SciCombinator

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Journal: Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)

630

Autism spectrum disorder is a neurodevelopmental disorder of unknown aetiology. It is suggested to involve both genetic susceptibility and environmental factors including in the latter environmental toxins. Human exposure to the environmental toxin aluminium has been linked, if tentatively, to autism spectrum disorder. Herein we have used transversely heated graphite furnace atomic absorption spectrometry to measure, for the first time, the aluminium content of brain tissue from donors with a diagnosis of autism. We have also used an aluminium-selective fluor to identify aluminium in brain tissue using fluorescence microscopy. The aluminium content of brain tissue in autism was consistently high. The mean (standard deviation) aluminium content across all 5 individuals for each lobe were 3.82(5.42), 2.30(2.00), 2.79(4.05) and 3.82(5.17) μg/g dry wt. for the occipital, frontal, temporal and parietal lobes respectively. These are some of the highest values for aluminium in human brain tissue yet recorded and one has to question why, for example, the aluminium content of the occipital lobe of a 15year old boy would be 8.74 (11.59) μg/g dry wt.? Aluminium-selective fluorescence microscopy was used to identify aluminium in brain tissue in 10 donors. While aluminium was imaged associated with neurones it appeared to be present intracellularly in microglia-like cells and other inflammatory non-neuronal cells in the meninges, vasculature, grey and white matter. The pre-eminence of intracellular aluminium associated with non-neuronal cells was a standout observation in autism brain tissue and may offer clues as to both the origin of the brain aluminium as well as a putative role in autism spectrum disorder.

Concepts: Central nervous system, Nervous system, Brain, Human brain, Cerebrum, Skull, Autism, Frontal lobe

338

The genetic predispositions which describe a diagnosis of familial Alzheimer’s disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer’s disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer’s disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer’s disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer’s disease brain tissue raise the spectre of aluminium’s role in this devastating disease.

Concepts: Alzheimer's disease, Scientific method, Protein, Neuron, Environment, Dementia, Beta amyloid, Amyloid precursor protein

307

Like the mechanisms of action as adjuvants, the pharmacodynamics of injected forms of aluminum commonly used in vaccines are not well-characterized, particularly with respect to how differences in schedules impact accumulation and how factors such as genetics and environmental influences on detoxification influence clearance. Previous modeling efforts are based on very little empirical data, with the model by Priest based on whole-body clearance rates estimated from a study involving a single human subject. In this analysis, we explore the expected acute exposures and longer-term whole-body accumulation/clearance across three vaccination schedules: the current US Centers for Disease Control and Prevention (CDC) schedule, the current CDC schedule using low aluminum or no aluminum vaccines, and Dr. Paul Thomas' “Vaccine Friendly Plan” schedule. We then study the effects of an implicit assumption of the Priest model on whether clearance dynamics from successive doses are influenced by the current level of aluminum or modeled by the assumption that a new dose has its own whole-body dynamics “reset” on the day of injection. We model two additional factors: variation (deficiency) in aluminum detoxification, and a factor added to the Priest equation to model the potential impact of aluminum itself on cellular and whole-body detoxification. These explorations are compared to a previously estimated pediatric dose limit (PDL) of whole-body aluminum exposure and provide a new statistic: %alumTox, the (expected) percentage of days (or weeks) an infant is in aluminum toxicity, reflecting chronic toxicity. We show that among three schedules, the CDC schedule results in the highest %alumTox regardless of model assumptions, and the Vaccine Friendly Plan schedule, which avoids >1 ACV per office visit results in the lowest (expected) %alumTox. These results are conservative, as the MSL is derived from data used by FDA to estimate safety of aluminum in adult humans. These results demonstrate high potential utility of modeling variation in patient responses to aluminum. More empirical data from individuals who are suspected of being intolerant of aluminum from vaccines, evidenced by high aluminum retention, neurodevelopmental disorders and/or a myriad of chronic illnesses would help answer questions on whether the model predictions can be used to estimate parameter values tied to genetic factors including genomic sequence variation and family history of chronic illnesses tied to aluminum exposure.

107

FDA regulations require safety testing of constituent ingredients in drugs (21 CFR 610.15). With the exception of extraneous proteins, no component safety testing is required for vaccines or vaccine schedules. The dosing of aluminum in vaccines is based on the production of antibody titers, not safety science. Here we estimate a Pediatric Dose Limit that considers body weight. We identify several serious historical missteps in past analyses of provisional safe levels of aluminum in vaccines, and provide updates relevant to infant aluminum exposure in the pediatric schedule considering pediatric body weight. When aluminum doses are estimated from Federal Regulatory Code given body weight, exposure from the current vaccine schedule are found to exceed our estimate of a weight-corrected Pediatric Dose Limit. Our calculations show that the levels of aluminum suggested by the currently used limits place infants at risk of acute, repeated, and possibly chronic exposures of toxic levels of aluminum in modern vaccine schedules. Individual adult exposures are on par with Provisional Tolerable Weekly Intake “limits”, but some individuals may be aluminum intolerant due to genetics or previous exposures. Vaccination in neonates and low birth-weight infants must be re-assessed; other implications for the use of aluminum-containing vaccines, and additional limitations in our understanding of neurotoxicity and safety levels of aluminum in biologics are discussed.

