Manganese concentration in patients with encephalopathy following ephedrone use: a narrative review and analysis of case reports.

BACKGROUND: Numerous case reports describe manganese encephalopathy in patients using ephedrone (methcathinone). The aim of this narrative review of case reports was to relate manganese ion concentrations in peripheral blood to the reported neurological deficits. METHODS: International databases, including Thomson (Web of Knowledge), PubMed/Medline, Science Direct, Scopus and Google Scholar were searched for literature items published between 2007 and 2020, in which the authors measured the manganese concentration in patients taking ephedrone. RESULTS: We identified 39 patients in two case series comprising of twenty-three and twelve patients, respectively, and four case reports meeting inclusion criteria. The study showed that 93% of them had elevated blood manganese concentration in relation to the accepted norm (>219 nmol/L), and the median was 364 nmol/L. The median duration of ephedrone use in individual groups of patients was approximately 48 months, and it did not show a relationship with the manganese concentration in the blood. A greater percentage of the people with manganese concentration higher than 250 nmol/L exhibited more severe gait, speech and handwriting disorders. The median duration of ephedrone withdrawal was a month in the group of people with the highest level of manganese ions (>500 nmol/L). CONCLUSION: Manganese concentrations did not vary with the duration of ephedrone use.

Manganese Encephalopathy Caused by Homemade Methcathinone (Ephedrone) Prevalence in Poland.

Manganese encephalopathy is a known disorder in occupational medicine. A serious phenomenon has been the emergence of manganese encephalopathy in intravenous users of homemade methcathinone (ephedrone). A short survey was developed for clinical environments dealing with people who use psychoactive substances. The data were obtained from 72 rehabilitation therapy centers. Surveys carried out in about a third of Polish centers dealing with providing medical assistance to people addicted to substances other than alcohol and tobacco have shown that over 4% of people treated there had symptoms of manganese encephalopathy, of which more than half are people in whom the probability of a clinical diagnosis of this disorder is significant. It has been shown that knowledge of manganese encephalopathy is none or minimal in more than 70% of the surveyed institutions. An urgent need for personnel training in this field was pointed out. Attention was paid to the importance of disseminating good review articles on new and dynamically developing problem phenomena.

The role of manganese dysregulation in neurological disease: emerging evidence.

Manganese is an essential trace metal. The dysregulation of manganese seen in a broad spectrum of neurological disorders reflects its importance in brain development and key neurophysiological processes. Historically, the observation of acquired manganism in miners and people who misuse drugs provided early evidence of brain toxicity related to manganese exposure. The identification of inherited manganese transportopathies, which cause neurodevelopmental and neurodegenerative syndromes, further corroborates the neurotoxic potential of this element. Moreover, manganese dyshomoeostasis is also implicated in Parkinson's disease and other neurodegenerative conditions, such as Alzheimer's disease and Huntington's disease. Ongoing and future research will facilitate the development of better targeted therapeutical strategies than are currently available for manganese-associated neurological disorders.

Metal-induced neurotoxicity in a RAGE-expressing C. elegans model.

Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.

MRI Signal Intensity and Parkinsonism in Manganese-Exposed Workers.

OBJECTIVE: T1-weighted brain magnetic resonance imaging (MRI) of the basal ganglia provides a noninvasive measure of manganese (Mn) exposure, and may also represent a biomarker for clinical neurotoxicity. METHODS: We acquired T1-weighted MRI scans in 27 Mn-exposed welders, 12 other Mn-exposed workers, and 29 nonexposed participants. T1-weighted intensity indices were calculated for four basal ganglia regions. Cumulative Mn exposure was estimated from work history data. Participants were examined using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3). RESULTS: We observed a positive dose-response association between cumulative Mn exposure and the pallidal index (PI) (ß = 2.33; 95% confidence interval [CI], 0.93 to 3.74). There was a positive relationship between the PI and UPDRS3 (ß = 0.15; 95% CI, 0.03 to 0.27). CONCLUSION: The T1-weighted pallidal signal is associated with occupational Mn exposure and severity of parkinsonism.

Latent subgroups of cognitive performance in lead- and manganese-exposed Uruguayan children: Examining behavioral signatures.

OBJECTIVES: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals. METHOD: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested. RESULTS: Mean ± SD of blood Pb was 4.1 ± 2.1 µg/dL and 35% of children had blood Pb ≥ 5 µg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn. CONCLUSIONS: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children.

