Associations among environmental exposure to trace elements and biomarkers of early kidney damage in the pediatric population.

BACKGROUND: In kidney damage, molecular changes can be used as early damage kidney biomarkers, such as Kidney Injury Molecule-1 and Neutrophil gelatinase-associated lipocalin. These biomarkers are associated with toxic metal exposure or disturbed homeostasis of trace elements, which might lead to serious health hazards. This study aimed to evaluate the relationship between exposure to trace elements and early damage kidney biomarkers in a pediatric population. METHODS: In Tlaxcala, a cross-sectional study was conducted on 914 healthy individuals. The participants underwent a medical review and a socio-environmental questionnaire. Five early damage kidney biomarkers were determined in the urine with Luminex, and molybdenum, copper, selenium, nickel, and iodine were measured with ICP-Mass. RESULTS: The eGFR showed a median of 103.75 mL/min/1.73 m2. The median levels for molybdenum, copper, selenium, nickel, and iodine were 24.73 ng/mL, 73.35 ng/mL, 4.78 ng/mL, 83.68 ng/mL, and 361.83 ng/mL, respectively. Except for molybdenum and nickel, the other trace elements had significant associations with the eGFR and the early kidney damage biomarkers. Additionally, we report the association of different exposure scenarios with renal parameters. DISCUSSION: and Conclusions. Among the explored metals, exposure to Cu and iodine impairs renal function. In contrast, Se may manifest as a beneficial metal. Interactions of Mo-Se and Mo-Iodine seem to alter the expression of NGAL; Mo-Cu for CLU; Mo-Cu, Mo-Se, and Mo-iodine for Cys-C and a-1MG; and Mo-Cu and Mo-iodine for KIM-1; were noticed. Our study could suggest that trace element interactions were associated with early kidney damage biomarkers.

Systemic lupus erythematosus combined with Wilson's disease: a case report and literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) and Wilson's disease (WD) are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, making it challenging to diagnose. CASE REPORT: We present the case of a 9-year-old girl who initially presented with proteinuria, haematuria, pancytopenia, hypocomplementemia, and positivity for multiple autoantibodies. She was diagnosed with SLE, and her blood biochemistry showed elevated liver enzymes at the time of diagnosis. Despite effective control of her symptoms, her liver enzymes remained elevated during regular follow-up. Laboratory tests revealed decreased serum copper and ceruloplasmin levels, along with elevated urinary copper. Liver biopsy revealed chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and a trend towards local cirrhosis. Genetic sequencing revealed compound heterozygous mutations in the ATP7B gene, confirming the diagnosis of SLE with WD. The girl received treatment with a high-zinc/low-copper diet, but her liver function did not improve. Upon recommendation following multidisciplinary consultation, she underwent liver transplantation. Unfortunately, she passed away on the fourth day after the surgery. CONCLUSIONS: SLE and WD are diseases that involve multiple systems and organs in the body, and SLE complicated with WD is rarely encountered in the clinic; therefore, it is easy to misdiagnose. Because penicillamine can induce lupus, it is not recommended. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment with WD. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated with WD.

Teaching NeuroImage: Neuroimaging Features of Wilson Disease.

A 13-year-old boy of nonconsanguineous parents presented with abnormal body movements, gait difficulty, and slurring of speech for 2 years. On examination, he had rigidity, dystonia, dysarthria, and drooling. Ophthalmologic examination revealed bilateral Kayser-Fleischer rings. He had elevated serum "free" copper levels (41.2 µg/dL [range:10-15]), 24-hour urine copper levels (895.7 µg/d [range:<60]), and reduced serum ceruloplasmin levels (4.3 mg/dL (range:20-40]). MRI revealed "face of giant panda" appearance (Figure A), T2-fluid attenuated inversion recovery hyperintensities (Figure, B and C), and frontal cystic encephalomalacic changes (Figure D), suggestive of Wilson disease (WD). Face of giant panda in WD, first described by Hitoshi et al.,1 is due to high signal intensity in tegmentum with normal signals in red nuclei forming the eyes, normal signals of pars reticulata (lateral portion) of substantia nigra forming the ears, and hypointensity of superior colliculus forming the chin.2 Bilateral cystic changes are less commonly reported in WD.3 Recognizing diverse neuroimaging signatures beyond well-known findings in WD enhances diagnostic accuracy.

