Publications by authors named "Tomas Navratil"

87 Publications

Uptake of Cd, Pb, U, and Zn by plants in floodplain pollution hotspots contributes to secondary contamination.

Environ Sci Pollut Res Int 2021 May 12. Epub 2021 May 12.

Institute of Geology of the Czech Academy of Sciences, Rozvojová 269, 165 00, Prague 6, Czech Republic.

Willows, woody plants of genus Salix common in floodplains of temperate regions, act as plant pumps and translocate the Cd and Zn in the soil profiles of uncontaminated and weakly contaminated floodplains from the sediment bulk to the top strata. We suggest this process occurs because the Cd and Zn concentrations in willow leaves exceed those in the sediments. Senescing foliage of plant species common in floodplains can increase the Cd and Zn ratios as compared to other elements (Pb and common 'lithogenic elements' such as Al) in the top strata of all floodplains, including those that have been severely contaminated. The top enrichment is caused by the root uptake of specific elements by growing plants, which is followed by foliage deposition. Neither the shallow groundwater nor the plant foliage shows that Cd, Zn, and Pb concentrations are related to those in the sediments, but they clearly reflect the shallow groundwater pH, with the risk element mobilised by the acidity that is typical for the subsurface sediments in floodplains. The effect that plants have on the Pb in floodplains is significantly lower than that observed for Cd and Zn, while U can be considered even less mobile than Pb. Groundwater and plant leaves can contribute to secondary contamination with Cd and Zn from floodplain pollution hotspots, meaning that plants can accumulate these elements on the floodplain surface or even return them back to the fluvial transport, even if bank erosion would not occur. For Pb and U at the sites studied, these risks were negligible.
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http://dx.doi.org/10.1007/s11356-021-14331-5DOI Listing
May 2021

NCX 667, a Novel Nitric Oxide Donor, Lowers Intraocular Pressure in Rabbits, Dogs, and Non-Human Primates and Enhances TGFβ2-Induced Outflow in HTM/HSC Constructs.

Invest Ophthalmol Vis Sci 2021 Mar;62(3):17

Nicox Research Institute, Milan, Italy.

Purpose: NCX 667, a novel nitric oxide (NO) donor with an isomannide core, was characterized for its IOP-lowering ability in animal models of ocular hypertension and glaucoma. Bioengineered human trabecular meshwork/Schlemm's canal (HTM/HSC) constructs were used to explore the mode of action.

Methods: Ocular normotensive New Zealand white (NZW) rabbits (ONT-rabbits), spontaneously ocular hypertensive pigmented Dutch-belted rabbits (sOHT-rabbits), hypertonic saline (5%)-induced transient ocular hypertensive NZW rabbits (tOHT-rabbits), ocular normotensive Beagle dogs (ONT-dogs), and laser-induced ocular hypertensive cynomolgus monkeys (OHT-monkeys) were used. NCX 667 or vehicle (30 µL) was instilled in a crossover, masked fashion and intraocular pressure (IOP) measured before dosing (baseline) and for several hours thereafter. The ONT-rabbits were used for cyclic guanosine monophosphate (cGMP) determination in ocular tissues after ocular dosing with NCX 667. Transforming growth factor-beta2 (TGFβ2) (2.5 ng/mL, six days)-treated HTM/HSC constructs were used to address changes in outflow facility.

Results: NCX 667 resulted in robust and dose-dependent IOP decrease in all models used. Maximal IOP-lowering efficacy at 1% was -4.1 ± 0.6, -12.2 ± 2.7, -10.5 ± 2.0, -5.3 ± 0.8, and -6.6 ± 1.9 mmHg, respectively, in ONT-dogs, sOHT-rabbits, tOHT-rabbits, ONT-rabbits, and OHT-monkeys. In ONT-rabbits NCX 667 (1%) increased cGMP in aqueous humor (AH) but not in retina and iris/ciliary body. NCX 667 concentration-dependently increased outflow facility in TGFβ2-treated HTM/HSC constructs (outflow facility, 0.10 ± 0.06 and 0.30 ± 0.10 µL/min/mmHg/mm2, respectively, in vehicle- and NCX 667-treated constructs).

