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Bjorklund G.,Council for Nutritional and Environmental Medicine | Chartrand M.S.,DigiCare Behavioral Research | Aaseth J.,Health Science University | Aaseth J.,Innlandet Hospital Trust
Environmental Research | Year: 2017

Manganese (Mn) is the fifth most abundant metal on earth. Although it is a well understood essential trace element, in excess, Mn is neurotoxic. Initial toxic symptoms associated with Mn are of psychiatric nature and are clinically defined as locura manganica. Neurological signs of Mn toxicity include dystonia, progressive bradykinesia, and disturbance of gait, slurring, and stuttering of speech with diminished volume. Studies indicate that children who ingested Mn in the drinking water (WMn) at or above a level of 0.241 mg/L for a minimum of three years performed more poorly in school as measured by mastery of language, mathematics, and in their overall grade average. The Mn-exposed children also performed more poorly on a battery of neurobehavioral tests. It was also found a significant association between higher WMn and lower cognitive performance, verbal function, and full-scale intelligence quotient (IQ) scores. Young children appear to make up a vulnerable group in exposed populations. Toxicity of WMn is a problem particularly in areas of industrial waste or where Mn is leaching from the soil into public drinking water. Practical and cost-effective approaches are available to remove Mn from drinking water. It is crucial to protect developing brains against Mn toxicity. © 2017 Elsevier Inc.


PubMed | University of Verona, Council for Nutritional and Environmental Medicine, National Nutrition Institute and National Research Center of Egypt
Type: | Journal: Metabolic brain disease | Year: 2017

Although the etiology and pathology of autism spectrum disorder (ASD) is still poorly understood, a number of environmental, anthropological, neurobiological and genetic factors have been related to the pathophysiology of ASD, even the impact of oxidative stress response related to the environment and nutrition intake. Usual recommended dietary habits are based on the combination of behavioral and dietary or nutraceutical interventions together with pharmacotherapy. Investigations about a reliable relationship between diet and ASD are still lacking. The present study aimed at comparing dietary regimens and habits of normally developing apparently healthy children, without diagnosed ASD, with a pediatric population of individuals affected by autistic disorder. Assessments of nutritional and anthropometric data, in addition to biochemical evaluation for nutrient deficiencies, were performed. A total of 80 children with autistic disorder and 80 healthy, normally developing pediatric individuals were enrolled in the study. Parents were asked to complete the standardized questionnaire regarding the different types of food and the proportion of a serving for their children. Biochemical analysis of micro- and macronutrients were also done. Plotting on the Egyptian sex-specific anthropometric growth (auximetric) chart, absolute weights as well as weight-related for age classes, were significantly higher in cases than healthy controls. No differences between groups were observed in regard to total kilocalories (kcal), carbohydrates, and fat intake. A total of 23.8% of children with autistic disorder vs. 11.3% in the healthy control group had a nutrient intake with features below the Recommended Dietary Allowance (RDA) of protein. Children with autistic disorder showed low dietary intake of some micronutrients; calcium (Ca), magnesium (Mg), iron (Fe), selenium (Se) and sodium (Na), also they had significantly high intake of potassium (K) and vitamin C compared to healthy controls. Serum Mg, Fe, Ca, folate and vitamin B12 in children with autistic disorder were significantly low compared with healthy children. Significant positive correlations between serum Mg, Fe, Ca, vitamin B12 and folate and their levels in food were present. These results confirmed that different nutritional inadequacy was observed in Egyptian children with autistic disorder. The evidence reported in the present study should recommend screening of the nutritional status of ASD children for nutrient adequacy to reduce these deficiencies by dietary means or by administering appropriate vitamin and mineral supplements. Nutritional intervention plan should be tailored to address specific needs.


Stejskal V.,University of Stockholm | Ockert K.,Gardatandlakarna | Bjorklund G.,Council for Nutritional and Environmental Medicine
Neuroendocrinology Letters | Year: 2013

BACKGROUND: Fibromyalgia (FM) is a disease of unknown aetiology. Inflammation could be one of the mechanisms behind this disease. OBJECTIVES: We studied the frequency and clinical relevance of metal allergy in FM patients. METHODS: Fifteen female FM patients were included in the study. Metal allergy was measured by a lymphocyte transformation test, MELISA®. Ten healthy age-matched women were used as controls for in vitro studies. Reduction of metal exposure in the FM patients was achieved by replacement of dental metal restorations and by the avoidance of known sources of metal exposure. Objective health assessment was performed 5 years after treatment. Subjective health assessment was established by a questionnaire, completed 2, 5 and in some cases 10 years after the start of the study. Follow-up MELISA was also performed. RESULTS: All FM patients tested positive to at least one of the metals tested. The most frequent reactions were to nickel, followed by inorganic mercury, cadmium and lead. Some healthy controls responded to inorganic mercury in vitro but most of the tests were negative. Objective examination 5 years later showed that half of the patients no longer fulfilled the FM diagnosis, 20% had improved and the remaining 30% still had FM. All patients reported subjective health improvement. This correlated with the normalisation of metal-specific responses in vitro. CONCLUSION: Metal allergy is frequent in FM patients. The reduction of metal exposure resulted in improved health in the majority of metal-sensitized patients. This suggests that metal-induced inflammation might be an important risk factor in a subset of patients with FM. © 2013 Neuroendocrinology Letters.