Relationships Between Urinary Metals and Diabetes Traits Among Mexican Americans in Starr County, Texas, USA.

Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of diabetes and diabetes-associated mortality. We used multivariable linear regression to quantify the differences in homeostatic model assessments for pancreatic ß-cell function, insulin resistance, and insulin sensitivity (HOMA-ß, HOMA-IR, HOMA-S, respectively), plasma insulin, plasma glucose, and hemoglobin A1c (HbA1c) associated with increasing urinary metal concentrations. Quantile-based g-computation was utilized to assess mixture effects. After multivariable adjustment, urinary arsenic and molybdenum were associated with lower HOMA-ß, HOMA-IR, and plasma insulin levels and higher HOMA-S. Additionally, higher urinary copper levels were associated with a reduced HOMA-ß. Lastly, a higher concentration of the 8 metal mixtures was associated with lower HOMA-ß, HOMA-IR, and plasma insulin levels as well as higher HOMA-S. Our data indicate that arsenic, molybdenum, copper, and this metal mixture are associated with alterations in measures of glucose homeostasis among non-diabetics in Starr County. This study is one of the first to comprehensively evaluate associations of urinary metals with glycemic measures in a high-risk Mexican American population.

Effects of multi-metal exposure on the risk of diabetes mellitus among people aged 40-75 years in rural areas in southwest China.

AIMS/INTRODUCTION: Metals play an important role in diabetes mellitus. This cross-sectional study aimed to evaluate the overall, individual and interactive effects of multi-metal exposure on the prevalence of diabetes mellitus, impaired fasting glucose (IFG) rate and fasting blood glucose (FBG) levels. MATERIALS AND METHODS: The FBG levels of a study population from a cadmium (Cd)-polluted area (n = 250) and an unpolluted area (n = 204), and the metal levels, including magnesium, calcium (Ca), iron (Fe), zinc (Zn), arsenic (As), Cd, copper and lead (Pb) in blood and urine were detected. The study population was divided into a normal fasting glucose group, an IFG group and a diabetes mellitus group on the basis of FBG levels. RESULTS: The IFG rate and diabetes mellitus prevalence were negatively associated with blood Cd and urine Zn levels (IFG rate: odds ratio [OR] 0.780, 95% confidence interval [CI] 0.655-0.928; OR 0.622, 95% CI 0.465-0.831. Diabetes mellitus prevalence: OR 0.506, 95% CI 0.288-0.888; OR 0.609, 95% CI 0.395-0.939), the IFG rate was positively associated with urine Fe levels (OR 1.876, 95% CI 1.290-2.778), and diabetes mellitus prevalence was positively associated with urine Pb and blood Fe levels (OR 1.185, 95% CI 1.022-1.376; OR 1.008, 95% CI 1.001-1.014). A linear negative correlation was observed between FBG levels and blood Cd, and non-linear inverted U-shaped associations were found between FBG levels and Zn, Pb and copper in urine. CONCLUSIONS: This research suggests that multi-metal exposure, especially Cd, Fe, Zn, copper and Pb, is linked to diabetes mellitus, and the interactive effects of multiple metals require further exploration.