Conclusions: NCX 667 leads to robust IOP lowering in several animal models. Evidence in HTM/HSC constructs indicate that the IOP reduction likely results from NO-mediated increase of the conventional outflow pathway. Other mechanisms including changes in AH production and episcleral vein pressure may not be excluded at this time.
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http://dx.doi.org/10.1167/iovs.62.3.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960798PMC
March 2021

NCX 1741, a Novel Nitric Oxide-Donating Phosphodiesterase-5 Inhibitor, Exerts Rapid and Long-Lasting Intraocular Pressure-Lowering in Cynomolgus Monkeys.

J Ocul Pharmacol Ther 2021 May 15;37(4):215-222. Epub 2021 Feb 15.

Nicox Research Institute, Milan, Italy.

We studied the IOP-lowering effects of NCX 1741, a novel nitric oxide (NO)-donating derivative of the phosphodiesterase type-5 inhibitor, avanafil, in Cynomolgus monkey with laser-induced ocular hypertension (OHT-monkeys). NCX 1193 (NO-donating moiety), NCX 1744 (NCX 1741 without ester nitrate moiety), and travoprost (PGF2α analogue) were used for comparison. Ocular exposure after NCX 1741 dosing also was addressed. Vehicle (phosphate buffer pH 6.0, Kolliphor 5%, DMSO 0.3%, benzalkonium chloride 0.02%), NCX 1741, NCX 1193, NCX 1744, or travoprost were instilled (30 μL; single dose) masked and conscious IOPs were measured by pneumatonometry. LC-MS/MS-based methods were employed to monitor ocular exposure of NCX 1741 and main metabolites after ocular dosing in New Zealand White rabbits. NCX 1741 (2.2%, 0.8 μmol/eye) lowered IOP with an E (ΔΔIOP, IOP change vs. pre-dose and vehicle) between 5 and 8 h post-dosing (ΔΔIOP, -5.3 ± 2.0 mmHg and ΔΔIOP, -6.0 ± 2.1 mmHg). Conversely, equimolar (0.47%, 0.8 μmol/eye) NCX 1193 IOP-lowering effects were maximal 3 h post-dosing (ΔΔIOP, -4.7 ± 1.6 mmHg) and declined thereafter (ΔΔIOP, -1.6 ± 1.1 mmHg). In a follow-up study, NCX 1741 (1.5%, 0.5 μmol/eye) was more effective than NCX 1744 despite a similar duration. Further, NCX 1741 was as effective as travoprost (0.1%, 0.06 μmol/eye) at 5 and 8 h post-dosing (travoprost, ΔΔIOP, -3.4 ± 2.2 mmHg and ΔΔIOP, -4.9 ± 1.3 mmHg) but had shorter duration (NCX 1741, ΔΔIOP, -1.5 ± 1.1 mmHg; travoprost, ΔΔIOP, -7.1 ± 2.8 mmHg). NCX 1741 resulted in significant aqueous humor exposure, as determined by the levels of the main metabolite, avanafil. NCX 1741 rapidly and effectively lowers IOP in OHT-monkeys for several hours post-dosing. How these effects translate in humans is still to be defined.
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http://dx.doi.org/10.1089/jop.2020.0126DOI Listing
May 2021

Voltammetric determination of heavy metals in honey bee venom using hanging mercury drop electrode and PLA/carbon conductive filament for 3D printer.

Monatsh Chem 2021 Jan 16:1-7. Epub 2021 Jan 16.

J. Heyrovský Institute of Physical Chemistry of the Czech Academy of Sciences, Dolejškova 3, 182 23 Prague 8, Czech Republic.