PubMed | Orenburg State University, Council for Nutritional and Environmental Medicine and Russian Society of Trace Elements in Medicine
Type: | Journal: Medical hypotheses | Year: 2016

The incidence of both obesity and autism spectrum disorders (ASD) has dramatically increased during the last decades. Moreover, the most recent studies have revealed increased risk of ASD in offspring of overweight and obese women. However, the mechanisms of association between ASD and maternal obesity are unknown. Taking into account the existing data indicating the association between mercury (Hg) exposure and development of obesity and ASD, we hypothesize that Hg may serve as an additional link between maternal obesity and ASD. In particular, it is supposed that obesity is associated with excessive accumulation of Hg in the maternal organism. After conception, the fetus is developing in the conditions of Hg overload within the body of obese women thus predisposing to the development of ASD. The proposed hypothesis may be confirmed by the existing data. In particular, previous studies demonstrated that overweight and obese persons are characterized by a significantly higher level of Hg in hair, blood and urine than the lean ones. Therefore, an obese organism is characterized by elevated Hg burden that may be transferred to the fetus during pregnancy. Moreover, multiple studies have demonstrated a tight association between maternal and children Hg status being indicative of placental transfer of metal from maternal organism to offspring. Finally, a growing body of data indicates the influence of Hg exposure and Hg status on the risk of ASD in children. However, additional experimental and clinical studies are required to prove the hypothesis and provide novel data on the role of Hg in maternal obesity-associated ASD development. In particular, the contribution of Hg to ASD development in children from obese mothers should be determined. If a significant role of Hg in maternal obesity ASD risk will be confirmed, this will open additional perspectives of risk modification. Taking into account the universal mechanisms of Hg toxicity, transport, and accumulation, further preventive actions may be undertaken to reduce the risk of Hg toxicity and Hg-associated ASD development. In particular, it is supposed that the use of Hg chelators (like N,Nbis-(2-mercaptoethyl)isophthalamide, NMBI), antioxidants, and anti-inflammatory compounds prior or during pregnancy may have a beneficial effect. However, the safety of such actions should repeatedly be tested to avoid adverse health effects in a developing fetus.


PubMed | Al - Azhar University of Egypt, University of Verona, Council for Nutritional and Environmental Medicine and National Research Center of Egypt
Type: Journal Article | Journal: Metabolic brain disease | Year: 2016

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social, communication, and behavioral development. Recent evidence supported but also questioned the hypothetical role of compounds containing mercury (Hg) as contributors to the development of ASD. Specific alterations in the urinary excretion of porphyrin-containing ring catabolites have been associated with exposure to Hg in ASD patients. In the present study, the level of urinary porphyrins, as biomarkers of Hg toxicity in children with ASD, was evaluated, and its correlation with severity of the autistic behavior further explored. A total of 100 children was enrolled in the present study. They were classified into three groups: children with ASD (40), healthy controls (40), and healthy siblings of the ASD children (20). Children with ASD were diagnosed using DSM-IV-TR, ADI-R, and CARS tests. Urinary porphyrins were evaluated within the three groups using high-performance liquid chromatography (HPLC), after plasma evaluation of mercury (Hg) and lead (Pb) in the same groups. Results showed that children with ASD had significantly higher levels of Hg, Pb, and the porphyrins pentacarboxyporphyrin, coproporphyrin, precoproporphyrin, uroporphyrins, and hexacarboxyporphyrin compared to healthy controls and healthy siblings of the ASD children. However, there was no significant statistical difference in the level of heptacarboxyporphyrin among the three groups, while a significant positive correlation between the levels of coproporphyrin and precoproporphyrin and autism severity was observed. Mothers of ASD children showed a higher percentage of dental amalgam restorations compared to the mothers of healthy controls suggesting that high Hg levels in children with ASD may relate to the increased exposure to Hg from maternal dental amalgam during pregnancy and lactation. The results showed that the ASD children in the present study had increased blood Hg and Pb levels compared with healthy control children indicating that disordered porphyrin metabolism might interfere with the pathology associated with the autistic neurologic phenotype. The present study indicates that coproporphyrin and precoproporhyrin may be utilized as possible biomarkers for heavy metal exposure and autism severity in children with ASD.


Chirumbolo S.,University of Verona | Bjorklund G.,Council for Nutritional and Environmental Medicine
European Journal of Cancer | Year: 2016

Wnt5a has been recently reported as a possible triggering factor of adipocyte de-differentiation into an adipocyte-derived fibroblast in the tumour microenvironment of pancreas cancer. The Wnt/β-catenin pathway was described in processes involving de-differentiation and epithelial-mesenchymal transition but some Wnt family-belonging molecules exert an adipogenic role on adipocyte, while other ones, such as Wnt10b or Wnt3a, an anti-adipogenic role. Although this ability depends on the different tumoural microenvironments, it is intriguing to ascertain if some Wnt molecules, participating in the non-canonical pathway, may be targeted as fundamental factors able to trigger the desmoplastic reaction of peritumoural white adipose tissue. © 2016 Elsevier Ltd


PubMed | University of Verona and Council for Nutritional and Environmental Medicine
Type: Review | Journal: International journal of molecular sciences | Year: 2017

In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The PERM hypothesis suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch.