Copper chelation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Disturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson's disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that Cu2+-selective chelation with trientine dihydrochloride may slow or reverse disease progression in HCM. The aim of this study was, therefore to explore the clinical efficacy, safety and tolerability of trientine in HCM. METHODS: In this medicines and healthcare products regulatory agency (MHRA) registered open-label pilot study, we treated 20 HCM patients with trientine for 6 months. Patients underwent a comprehensive assessment schedule including separate cardiac magnetic resonance imaging (CMR) and CMR 31P-spectroscopy at baseline and end of therapy. Predefined end points included changes in left ventricular mass (LVM), markers of LV fibrosis, markers of LV performance and myocardial energetics. Ten matched patients with HCM were studied as controls. RESULTS: Trientine treatment was safe and tolerated. Trientine caused a substantial increase in urinary copper excretion (0.42±0.2 vs 2.02±1.0, p=0.001) without affecting serum copper concentrations. Treatment was associated with significant improvements in total atrial strain and global longitudinal LV strain using both Echo and CMR. LVM decreased significantly in the treatment arm compared with the control group (-4.2 g v 1.8 g, p=0.03). A strong trend towards an absolute decrease in LVM was observed in the treatment group (p=0.06). These changes were associated with a significant change in total myocardial volume driven by a significant reduction in extracellular matrix (ECM) volume (43.83±18.42 mL vs 41.49±16.89 mL, p=0.04) as opposed to pure cellular mass reduction and occurred against a background of significant ECM volume increase in the control group (44.59±16.50 mL vs 47.48±19.30 mL, p=0.02). A non-significant 10% increase in myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio with trientine therapy (1.27±0.44 vs 1.4±0.39) was noted. CONCLUSIONS: Cu2+-selective chelation with trientine in a controlled environment is safe and a potential future therapeutic target. A phase 2b trial is now underway.

Ratiometric fluorescence and colorimetric dual-mode sensing platform based on carbon dots for detecting copper(II) ions and D-penicillamine.

A sensing platform with both ratiometric fluorescence and colorimetric responses towards copper(II) ions (Cu2+) and D-penicillamine (D-pen) was constructed based on carbon dots (CDs). o-Phenylenediamine (OPD) was employed as a chromogenic development reagent for reaction with Cu2+ to generate the oxidation product 2,3-diaminophenazine (oxOPD), which not only emits green fluorescence at 555 nm, but also quenches the blue fluorescence of CDs at 443 nm via the inner filter effect (IFE) and Förster resonance energy transfer (FRET). Additionally, oxOPD exhibits obvious absorption at 420 nm. Since the intense chelation affinity of D-pen to Cu2+ greatly inhibits the oxidation of OPD, the intensity ratio of fluorescence at 443 nm to that at 555 nm (F443/F555) and the absorbance at 420 nm (A420) were conveniently employed as spectral response signals to represent the amount of D-pen introduced into the testing system. This dual-signal sensing platform exhibits excellent selectivity and sensitivity towards both Cu2+ and D-pen, with low detection limits of 0.019 µM and 0.092 µM, respectively. In addition, the low cytotoxicity of the testing reagents involved in the proposed sensing platform facilitates its application for live cell imaging.

Biochemical testing for the diagnosis of Wilson's disease: A systematic review.

BACKGROUND: Wilson's disease (WD) is a rare inherited disorder that leads to copper accumulation in the liver, brain, and other organs. WD is prevalent worldwide, with an occurrence of 1 per 30,000 live births. Currently, there is no gold standard diagnostic test for WD. The objective of this systematic review is to determine the diagnostic accuracy for WD of three biochemical tests, namely hepatic copper, 24-hour urinary copper, and ceruloplasmin using the Leipzig criteria. METHODS: Adhering to PRISMA guidelines, databases including PubMed/MEDLINE, CINAHL Plus, Web of Science, and Cochrane were searched. Studies that comprised of confirmed or suspected WD along with normal populations were included with adult and pediatric group. The sensitivity, specificity, negative predictive value and positive predictive value were computed using RevMan 5.4. RESULTS: Nine studies were included. The best practice evidence for 24-hour urinary copper test ranged from a cutoff value of 0.64-1.6 µmol/24 h (N = 268; sensitivity = 75.6%, specificity = 98.3%). Hepatic copper test was optimally cutoff based on the ROC curve analysis at 1.2 µmol/g yielding a power of 96.4% sensitivity and 95.4% specificity (N = 1,150); however, the tried and tested 4 µmol/g cutoff, with 99.4% sensitivity and 96.1% specificity, is more widely accepted. The ceruloplasmin test cutoff value was found to be ranging from 0.14 to 0.2 g/L (N = 4,281; sensitivity = 77.1%-99%, specificity = 55.9%-82.8%). CONCLUSION: This paper provides a large-scale analysis of current evidence pertaining to the biochemical diagnosis of WD employing the Leipzig criteria. The laboratory values are typically based on specific subgroups based on age, ethnicity, and clinical subgroups. The findings of this systematic review must be used with caution, given the over- or under-estimation of the index tests.