Ethanol increases manganese-Induced spatial learning and memory deficits via oxidative/nitrosative stress induced p53 dependent/independent hippocampal apoptosis.

Manganese (Mn) is an essential nutrient element. However, Mn is causing great environmental and occupational exposure health risk concern globally, even high rate of alcohol consumption. There is dearth of scientific information on the interaction of manganese (Mn) and ethanol (EtOH) on hippocampal functions. This study was designed to investigate the effect of EtOH on Mn - induced hippocampal toxicity with special reference to spatial learning and memory and its underlying mechanism in adults male Wistar Rats. Rats were exposed to Mn alone at 30 mg/kg or co-expose with EtOH at 1.25 and 5 g/kg body weight by oral gavage for 35 consecutive days. Morris Water Maze task was used to assessed spatial learning and memory. Subsequently, oxidative/nitrosative stress, neuro-inflammation (myeloperoxidase and cyclooxygenase-2) and protein expression of apoptotic proteins (p53 and Bax), active executioner caspase (caspase-3) and B - cell lymphoma - 2 (Bcl - 2) markers in the hippocampus were investigated. The results indicate that Mn and EtOH exposure induces spatial learning and memory deficits, increase oxidative/nitrosative stress, neuro-inflammation resulting in enhanced hippocampal apoptosis. Moreover, the results indicated that Mn co-exposure with EtOH at 1.25 and 5 g/kg body weight further exacerbates neurotoxicity in rat hippocampus when compared with single dose of Mn and EtOH alone. Collectively, EtOH increases Mn - induced oxidative/nitrosative stress, neuro-inflammation and hippocampal apoptosis via mechanism involving oxidative damages of cellular constituents, neuronal inflammation and subsequent upregulation of Bax and caspase-3 and downregulation of Bcl-2 protein expression via p53 dependent/independent pathways to induced hippocampal apoptosis associated with impaired spatial learning and memory.

The effects of manganese exposure from drinking water on school-age children: A systematic review.

The aim of this study was to analyse the published literature on the potential effects of manganese exposure from drinking water on school-age children, with emphasis on cognitive, and neurodevelopment and behavioural effects. A systematic review of up-to-date scientific evidence published from 2006 to 2017 was conducted using Science Direct. A further search was carried out using PubMed and Web of Science. A total of 21 studies were reviewed and categorised into 12 cognitive and 9 neurodevelopment and behavioural effects. The most utilised cognitive test was the Wechsler Intelligence Scale for Children (WISC) or some subtests from it. 10 of the 12 studies on cognitive effects reported an adverse effect of manganese exposure from drinking water on children. 3 out of the 9 studies on neurodevelopment and behavioural effects reported that manganese exposure from drinking water was associated with poorer neurobehavioural performances in school children. 4 others implied the presence of some sex-specific associations with manganese exposure. 1 study suggested that children suffering from attention deficit hyperactivity disorder (ADHD) may be more susceptible to manganese exposure. Another study suggested that manganese was a beneficial nutrient as well as a neurotoxicant. Regardless of the limitations of the studies analysed, the adverse effects of manganese exposure from drinking water on school-aged children is sufficiently demonstrated. Further investigation into the subject to address inconsistencies in existing studies is recommended.

Heme Oxygenase-1 protects astroglia against manganese-induced oxidative injury by regulating mitochondrial quality control.

Heme Oxygenase-1 (HO-1), a stress- responsive enzyme which catalyzes heme degradation into iron, carbon monoxide, and biliverdin, exerts a neuroprotective role involving many different signaling pathways. In Parkinson disease patients, elevated HO-1 expression levels in astrocytes are involved in antioxidant defense. In the present work, employing an in vitro model of Mn2+-induced Parkinsonism in astroglial C6 cells, we investigated the role of HO-1 in both apoptosis and mitochondrial quality control (MQC). HO-1 exerted a protective effect against Mn2+ injury. In fact, HO-1 decreased both intracellular and mitochondrial reactive oxygen species as well as the appearance of apoptotic features. Considering that Mn2+ induces mitochondrial damage and a defective MQC has been implicated in neurodegenerative diseases, we hypothesized that HO-1 could mediate cytoprotection by regulating the MQC processes. Results obtained provide the first evidence that the beneficial effects of HO-1 in astroglial cells are mediated by the maintenance of both mitochondrial fusion/fission and biogenesis/mitophagy balances. Altogether, our data demonstrate a pro-survival function for HO-1 in Mn2+-induced apoptosis that involves the preservation of a proper MQC. These findings point to HO-1 as a new therapeutic target linked to mitochondrial pathophysiology in Manganism and probably Parkinson´s disease.