37

The brain pathology in autism spectrum disorders (ASD) indicates marked and ongoing inflammatory reactivity with concomitant neuronal damage. These findings are suggestive of neuronal insult as a result of external factors, rather than some type of developmental mishap. Various xenobiotics have been suggested as possible causes of this pathology. In a recent review, the top ten environmental compounds suspected of causing autism and learning disabilities were listed and they included: lead, methyl-mercury, polychorinated biphenyls, organophosphate pesticides, organochlorine pesticides, endocrine disruptors, automotive exhaust, polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers, and perfluorinated compounds. This current review, however, will focus specifically on mercury exposure and ASD by conducting a comprehensive literature search of original studies in humans that examine the potential relationship between mercury and ASD, categorizing, summarizing, and discussing the published research that addresses this topic. This review found 91 studies that examine the potential relationship between mercury and ASD from 1999 to February 2016. Of these studies, the vast majority (74%) suggest that mercury is a risk factor for ASD, revealing both direct and indirect effects. The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD.

Concepts: Brain, Causality, Factor analysis, Polycyclic aromatic hydrocarbon, Autism, Aromatic hydrocarbon, Biphenyl, Chelation therapy

28

Despite the introduction of salt iodization programmes as national measures to control iodine deficiency, several European countries are still suffering from mild iodine deficiency (MID). In iodine sufficient or mildly iodine deficient areas, iodine deficiency during pregnancy frequently appears in case the maternal thyroid gland cannot meet the demand for increasing production of thyroid hormones (TH) and its effect may be damaging for the neurodevelopment of the foetus. MID during pregnancy may lead to hypothyroxinaemia in the mother and/or elevated thyroid-stimulating hormone (TSH) levels in the foetus, and these conditions have been found to be related to mild and subclinical cognitive and psychomotor deficits in neonates, infants and children. The consequences depend upon the timing and severity of the hypothyroxinaemia. However, it needs to be noted that it is difficult to establish a direct link between maternal iodine deficiency and maternal hypothyroxinaemia, as well as between maternal iodine deficiency and elevated neonatal TSH levels at birth. Finally, some studies suggest that iodine supplementation from the first trimester until the end of pregnancy may decrease the risk of cognitive and psychomotor developmental delay in the offspring.

Concepts: Pregnancy, Infant, Thyroid-stimulating hormone, Hypothyroidism, Thyroid, Thyroid hormone, Iodine, Triiodothyronine

28

In view of the wide-spread deficiency of iron and zinc in populations dependent on plant foods, it is desirable to improve the bioavailability of the same. Specific dietary spices may alter the ultrastructure and permeability characteristics of intestines. Groups of Wistar rats were fed piperine, capsaicin and ginger containing diets for 8 weeks in order to examine their possible influence on intestinal absorption of iron, zinc and calcium. Everted segments of duodenum, jejunum and ileum portions of small intestines isolated from these rats were examined for ex vivo uptake of iron, zinc and calcium from incubations containing digesta of finger millet. Higher uptake of iron, zinc and calcium by the intestinal segments from spice-fed animals was observed. The increase in the mineral uptake was the highest for calcium with >100% in some cases. The positive influence of dietary capsaicin was more pronounced on zinc uptake as compared to that of iron. Uptake of the glutamic acid standard was 87% and 62% higher in the case of jejunal segments of rats fed piperine and ginger. The higher intestinal uptake of iron and zinc as a result of consumption of pungent spices could encourage a strategy to reduce deficiency of these trace elements prevalent in population dependent on plant based foods.