Copper Resistance Promotes Fitness of Methicillin-Resistant Staphylococcus aureus during Urinary Tract Infection.

Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis, S. aureus, S. epidermidis, and S. saprophyticus. MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL, exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus. Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI. IMPORTANCE Urinary tract infection (UTI) is an extremely common infectious condition affecting people throughout the world. Increasing antibiotic resistance in pathogens causing UTI threatens our ability to continue to treat patients in the clinics. Better understanding of the host-pathogen interface is critical for development of novel interventional strategies. Here, we sought to elucidate the role of copper in host-Staphylococcus aureus interaction during UTI. Our results reveal that copper is mobilized to the urine as a host response in patients with UTI. Our findings from the murine model of UTI demonstrate that copper resistance is involved in the fitness of methicillin-resistant S. aureus (MRSA) during interaction with the host. We also establish a critical link between adaptation to copper stress and iron homeostasis in S. aureus.

Neuropsychiatric Manifestations of Wilson Disease: Correlation with MRI and Glutamate Excitotoxicity.

This study aims to identify neuropsychiatric manifestations in neurological Wilson disease (NWD), and their correlation with MRI changes and glutamate excitotoxicity. Forty-three consecutive patients with NWD from a tertiary care teaching hospital were evaluated prospectively who fulfilled the inclusion criteria. The neuropsychiatric evaluation was done using Neuropsychiatric Inventory (NPI) battery that assesses 12 domains including delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor activity, appetite change, and abnormal nighttime behavior. Cranial MRI was done using a 3 T machine, and locations of signal changes were noted including the total number of MRI lesions. Serum glutamate level was measured by a fluorescence microplate reader. Abnormal NPI in various domains and total NPI scores were correlated with MRI lesions, serum and urinary copper, and glutamate level. The median age of the patients was 16 years. Forty-one (48.8%) patients had cognitive impairment and 37 (86%) had movement disorder. Neurobehavioral abnormality was detected in all-commonest being agitation (90.7%) followed by appetite change (81.4%), elation (74.4%), irritability (69.8%), anxiety (67.4%), depression (65.1%), apathy (44.2%), night time abnormal behavior (32.6%), aberrant motor behavior (20.9%), delusions (16.3%), and hallucination (18.6%). The thalamic lesion was associated with depression, globus pallidus with depression and anxiety, caudate with anxiety and agitation, brainstem with irritability, and frontal cortex with apathy. Serum glutamate level was higher in NWD. NPI sum score correlated with MRI load and glutamate level. Varying severity of neurobehavioral abnormalities are common in the patients with NWD and correlate with the location of MRI lesion and glutamate level.

Association of Heavy Metals with Overall Mortality in a Taiwanese Population.