Role of histone acetylation in activation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway by manganese chloride.

Manganese neurotoxicity is characterized by Parkinson-like symptoms with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studies may contribute to a good understanding of the mechanism of Parkinson's disease (PD). In this study, we first confirmed that MnCl2 can promote the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein in the nucleus or cytoplasm while increasing the binding activity of Nrf2 and antioxidant response elements, further promoting the expression of downstream target gene heme oxygenase 1 (HO-1) and leading to increase levels of reactive oxygen species (ROS) and reduce the levels of reduced glutathione (GSH). Second, we investigated the role of histone acetylation in the activation of Nrf2/HO-1 pathway by manganese chloride in rat adrenal pheochromocytoma (PC12) cells. Histone acetyltransferase inhibitor (anacardic acid) and histone deacetylase inhibitor (trichostatin A, TSA) were used as pretreatment reagents to adjust the level of histone acetylation. Here, we show that downregulation of histone acetylation can inhibit Mn-induced Nrf2 nuclear translocation and further inhibits the Mn-activated Nrf2/HO-1 pathway. This downregulation also promotes manganese-induced increase of ROS and decrease of GSH in neurons. These results suggest that the downregulation of histone acetylation may play an important role in the neurotoxicity caused by manganese and that TSA may provide new ideas and targets in treating manganese-induced Parkinson's syndrome and PD.

Influence of iron metabolism on manganese transport and toxicity.

Although manganese (Mn) is critical for the proper functioning of various metabolic enzymes and cofactors, excess Mn in the brain causes neurotoxicity. While the exact transport mechanism of Mn has not been fully understood, several importers and exporters for Mn have been identified over the past decade. In addition to Mn-specific transporters, it has been demonstrated that iron transporters can mediate Mn transport in the brain and peripheral tissues. However, while the expression of iron transporters is regulated by body iron stores, whether or not disorders of iron metabolism modify Mn homeostasis has not been systematically discussed. The present review will provide an update on the role of altered iron status in the transport and toxicity of Mn.

Severity scoring of manganese health effects for categorical regression.

Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data.

Modeling U-shaped dose-response curves for manganese using categorical regression.

INTRODUCTION: Manganese is an essential nutrient which can cause adverse effects if ingested to excess or in insufficient amounts, leading to a U-shaped exposure-response relationship. Methods have recently been developed to describe such relationships by simultaneously modeling the exposure-response curves for excess and deficiency. These methods incorporate information from studies with diverse adverse health outcomes within the same analysis by assigning severity scores to achieve a common response metric for exposure-response modeling. OBJECTIVE: We aimed to provide an estimate of the optimal dietary intake of manganese to balance adverse effects from deficient or excess intake. METHODS: We undertook a systematic review of the literature from 1930 to 2013 and extracted information on adverse effects from manganese deficiency and excess to create a database on manganese toxicity following oral exposure. Although data were available for seven different species, only the data from rats was sufficiently comprehensive to support analytical modelling. The toxicological outcomes were standardized on an 18-point severity scale, allowing for a common analysis of all available toxicological data. Logistic regression modelling was used to simultaneously estimate the exposure-response profile for dietary deficiency and excess for manganese and generate a U-shaped exposure-response curve for all outcomes. RESULTS: Data were available on the adverse effects of 6113 rats. The nadir of the U-shaped joint response curve occurred at a manganese intake of 2.70mg/kgbw/day with a 95% confidence interval of 2.51-3.02. The extremes of both deficient and excess intake were associated with a 90% probability of some measurable adverse event. CONCLUSION: The manganese database supports estimation of optimal intake based on combining information on adverse effects from systematic review of published experiments. There is a need for more studies on humans. Translation of our results from rats to humans will require adjustment for interspecies differences in sensitivity to manganese.

Grey matter abnormalities in methcathinone abusers with a Parkinsonian syndrome.