Concepts: Digestive system, Large intestine, Intestine, Small intestine, Duodenum, Ginger, Jejunum, Spice

28

Zinc which is an essential element has very important effects on growth and immune system in patients with thalassemia major ™. The effects of two oral iron chelator agents, desferrioxamine (DFO) and deferiprone (DFP), on zinc levels were investigated in previous studies and they were found to cause zinc deficiency. Zinc level alteration by the new chelator deferasirox (DFX) is not present in the literature. The aim of this study was to examine the effects of different oral chelators on serum and urine zinc levels in TM patients. Zinc levels are compared in the patients who received different chelators: only DFX, combined chelation with DFO plus DFP and the healthy control group. A total of 56 patients with TM were involved in this study: 39 patients received only DFX and 17 patients were given combined treatment DFO+DFP between August 2008 and August 2009. In addition, a control group was established from the healthy population. Blood was taken from all the patients for serum zinc levels and 24hour-urine samples were collected for urine zinc levels. Serum zinc levels were found to be 64.8±14.8μg/dL in DFX group and 66.5±15.1μg/dL in DFO+DFP group. These levels were statistically lower than that in the control group (149±54.3μg/dL) (p<0.05), but there was no statistically difference between the two different chelation groups (p>0.05). The urine zinc levels of DFX and DFO+DFP group were 662.2±428.2μg/day and 1182.3±980.3μg/day respectively (p<0.05). Urinary zinc excretion in the chelation groups (DFX and DFO+DFP) was significantly higher than the control group (395.1±208.9μg/day) (p<0.05). As a conclusion, the new chelation agent, DFX, also leads to zinc deficiency, though its urinary zinc excretion is lower. New studies are required to examine the effects of DFX on zinc extensively. Zinc levels of patients with TM should be followed up regularly and zinc supply should be given at early ages.

Concepts: Blood, Mathematics, Red blood cell, Thalassemia, Zinc, Chelation, Chelation therapy, Deferoxamine

27

Recent brain research reveals a major role of trace elements in various diseases such as multiple sclerosis, Alzheimer’s and Wilson’s disease. The majority of published tissue concentrations dates back decades, and was assessed with various methods. Little is known about hemispherical differences, the correlation of trace elements or age-dependent changes in the human brain. Thus, the aim of this study was to examine trace element concentrations in different human brain regions after whole brain formalin fixation. 549 samples of 13 brain regions were investigated in 11 deceased subjects without known history of brain pathology. Regional wet-to-dry mass ratios and concentrations of iron, copper, magnesium, manganese, calcium and zinc were determined using inductively coupled plasma mass spectrometry. Cortical gray matter revealed higher water content (wet-to-dry mass ratios 5.84-6.40) than white matter regions (wet-to-dry mass ratios 2.95-3.05). Element concentrations displayed specific regional differences. Good linear correlation of concentrations between elements was found for iron/copper as well as for manganese/magnesium (Spearman’s rank correlation coefficient 0.74 and 0.65, respectively). Significant inter-hemispherical differences were found for copper in occipital white matter, for magnesium and calcium in putamen and for iron and copper in temporal white matter. An age dependent increase was seen in cortical gray matter for calcium, for magnesium in all regions except in cortical gray matter, for copper in substantia nigra and for zinc in occipital cortex. The presented trace element concentrations can serve as a fundamental basis for further brain research. Wet-to-dry mass ratios allow a comparison with reference data from other studies.

Concepts: Spearman's rank correlation coefficient, Cerebral cortex

22

This study provides the dietary intakes of six trace elements (cadmium, chromium, copper, manganese, selenium and zinc), generally characterized by both nutritional and toxicological features depending on their exposure. Being diet the most relevant source of exposure to trace elements in non-professionally exposed subjects, we measured content of these trace elements in foods composing the typical Italian diet using inductively coupled plasma-mass spectrometry, and assessing dietary habits using a validated semi-quantitative food frequency questionnaire we eventually estimated dietary daily intake of trace elements in a Northern Italian community. In the 890 analyzed food samples, the main contributors to cadmium intake are cereals, vegetables and sweets, while cereals, beverages and vegetable are to primary source of manganese. The primary contributors for copper are cereals, fresh fruits and vegetables, while for chromium are beverages, cereals and meat. The main source of selenium intake are cereals and meat, followed by fish, seafood and milk and dairy products, while of zinc intake are meat, cereals, milk and dairy products. In our Italian population sample, the estimated median (interquartile range) dietary daily intakes are 5.00 (3.17-7.65), 56.70 (36.08-86.70) and 66.53 (40.04-101.32) μg/day for cadmium, chromium and selenium, and corresponding figures are 0.98 (0.61-1.49), 2.34 (1.46-3.52) and 8.50 (5.21-12.48) mg/day for copper, manganese and zinc. The estimated intakes are generally within the average intake reported in other European populations, and in such cases well above the daily dietary intakes recommended by national international agencies, avoiding the risk of excess or deficiency. The present estimated intake data can be used to examine a specific trace element of interest and would afford enhanced health protection from those trace elements characterized by both nutritional and toxicological effects.

Concepts: Nutrition, Milk, Metal, Diet, Seafood, Italy, Chemical elements, Biology and pharmacology of chemical elements