Previous studies have shown links between heavy metals and many health issues. However, data on the association between heavy metals and mortality in the general population are still limited. Therefore, the aim of this study was to investigate the relationship between heavy metals and overall mortality in the general population. We enrolled 2497 participants (1001 males and 1496 females) living in southern Taiwan, and measured levels of seven heavy metals: lead (Pb) in blood and cadmium (Cd), nickel (Ni), copper (Cu), chromium (Cr), manganese (Mn) and arsenic (As) in urine. The median follow-up period was 41.8 (4-50) months, during which 40 (1.6%) patients died. Compared to the participants who survived, those who died had higher urine Cd, higher urine Cu and lower urine Mn levels. Multivariate analysis showed that high urine Cd (per 1 µg/L; hazard ratio [HR], 1.352; 95% confidence interval [CI], 1.089-1.680; p = 0.006), high urine Cu (per 1 µg/dL; HR, 1.350; 95% CI, 1.151-1.583; p < 0.001), and low urine Mn (per 1 µg/L; HR, 0.717; 95% CI, 0.557-0.923; p = 0.010) were associated with increased overall mortality. In conclusion, our results demonstrated that high levels of urine Cd and Cu and low urine Mn level were associated with increased overall mortality in the general population.

Copper concentration in erythrocytes, platelets, plasma, serum and urine: influence of physical training.

BACKGROUND: Physical training produces changes in the extracellular and intracellular concentrations of trace minerals elements. To our knowledge, only three compartments have been studied simultaneously. The aim of the present study was to analyze the influence of physical training on extracellular (serum, plasma and urine) and intracellular (erythrocytes and platelets) concentrations of Copper (Cu). METHODS: Forty young men participated in this study. The participants were divided into a training group (TG; n = 20; 18.15 ± 0.27 years; 68.59 ± 4.18 kg; 1.76 ± 0.04 m) and a control group (CG; n = 20; 19.25 ± 0.39 years; 73.45 ± 9.04 kg; 1.79 ± 0.06 m). The TG was formed by semi-professional soccer players from a youth category with a regular training plan of 10 h/week. All of them had been participating in high level competitions and had trained for at least 5 years. Plasma, serum, urine, erythrocyte and platelet samples of Cu were obtained and analyzed by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: The TG showed lower concentrations of Cu in erythrocytes (p < 0.05) despite similar intakes. There were no significant differences in Cu concentrations in plasma, serum, urine and platelets although the trend was similar to that observed in erythrocytes. CONCLUSIONS: The assessment of trace element concentrations should be carried out in both extracellular and intracellular compartments to obtain a proper evaluation and to identify possible deficiencies of the element. We believe that additional Cu supplementation is needed in athletes who perform physical training regularly.

Evaluation of the release of nickel and titanium under orthodontic treatment.

The metal alloys used in dentistry are made mainly of nickel (Ni), titanium (Ti), and other elements such as molybdenum (Mo), zirconium (Zr), iron (Fe), tin (Sn), chrome (Cr), carbon (C), copper (Cu) and niobium (Nb) which can release metal ions in unstable environments. The aim of this work was determine the salivary pH before and during orthodontic treatment; evaluate the release of metal ions, mainly Ni and Ti, in urine and saliva using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES); and evaluate the corrosion using Scanning Electronic Microscopy (SEM). In this study, we selected 35 individuals under orthodontic treatment, from whom saliva and urine samples were collected in 3 stages: (a) basal, (b) at 3 and (c) 6 months after the placement of the fixed appliances. SEM analyzed the Ni-Ti (0.016″) and stainless steel (SS) (0.016 × 0.022″) archs after 1 month of being in contact with the oral cavity. Statistical analysis was performed with Stata using the ANOVA model of repeated measures with a p < 0.05. A statistically significant difference in the concentration of Ni in saliva were found between 3 and 6 months of intervention and Ti in urine was found 3 and 6 months.

High-Performance Flexible Electrochemical Heavy Metal Sensor Based on Layer-by-Layer Assembly of Ti3C2Tx/MWNTs Nanocomposites for Noninvasive Detection of Copper and Zinc Ions in Human Biofluids.