BACKGROUND: A permanent Parkinsonian syndrome occurs in intravenous abusers of the designer psychostimulant methcathinone (ephedrone). It is attributed to deposition of contaminant manganese, as reflected by characteristic globus pallidus hyperintensity on T1-weighted MRI. METHODS: We have investigated brain structure and function in methcathinone abusers (n = 12) compared to matched control subjects (n = 12) using T1-weighted structural and resting-state functional MRI. RESULTS: Segmentation analysis revealed significant (p < .05) subcortical grey matter atrophy in methcathinone abusers within putamen and thalamus bilaterally, and the left caudate nucleus. The volume of the caudate nuclei correlated inversely with duration of methcathinone abuse. Voxel-based morphometry showed patients to have significant grey matter loss (p < .05) bilaterally in the putamina and caudate nucleus. Surface-based analysis demonstrated nine clusters of cerebral cortical thinning in methcathinone abusers, with relative sparing of prefrontal, parieto-occipital, and temporal regions. Resting-state functional MRI analysis showed increased functional connectivity within the motor network of patients (p < .05), particularly within the right primary motor cortex. CONCLUSION: Taken together, these results suggest that the manganese exposure associated with prolonged methcathinone abuse results in widespread structural and functional changes affecting both subcortical and cortical grey matter and their connections. Underlying the distinctive movement disorder caused by methcathinone abuse, there is a more widespread pattern of brain involvement than is evident from the hyperintensity restricted to the basal ganglia as shown by T1-weighted structural MRI.

Analysis of a distinct speech disorder seen in chronic manganese toxicity following Ephedrone abuse.

INTRODUCTION: In the last fifteen years a new cause of chronic manganese toxicity has been recognized. It follows recreational intravenous injections of Ephedrone, synthesized from a cold remedies contained pseudoephedrine. Potassium permanganate is used as an oxidant. It presents with severe parkinsonism-dystonia and a characteristic dysarthria. OBJECTIVES: We performed a focus perceptual study of dysarthria in Ephedrone induced parkinsonism and compared the findings with the speech disorders seen in Parkinson's disease (PD) and Progressive Supranuclear Palsy (PSP). METHODS: A digital voice recording, perceptual speech analysis (Darley, 1975) [18], serial neurological assessment and Brain Magnetic Resonance (MR) imaging were performed at the Lviv regional Clinical Hospital. The results were analysed at the Institute of Neurology in London. RESULTS: Dysarthria developed after 8.5±3.2months of daily intravenous Ephedrone abuse and was an initial symptom in a third of cases. It was characterised by a robotic-flat prosody, whispering or continuous phonation, an inability to regulate pitch and volume, frozen lip articulation, a variable degree of dystonic tightness, difficulties in speech initiation and palladia, There was no nasality and swallowing was normal. In some patients speech deteriorated even after the discontinuation of Ephedrone. MR imaging, performed soon after drug cessation showed T1 signal hyperintesity in striatum and pallidum, especially in the Globus Pallidum interna. CONCLUSION: Ephedrone induced chronic manganese toxicity can lead to a mixed hypokinetic-dystonic dysarthria with a distinct dystonic pattern. Perceptual speech analysis can be a helpful ancillary investigation in the differential diagnosis of parkinsonism, and may permit the recognition of chronic manganese toxicity.

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats.

Manganese (Mn) is used in industrial metal alloys and can be released into the atmosphere during methylcyclopentadienyl manganese tricarbonyl combustion. Increased Mn deposition in the brain after long-term exposure to the metal by inhalation is associated with altered dopamine metabolism and neurobehavioral problems, including impaired motor skills. However, neurotoxic effects of short-term exposure to inhaled Mn are not completely characterized. The purpose of this study is to define the neurobehavioral and neurochemical effects of short-term inhalation exposure to Mn at a high concentration using rats. Male Sprague-Dawley rats were exposed to MnCl2 aerosol in a nose-only inhalation chamber for 3 weeks (1.2 µm, 39 mg/m(3)). Motor coordination was tested on the day after the last exposure using a rotarod device at a fixed speed of 10 rpm for 2 min. Also, dopamine transporter and dopamine receptor protein expression levels in the striatum region of the brain were determined by Western blot analysis. At a rotarod speed of 10 rpm, there were no significant differences in the time on the bar before the first fall or the number of falls during the two-minute test observed in the exposed rats, as compared with controls. The Mn-exposed group had significantly higher Mn levels in the lung, blood, olfactory bulb, prefrontal cortex, striatum, and cerebellum compared with the control group. A Mn concentration gradient was observed from the olfactory bulb to the striatum, supporting the idea that Mn is transported via the olfactory pathway. Our results demonstrated that inhalation exposure to 39 mg/m(3) Mn for 3 weeks induced mild lung injury and modulation of dopamine transporter expression in the brain, without altering motor activity.