A new method for determination of selected heavy metals (Cd, Pb, Cu, Zn, and Ni) in honey bee venom was developed. Heavy metals are metabolized and incorporated into bee products, including honey and honey bee venom (apitoxin). Their composition reflects contamination of "bee environment", providing information about heavy metal contamination in the neighborhood of human dwellings. Moreover, assessment of bee products contamination is relevant for medicine, as they are a tool for promising therapeutic and chemoprophylactic strategies against COVID-19 (SARS-CoV-2). Owing to the complicated matrix, the developed method consists of wet mineralization with sulfuric acid, nitric acid, under increased temperature, and pressure and subsequent repeated boiling with concentrated nitric acid. Determination of the selected metals was carried out by anodic or cathodic stripping voltammetry on two types of electrodes: pen-type hanging mercury drop electrode (HMDE) and PLA filament with carbon conductive admixture (PLA-C) for 3D printer. Contents of lead and cadmium in all analyzed bee venom samples were on the level of mg kg, of nickel and copper about ten times higher, and of zinc on the level of g kg. The results achieved using HMDE were recorded with average relative standard deviation (RSD) 5.4% (from 3.2% to 8.6%) and using PLA-C 11.8% (from 6.5% to 18.0%). The results achieved using both electrodes proved to be equivalent with statistical probability higher than 95%.
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http://dx.doi.org/10.1007/s00706-020-02725-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811382PMC
January 2021

Contrasting tree ring Hg records in two conifer species: Multi-site evidence of species-specific radial translocation effects in Scots pine versus European larch.

Sci Total Environ 2021 Mar 9;762:144022. Epub 2020 Dec 9.

Institute of Geology of the Czech Academy of Sciences, Rozvojová 269, 165 00 Prague 6, Czech Republic.

Tree ring records are increasingly being used as a geochemical archive of past atmospheric mercury (Hg) pollution. However, it is not clear whether all tree species can be used reliably for this purpose. We compared tree-ring Hg records of two coniferous species - widely used Scots pine (Pinus sylvestris) and less frequently used European larch (Larix decidua) at 6 study sites across the Czech Republic. Site-specific mean Hg concentrations in tree-ring segments of larch ranged from 2.1 to 5.2 μg kg, whereas pine had higher mean Hg concentrations (3.6-8.3 μg kg). Temporal records of Hg concentrations in tree rings of larch and pine differed significantly. Comparisons with previously documented peat Hg records showed that larch tree-ring Hg records more closely agreed with peat archive records. For pines, which had a large, tree-age dependent number of sapwood rings (62 ± 17, 1SD), we found a strong relationship between the year of peak Hg and the number of sapwood tree rings (p = 0.012, r = 0.35), as well as between peak Hg year and the sapwood-heartwood boundary year (p < 0.001, r = 0.65), rather than with temporal changes in atmospheric Hg levels. The much greater number of pine sapwood tree rings appears to promote radial Hg translocation, resulting in the shift of Hg peaks backward in time through the tree-ring record. In contrast, Larch consistently had a low number of sapwood tree rings (19 ± 6, 1SD), and more closely agreed with peat Hg records. This study suggests that European larch, a tree species characterized by a relatively low and consistent number of sapwood tree rings, records changes in atmospheric Hg concentrations more reliably than does Scots pine, a species with a relatively high and variable number of sapwood tree rings.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144022DOI Listing
March 2021

Three-Year Study of Markers of Oxidative Stress in Exhaled Breath Condensate in Workers Producing Nanocomposites, Extended by Plasma and Urine Analysis in Last Two Years.

Nanomaterials (Basel) 2020 Dec 6;10(12). Epub 2020 Dec 6.

J. Heyrovský Institute of Physical Chemistry CAS, Dolejškova 3, 182 23 Prague 8, Czech Republic.

Human data concerning exposure to nanoparticles are very limited, and biomarkers for monitoring exposure are urgently needed. In a follow-up of a 2016 study in a nanocomposites plant, in which only exhaled breath condensate (EBC) was examined, eight markers of oxidative stress were analyzed in three bodily fluids, i.e., EBC, plasma and urine, in both pre-shift and post-shift samples in 2017 and 2018. Aerosol exposures were monitored. Mass concentration in 2017 was 0.351 mg/m during machining, and 0.179 and 0.217 mg/m during machining and welding, respectively, in 2018. In number concentrations, nanoparticles formed 96%, 90% and 59%, respectively. In both years, pre-shift elevations of 50.0% in EBC, 37.5% in plasma and 6.25% in urine biomarkers were observed. Post-shift elevation reached 62.5% in EBC, 68.8% in plasma and 18.8% in urine samples. The same trend was observed in all biological fluids. Individual factors were responsible for the elevation of control subjects' afternoon vs. morning markers in 2018; all were significantly lower compared to those of workers. Malondialdehyde levels were always acutely shifted, and 8-hydroxy-2-deoxyguanosine levels best showed chronic exposure effect. EBC and plasma analysis appear to be the ideal fluids for bio-monitoring of oxidative stress arising from engineered nanomaterials. Potential late effects need to be targeted and prevented, as there is a similarity of EBC findings in patients with silicosis and asbestosis.
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http://dx.doi.org/10.3390/nano10122440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762143PMC
December 2020

Differential pulse voltammetric determination of homovanillic acid as a tumor biomarker in human urine after hollow fiber-based liquid-phase microextraction.