A flexible electrochemical heavy metal sensor based on a gold (Au) electrode modified with layer-by-layer (LBL) assembly of titanium carbide (Ti3C2Tx) and multiwalled carbon nanotubes (MWNTs) nanocomposites was successfully fabricated for the detection of copper (Cu) and zinc (Zn) ions. An LBL drop-coating process was adopted to modify the surface of Au electrodes with Ti3C2Tx/MWNTs treated via ultrasonication to fabricate this novel nanocomposite electrode. In addition, an in situ simultaneous deposition of "green metal" antimony (Sb) and target analytes was performed to improve the detection performance further. The electrochemical measurement was realized using square wave anodic stripping voltammetry (SWASV). Moreover, the fabricated sensor exhibited excellent detection performance under the optimal experimental conditions. The detection limits for Cu and Zn are as low as 0.1 and 1.5 ppb, respectively. Furthermore, Cu and Zn ions were successfully detected in biofluids, that is, urine and sweat, in a wide range of concentration (urine Cu: 10-500 ppb; urine Zn: 200-600 ppb; sweat Cu: 300-1500 ppb; and sweat Zn: 500-1500 ppb). The fabricated flexible sensor also possesses other advantages of ultra-repeatability and excellent stability. Thus, these advantages provide a great possibility for the noninvasive smart monitoring of heavy metals in the future.

Associations of Heavy Metals with Metabolic Syndrome and Anthropometric Indices.

Previous studies have revealed associations between heavy metals and extensive health problems. However, the association between heavy metals and metabolic problems remains poorly defined. This study aims to investigate relationships between heavy metals and metabolic syndrome (MetS), lipid accumulation product (LAP), visceral adiposity index (VAI), and anthropometric indices, including body roundness index (BRI), conicity index (CI), body adiposity index (BAI), and abdominal volume index (AVI). We conducted a health survey of people living in southern Taiwan. Six heavy metals were measured: lead (Pb) in blood and nickel (Ni), chromium (Cr), manganese (Mn), arsenic (As), and copper (Cu) in urine. A total of 2444 participants (976 men and 1468 women) were enrolled. MetS was defined according to the Adult Treatment Panel III for Asians. Multivariable analysis showed that participants with high urine Ni (log per 1 µg/L; odds ratio (OR): 1.193; 95% confidence interval (CI): 1.019 to 1.397; p = 0.028) and high urine Cu (log per 1 µg/dL; OR: 3.317; 95% CI: 2.254 to 4.883; p < 0.001) concentrations were significantly associated with MetS. There was a significant trend of a stepwise increase in blood Pb and urine Ni, As, and Cu according to the number of MetS components (from 0 to 5, a linear p ≤ 0.002 for trend). For the determinants of indices, urine Cu was positively correlated with LAP, BRI, CI, and VAI; blood Pb was positively correlated with BRI, BAI, and AVI; urine Ni was positively correlated with LAP. High urine Cu and urine Ni levels were significantly associated with MetS, and there was a significant trend for stepwise increases in blood Pb and urine Ni, As, and Cu, accompanied by an increasing number of MetS components. Furthermore, several indices were positively correlated with urine Cu, urine Ni, and blood Pb.

Effects of exposure to high temperatures on serum, urine and sweat concentrations of iron and copper.