Manganese in Whole Blood and Hair in Patients with Long-Term Home Parenteral Nutrition.

BACKGROUND: Manganese is an essential trace element and indispensable component of nutrition mixtures in long-term home parenteral nutrition (HPN) of patients. On the other hand, neurotoxic effects of excess manganese in the organism have been known for a long time. The objective of the present study was to determine manganese concentration in whole blood and hair of patients with long-term home parenteral nutrition. METHODS: We examined 16 patients (7 men and 9 women) aged from 28 to 68 years on long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily dose of manganese ranged between 80 and 470 microg/day (1.2 to 8.5 pg/kg/day). RESULTS: In the investigated patients we detected approximately a doubled value of manganese concentration in whole blood in comparison to the control group (16.2 microg/L; 12.9-20.4 microg/L and 7.4 microg/L; 6.4-8.4 microg/L). In five patients with symptoms of cholestatic hepatopathy, Mn concentration in whole blood exceeded the value of 20.0 microg/L. Magnetic resonance of the brain in four of these patients detected a hyperintense T1-signal in the globus pallidus without any clinical symptoms similar to the Parkinson's syndrome. The content of manganese in the patients' hair was also significantly increased (p < 0.04). CONCLUSIONS: The results of our study corroborate the necessity of careful monitoring of the manganese concentration in the organism during HPN, especially in patients with liver disorders. Individualized HPN with greater accessibility of variable mixtures of trace elements would certainly be greatly beneficial, at least with regard to problems associated with manganese substitution.

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.

BACKGROUND: Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation. OBJECTIVE: This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure. DESIGN: Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures. RESULTS: Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 µg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 µg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R. CONCLUSION: A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.

Manganese homeostasis in the nervous system.

Manganese (Mn) is an essential heavy metal that is naturally found in the environment. Daily intake through dietary sources provides the necessary amount required for several key physiological processes, including antioxidant defense, energy metabolism, immune function and others. However, overexposure from environmental sources can result in a condition known as manganism that features symptomatology similar to Parkinson's disease (PD). This disorder presents with debilitating motor and cognitive deficits that arise from a neurodegenerative process. In order to maintain a balance between its essentiality and neurotoxicity, several mechanisms exist to properly buffer cellular Mn levels. These include transporters involved in Mn uptake, and newly discovered Mn efflux mechanisms. This review will focus on current studies related to mechanisms underlying Mn import and export, primarily the Mn transporters, and their function and roles in Mn-induced neurotoxicity. Though and essential metal, overexposure to manganese may result in neurodegenerative disease analogous to Parkinson's disease. Manganese homeostasis is tightly regulated by transporters, including transmembrane importers (divalent metal transporter 1, transferrin and its receptor, zinc transporters ZIP8 and Zip14, dopamine transporter, calcium channels, choline transporters and citrate transporters) and exporters (ferroportin and SLC30A10), as well as the intracellular trafficking proteins (SPCA1 and ATP12A2). A manganese-specific sensor, GPP130, has been identified, which affords means for monitoring intracellular levels of this metal.

Association of plasma manganese levels with chronic renal failure.

Manganese (Mn) is an essential trace element involved in the formation of bone and in amino acid, lipid and carbohydrate metabolism. Mn excess may be neurotoxic to humans, affecting specific areas of the central nervous system. However, relatively little is known about its physiological and/or toxicological effects, and very few data are available concerning the role of Mn in chronic renal failure (CRF). This paper describes a 12-month study of the evolution of plasma Mn levels in predialysis patients with CRF and the relationship with energy and macronutrient intake. The participants in this trial were 64 patients with CRF in predialysis and 62 healthy controls. Plasma levels of creatinine, urea, uric acid, total protein and Mn were measured. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault index. The CRF patients had higher plasma levels of creatinine, urea, uric acid and Mn and a lower GFR than the controls. Plasma Mn was positively correlated with creatinine, plasma urea and plasma uric acid and was negatively correlated with the GFR and the intake of energy and macronutrients. In conclusion, CRF in predialysis patients is associated with increases in circulating levels of Mn.