Talanta 2021 Jan 8;221:121594. Epub 2020 Sep 8.

J. Heyrovský Institute of Physical Chemistry of the Czech Academy of Sciences, Dolejškova 2155/3, 182 23, Prague 8, Czech Republic. Electronic address:

Novel method for the determination of a tumor marker homovanillic acid (HVA) in human urine was developed. Combination of hollow fiber - based liquid-phase microextraction (HF-LPME) and differential pulse voltammetry (DPV) at a cathodically pre-treated boron doped diamond electrode (BDDE) was applied for these purposes. Optimum conditions were: butyl benzoate as supported liquid membrane (SLM) formed on polypropylene HF, 0.1 mol L HCl as donor phase, 0.1 mol L sodium phosphate buffer of pH 6 as acceptor phase, and 30 min extraction time. HF-LPME-DPV concentration dependence was linear in the range from 1.2 to 100 μmol L. Limits of quantification (LOQ) and detection (LOD) were 1.2 and 0.4 μmol L, respectively. The applicability of the developed method was verified by analysis of human urine. Standard addition method was used, found HVA concentration was 13.5 ± 1.3 μmol L, RSD = 9.3% (n=5).
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http://dx.doi.org/10.1016/j.talanta.2020.121594DOI Listing
January 2021

Markers of oxidative stress after three days of nanoTiO sunscreen use in humans: a pilot study.

Cent Eur J Public Health 2020 10;28 Suppl:S17-S21

Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Objective: Recent experimental studies point to a high reactivity of nanoparticles and the potential of sunscreens to penetrate the skin. We measured 20 markers of oxidative stress and inflammation to find out whether skin exposure to nanoTiO sunscreen may elevate the level of the markers in exhaled breath condensate (EBC) and urine of exposed subjects, as was suggested by our earlier study.

Methods: Six volunteers (3 males and 3 females), with a mean age of 48.0 ± 6.7 years, used commercial sunscreen for three days continuously. The first samples were collected before the test. The second samples were collected on day 4, before the sunscreen was washed off, and the third samples on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, aldehydes C6-C12, 8-isoProstaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes B4, C4, D4, and E4, using liquid chromatography-electrospray ionisation-tandem mass spectrometry.

Results: In the urine, 4-hydroxy-trans-hexenal was significantly higher in post-exposure sample 2, and the same trend was seen in all urinary markers. In EBC, no difference was seen between the mean values of 20 post-test markers as compared with pre-test samples.

Conclusion: This study suggests potential side effects of the sunscreen - borderline elevation of markers of oxidative stress/inflammation - which may relate to the absorption of the nanoTiO, and the non-significant difference may be explained by the small number of subjects. The effect was not seen in EBC, where nanoTiO was not found. A larger study is needed, as according to our previous study, the beneficial effect of the sunscreen to suppress oxidative stress caused by UV radiation may be questioned.
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http://dx.doi.org/10.21101/cejph.a6158DOI Listing
October 2020

Special issue on the 52 Heyrovský discussion - Electrochemistry of Organic Compounds and Biopolymers.

J Electroanal Chem (Lausanne) 2020 Sep 16;873:114343. Epub 2020 Jun 16.

Institute of Biophysics of the Czech Academy of Sciences, Kralovopolská 135, 612 65 Brno, Czech Republic.

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http://dx.doi.org/10.1016/j.jelechem.2020.114343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297169PMC
September 2020

Efficiency of I-ioflupane SPECT as the marker of basal ganglia damage in acute methanol poisoning: 6-year prospective study.