The objective of this research was to determine the acute effect of a maximum test until exhaustion in normothermia and hyperthermia, and after repeated exposure to heat at high temperatures on the homeostasis of Fe and Cu. The sample was composed of twenty-nine male university students. The participants were divided into a control group (CG) and an experimental group (EG). All of them underwent an incremental test until exhaustion in normothermia and hyperthermia before and after the repeated exposure of EG to heat at high temperatures, consisting of 9 heat acclimatisation sessions in the sauna. Samples of urine and blood were taken before and after each test. Additionally, sweat samples were collected in the hyperthermia test. The samples were frozen at -80 °C for further analysis by ICP-MS. None of the metal concentrations in serum were affected by hyperthermia or exposure to heat. Urinary Fe increased in CG in the hyperthermia test before Heat exposure at High Temperature (HEHT)(p < 0.05) and in both groups after HEHT (p < 0.05). In EG there was an increase in the urinary excretion of Cu after HEHT (p < 0.01) in both trials. Fe suffered a decrease in sweat in EG after exposure to heat (p < 0.05). The concentrations of Fe and Cu in serum were not affected by acute exercise and exposure to high temperatures. However, there was a decrease in excretion of Fe in sweat due to HEHT, and an increase in urinary excretion in both. Therefore, we think that in conditions of high temperatures for long periods of time, attention should be paid to the body levels of these metals.

Dysregulated biodynamics in metabolic attractor systems precede the emergence of amyotrophic lateral sclerosis.

Evolutionarily conserved mechanisms maintain homeostasis of essential elements, and are believed to be highly time-variant. However, current approaches measure elemental biomarkers at a few discrete time-points, ignoring complex higher-order dynamical features. To study dynamical properties of elemental homeostasis, we apply laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) to tooth samples to generate 500 temporally sequential measurements of elemental concentrations from birth to 10 years. We applied dynamical system and Information Theory-based analyses to reveal the longest-known attractor system in mammalian biology underlying the metabolism of nutrient elements, and identify distinct and consistent transitions between stable and unstable states throughout development. Extending these dynamical features to disease prediction, we find that attractor topography of nutrient metabolism is altered in amyotrophic lateral sclerosis (ALS), as early as childhood, suggesting these pathways are involved in disease risk. Mechanistic analysis was undertaken in a transgenic mouse model of ALS, where we find similar marked disruptions in elemental attractor systems as in humans. Our results demonstrate the application of a phenomological analysis of dynamical systems underlying elemental metabolism, and emphasize the utility of these measures in characterizing risk of disease.

Reference intervals of spot urine copper excretion in preschool children and potential application in pre-symptomatic screening of Wilson disease.

The objectives were to determine the reference intervals of spot urine copper excretion indexes in pre-school children and to evaluate their utility in screening for Wilson disease (WD). With spot urine collected from a control sample of preschool children (aged 3-7 years, n=153), the reference intervals of spot urine copper excretion indexes and their biological variation were defined. In order to investigate their utility performance in screening for WD in this age group, multiple spot urine samples from six WD patients who were diagnosed at presymptomatic stage were also analysed and compared. Cut-off values useful for detection of WD were defined by receiver operator curve (ROC) analysis. Biological (inter-individual) variation of spot urine copper indexes expressed as coefficient of variation (CVg) were around 60% at this age group, which was moderate and similar to other clinically useful urine tests, such as urine albumin excretion ratio. Spot urine copper excretion strongly correlated with both urine creatinine and osmolality. Linear regression against both creatinine and osmolality showed that ∼94% of data points in healthy preschool children fell within the prediction interval, suggesting that both were useful normalisation factors. ROC showed that copper to osmolality ratio was the best index with an area under curve (AUC) greater than 0.98. Cut-off values of 0.5 µmol/L, 0.1 µmol/mmol and 0.00085 µmol/mOsmol (32 µg/L, 56 µg/g creatinine and 0.054 µg/mOsmol, respectively, in conventional units) for spot urine copper concentration, copper to creatinine ratio and copper to osmolality ratio, respectively, have potential application in the differentiation of WD patients. Based on the data, a new WD screening strategy targeting preschool children is proposed. Application of a bivariate screening strategy using spot urine copper concentration and urine osmolality may be useful in a population-wide screening program for WD among preschool children.

5-year-old boy • behavioral issues • elevated ALT and AST levels • Dx?

► Behavioral issues (impulsiveness, aggression) ► Liver edge 1 cm below costal margin ► Elevated ALT and AST levels.