damage stimulus was observed. In brief, it seems that aluminum-containing adjuvants are not simple delivery vehicles for antigens, but also induce endogenous danger signals that can stimulate the immune system. Whether this contributes to long-lasting immune activation or to the overstimulation of the immune system remains to be elucidated.

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PMID: 

Vaccine. 2018 09 18 ;36(39):5825-5831. Epub 2018 Aug 20. PMID: 30139653

Abstract Title: 

Aluminum in vaccines: Does it create a safety problem?

Abstract: 

For almost a century, aluminum (Al) in the form of Al oxyhydroxide (a crystalline compound), Al hydroxyphosphate (an amorphous Al phosphate hydroxide), Al phosphate, and Al potassium sulfate has been used to improve the immunogenicity of vaccines. Al is currently included in vaccines against tetanus, hepatitis A, hepatitis B, human papillomavirus, Haemophilus influenzae type b, and infections due to Streptococcus pneumoniae and Neisseria meningitidis. Official health authorities consider the inclusion of Al in most of the presently recommended vaccines to be extremely effective and sufficiently safe. However, the inclusion of Al salts in vaccines has been debated for several years because of studies that seem to indicate that chronic Al exposure through vaccine administration can interfere with cellular and metabolic processes leading to severe neurologic diseases. Children, who in their first years of life receive several vaccine doses over a reduced period of time, would be most susceptible to any risk that might be associated with vaccines or vaccine components. The main aim of this paper was to discuss the data presently available regarding Al neurotoxicity and the risk for children receiving vaccines or other pharmaceutical preparations containing Al. Analysis of the literature showed that no apparent reason exists to support the elimination of Al from vaccines for fear of neurotoxicity. The only problem that deserves attention is the suggested relationship between Al oxyhydroxide-containing vaccines and macrophagic myofaciitis or myalgic encephalomyelitis/chronic fatigue syndrome. Currently, definitive conclusions cannot be drawn on these risks and further studies must be conducted. Until then, Al remains the best solution to improve vaccine efficacy.

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