Clin Toxicol (Phila) 2021 Mar 7;59(3):235-245. Epub 2020 Aug 7.

Department of Occupational Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Context: Investigate whether I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning.

Methods: Prospective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUANT and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements.

Results: Forty-two patients (mean age 46.3 ± 4.2 years; 8 females), including 15 with MRI-detected putamen lesions (group I) and 27 patients with intact putamen (group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume ( = 0.665;  < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I ( < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH ( = 0.574;  < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations ( < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness ( < 0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC = 0.753 (95%CI 0.604-0.902;  = 0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen.

Conclusion: DaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.
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http://dx.doi.org/10.1080/15563650.2020.1802033DOI Listing
March 2021

MRI-based brain volumetry and retinal optical coherence tomography as the biomarkers of outcome in acute methanol poisoning.

Neurotoxicology 2020 09 15;80:12-19. Epub 2020 Jun 15.

Toxicological Information Centre, General University Hospital, Prague, Czech Republic; Department of Occupational Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: Basal ganglia lesions are typical findings on magnetic resonance imaging (MRI) of the brain in survivors of acute methanol poisoning. However, no data are available on the association between the magnitude of damaged brain regions, serum concentrations of markers of acute methanol toxicity, oxidative stress, neuroinflammation, and the rate of retinal nerve ganglion cell loss.

Objectives: To investigate the association between MRI-based volumetry of the basal ganglia, retinal nerve fibre layer (RNFL) thickness and prognostic laboratory markers of outcomes in acute methanol poisoning.

Methods: MRI-based volumetry of putamen, nucleus caudatus and globus pallidus was performed and compared with laboratory parameters of severity of poisoning and acute serum markers of oxidative damage of lipids (8-isoprostan, MDA, HHE, HNE), nucleic acids (8-OHdG, 8-OHG, 5-OHMU), proteins (o-Thyr, NO-Thyr, Cl-Thyr) and leukotrienes (LTC4, LTD4, LTE4, LTB4), as well as with the results of RNFL measurements by optic coherence tomography (OCT) in 16 patients with acute methanol poisoning (Group I) and in 28 survivors of poisoning two years after discharge with the same markers measured within the follow-up examination (Group II). The control group consisted of 28 healthy subjects without methanol poisoning.

Results: The survivors of acute methanol poisoning had significantly lower volumes of basal ganglia than the controls. The patients with MRI signs of methanol-induced toxic brain damage had significantly lower volumes of basal ganglia than those without these signs. A positive correlation was found between the volume of putamen and arterial blood pH on admission (r = 0.45; p = 0.02 and r = 0.44; p = 0.02 for left and right putamen, correspondingly). A negative correlation was present between the volumes of putamen and acute serum lactate (r = -0.63; p < 0.001 and r = -0.59; p = 0.01), creatinine (r = -0.53; p = 0.01 and r = -0.47; p = 0.01) and glucose (r = -0.55; p < 0.001 and r = -0.50; p = 0.01) concentrations. The volume of basal ganglia positively correlated with acute concentrations of markers of lipoperoxidation (8-isoprostan: r = 0.61; p < 0.05 and r = 0.59; p < 0.05 for left and right putamen, correspondingly) and inflammation (leukotriene LTB4: r = 0.61; p < 0.05 and r = 0.61; p < 0.05 for left and right putamen, correspondingly). The higher the volume of the basal ganglia, the higher the thickness of the RNFL, with the strongest positive association between global RNFL and the volume of putamen bilaterally (all p < 0.01). In the follow-up markers of oxidative stress and inflammation, only o-Thyr concentration negatively correlated with the volume of putamen bilaterally (r = -0.39; p < 0.05 and r = -0.37; p < 0.05 for left and right putamen, correspondingly).

Conclusion: In survivors of acute methanol poisoning with signs of toxic brain damage, the magnitude of affected areas correlated with acute parameters of severity of poisoning, markers of oxidative stress and neuroinflammation. There was a positive association between the basal ganglia volume and the thickness of RNFL, making OCT an important screening test and MRI-based volumetry the confirmative diagnostic method for the detection of CNS sequelae of methanol poisoning.
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http://dx.doi.org/10.1016/j.neuro.2020.06.006DOI Listing
September 2020

Estimation of Hg(II) in Soil Samples by Bioluminescent Bacterial Bioreporter ARL1, and the Effect of Humic Acids and Metal Ions on the Biosensor Performance.