Li S.-O.,Mudanjiang Medical University | Wang J.-L.,Mudanjiang Medical University | Bjorklund G.,Council for Nutritional and Environmental Medicine | Zhao W.-N.,Mudanjiang Medical University | Yin C.-H.,Mudanjiang Medical University
NeuroReport | Year: 2014

Trace elements play a critical role in the pathogenesis of autism spectrum disorders (ASD). The aim of this study was to investigate the serum levels of zinc (Zn) and copper (Cu) in Chinese children with ASD. Sixty patients (48 males, 12 females) diagnosed with ASD and 60 healthy sex-matched and age-matched control participants were assessed for serum Zn and Cu content at admission. The severity of ASD was also evaluated using the Childhood Autism Rating Scale (CARS) score. The results indicated that the mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD compared with normal cases (P<0.001, respectively), whereas serum Cu levels were significantly higher (P<0.001). There was a significant negative association between Zn/Cu and CARS scores (r=-0.345, P=0.007). On the basis of the receiver operating characteristic curve, the optimal cut-off value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.665, which yielded a sensitivity of 90.0% and a specificity of 91.7%; the area under the curve was 0.968 (95% confidence interval, 0.943-0.993). In conclusion, these results suggested an association between serum levels of Zn and Cu and ASD among Chinese patients, and the Zn/Cu ratio could be considered a biomarker of ASD. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Bjorklund G.,Council for Nutritional and Environmental Medicine
Nutrition and Cancer | Year: 2015

Adjuvant Nutritional Intervention in Cancer (ANICA) was a clinical study carried out in Denmark in the 1990s with 32 typical patients with breast cancer, aged 32-81 yr and classified high risk because of tumor spread to the lymph nodes. The patients received standard therapy for their breast cancer, but got from the start additionally an adjuvant therapy in form of a cocktail consisting of Vitamin C (2,850 mg/day), vitamin E (2,500 IU/day), beta-carotene (32.5 IU/day), selenium (Se; 387 micrograms/day), various other vitamins and essential trace elements, essential fatty acids (1.2 g gamma-linolenic acid/day and 3.5 g omega-3 PUFAs/day), and coenzyme Q10 (CoQ10, 90 mg/day). The protocol was later changed, with reduction of the Se intake and more coenzyme Q10 than when the study was started. The average survival of high-risk breast patients in the study was 50% after 5 yr, whereas for low-risk breast cancer patients (without metastases in the axilla when treatment was started), the average survival was 90% after ten years. The main investigator died, and the final report from the ANICA study was therefore never written. However, the published preliminary results from the trial were very promising; it seems, therefore, important to follow-up this study. Copyright © 2015, Taylor & Francis Group, LLC.


Stejskal V.,University of Stockholm | Reynolds T.,Burton | Bjorklund G.,Council for Nutritional and Environmental Medicine
Journal of Trace Elements in Medicine and Biology | Year: 2015

Background: Connective tissue disease (CTD) is a group of inflammatory disorders of unknown aetiology. Patients with CTD often report hypersensitivity to nickel. We examined the frequency of delayed type hypersensitivity (DTH) (Type IV allergy) to metals in patients with CTD. Methods: Thirty-eight patients; 9 with systemic lupus erythematosus (SLE), 16 with rheumatoid arthritis (RA), and 13 with Sjögren's syndrome (SS) and a control group of 43 healthy age- and sex-matched subjects were included in the study. A detailed metal exposure history was collected by questionnaire. Metal hypersensitivity was evaluated using the optimised lymphocyte transformation test LTT-MELISA® (Memory Lymphocyte Immuno Stimulation Assay). Results: In all subjects, the main source of metal exposure was dental metal restorations. The majority of patients (87%) had a positive lymphocyte reaction to at least one metal and 63% reacted to two or more metals tested. Within the control group, 43% of healthy subjects reacted to one metal and only 18% reacted to two or more metals. The increased metal reactivity in the patient group compared with the control group was statistically significant (P < 0.0001). The most frequent allergens were nickel, mercury, gold and palladium. Conclusions: Patients with SLE, RA and SS have an increased frequency of metal DTH. Metals such as nickel, mercury and gold are present in dental restorative materials, and many adults are therefore continually exposed to metal ions through corrosion of dental alloys. Metal-related DTH will cause inflammation. Since inflammation is a key process in CTDs, it is possible that metal-specific T cell reactivity is an etiological factor in their development. The role of metal-specific lymphocytes in autoimmunity remains an exciting challenge for future studies. © 2015 Elsevier GmbH.

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