Sensors (Basel) 2020 Jun 2;20(11). Epub 2020 Jun 2.

Institute of Geology of the Czech Academy of Sciences, Rozvojová 269, CZ-16500 Prague 6, Czech Republic.

Mercury is a ubiquitous environmental pollutant of dominantly anthropogenic origin. A critical concern for human health is the introduction of mercury to the food chain; therefore, monitoring of mercury levels in agricultural soil is essential. Unfortunately, the total mercury content is not sufficiently informative as mercury can be present in different forms with variable bioavailability. Since 1990, the use of bioreporters has been investigated for assessment of the bioavailability of pollutants; however, real contaminated soils have rarely been used in these studies. In this work, a bioassay with whole-cell bacterial bioreporter ARL1 was used for estimation of bioavailable concentration of mercury in 11 soil samples. The bioreporter emits bioluminescence in the presence of Hg(II). Four different pretreatments of soil samples prior to the bioassay were tested. Among them, laccase mediated extraction was found to be the most suitable over water extraction, alkaline extraction, and direct use of water-soil suspensions. Nevertheless, effect of the matrix on bioreporter signal was found to be severe and not possible to be completely eliminated by the method of standard addition. In order to elucidate the matrix role, influences of humic acid and selected metal ions present in soil on the bioreporter signal were tested separately in laboratory solutions. Humic acids were found to have a positive effect on the bioreporter growth, but a negative effect on the measured bioluminescence, likely due to shading and Hg binding resulting in decreased bioavailability. Each of the tested metal ions solutions affected the bioluminescence signal differently; cobalt (II) positively, iron (III) negatively, and the effects of iron (II) and nickel (II) were dependent on their concentrations. In conclusion, the information on bioavailable mercury estimated by bioreporter ARL1 is valuable, but the results must be interpreted with caution. The route to functional bioavailability bioassay remains long.
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http://dx.doi.org/10.3390/s20113138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308967PMC
June 2020

Peripheral polyneuropathy after acute methanol poisoning: Six-year prospective cohort study.

Neurotoxicology 2020 07 5;79:67-74. Epub 2020 May 5.

Toxicological Information Centre, General University Hospital, Prague, Czech Republic; Department of Occupational Medicine, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: Methanol is a widely used industrial short-chain aliphatic alcohol with known neurotoxic properties. Mass poisoning outbreaks due to the consumption of methanol-adulterated alcoholic drinks present a challenge to healthcare providers due to the high mortality and serious central nervous system (CNS) damage in survivors. However, the impact of methanol exposure on the peripheral nervous system is unknown.

Objectives: To investigate the role of acute methanol exposure in the development of peripheral polyneuropathy (PNP) during the years following discharge from the hospital.

Methods: A total of 55 patients with confirmed methanol poisoning (mean age of 47.9 ± 3.6 years; 9 females) were examined 4 times within a 6-year prospective longitudinal cohort study. The program included neurological and electromyographic examinations, visual evoked potentials, ocular examinations with retinal nerve fibre layer thickness measurements, brain magnetic resonance imaging, and a series of biochemical and toxicological tests.

Results: PNP was observed in 20/55 (36 %) patients, which, in most of the cases, was mild axonal sensorimotor neuropathy. In 8/55 (15 %) patients, worsening of electromyographic findings was registered during the follow-up period, including 5 cases with newly diagnosed PNP and 3 cases of PNP progression. In one subject, complete reversal of PNP was registered after cessation of alcohol intake. The patients with PNP were significantly older (57.3 ± 5.3 versus 42.5 ± 3.9 years; p < 0.001), with higher blood glucose (5.93 ± 0.97 versus 4.81 ± 0.32 mmol/L; p = 0.035) and lower vitamin B (45.5 ± 7.4 versus 57.5 ± 5.2 ug/L; p = 0.015) concentrations. The number of chronic alcohol abusers was significantly higher in the PNP group (17/20 versus 20/35; p = 0.034). No associations between PNP prevalence/ dynamics and acute parameters of poisoning severity, arterial blood pH (7.26 ± 0.07 with PNP versus 7.18 ± 0.09 without PNP; p = 0.150), or serum methanol (1320.0 ± 700.0 with PNP versus 1430.0 ± 510.0 mg/L without PNP; p = 0.813) and ethanol (460.0 ± 560.0 with PNP versus 340.0 ± 230.0 mg/L without PNP; p = 0.675) concentrations at admission were found. No difference in the number of patients with visual (9/20 with PNP versus 12/35 patients without PNP; p = 0.431) and CNS sequelae (9/20 with PNP versus 15/35 patients without PNP; p = 0.877) of poisoning was present.

Discussion: Despite the relatively high number of PNP cases, no association was found between the severity of acute methanol poisoning and the prevalence of PNP and its dynamics during six years of observation. We did not find an association between methanol-induced visual/ brain damage and the prevalence of PNP in survivors of poisoning. A high prevalence of PNP and its progression might be attributed to other causes, mainly a history of chronic alcohol abuse and insufficiently treated diabetes mellitus. Our results highlight the importance of complete cessation of alcohol consumption and better control of glycaemia in diabetic patients in the prevention and treatment of peripheral PNP.
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http://dx.doi.org/10.1016/j.neuro.2020.04.010DOI Listing
July 2020

Acute exposures to e-cigarettes and heat-not-burn products reported to the Czech Toxicological Information Centre over a 7-year period (2012-2018).

Basic Clin Pharmacol Toxicol 2020 Jul 19;127(1):39-46. Epub 2020 Mar 19.

Toxicological Information Centre, General University Hospital, Prague, Czech Republic.

E-cigarettes and heat-not-burn cigarettes (HNBC) present new health risks due to their rising popularity, high content of nicotine and serious adverse effects. The objective of the study was to analyse the cases of acute exposure to e-cigarettes, e-liquids and HNBC products containing nicotine that led to toxicological consultations at our poisons control centre during a 7-year period (2012-2018) and identify the categories of special concern that require further investigation and intervention. The demographic, toxicological and clinical data were analysed by descriptive statistics. Poisoning severity score (PSS) was estimated. From 119 229 consultations, 148 cases concerned acute exposure to e-cigarettes. Children and adolescents were exposed in 91 (61%) cases, including exposure of neonates and infants in 54 (36%) cases. The main route of exposure was ingestion in 129 (87%), inhalation in nine (6%), ocular in six (4%) and intravenous administration in three (2%) cases. The source of exposure was the cartridge with e-liquid (107; 72%), refillable tank in 29 (20%) and HNBC refill in nine (6%) cases. The reason for exposure was accidental in 110 (74%), incorrect application of the device in 10 (7%), abuse in six (4%), suicide attempt in six (4%) and other/unknown in 16 (11%) cases. The dose estimation was severe/lethal in 6 (4%), toxic in 53 (36%), low-to-moderate in 35 (24%) and unknown in 54 (36%) cases. Vomiting was observed in 38 (26%) patients; 72% of patients were hospitalised. In symptomatic cases, 41 patient had PSS 1, 12 patients had PSS 2, and one patient had PSS 3. Activated charcoal was applied in 57 (39%) patients, and symptomatic treatment was recommended in 75 (51%) patients. Cases of unintentional exposure of children demonstrate the need for preventive risk reduction measures.
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http://dx.doi.org/10.1111/bcpt.13393DOI Listing
July 2020

Determination of tumour biomarkers homovanillic and vanillylmandelic acid using flow injection analysis with amperometric detection at a boron doped diamond electrode.

Anal Chim Acta 2019 Dec 31;1087:44-50. Epub 2019 Aug 31.

Charles University, Faculty of Science, Department of Analytical Chemistry, UNESCO Laboratory of Environmental Electrochemistry, Hlavova 2030/8, 128 43 Prague 2, Czech Republic.

A new method for the simultaneous determination of two tumour biomarkers, homovanillic (HVA) and vanillylmandelic acid (VMA), using flow injection analysis (FIA) with amperometric detection (AD) at a commercially available boron doped diamond electrode (BDDE) was developed. It was found that this method is suitable for the determination of HVA (in the presence of VMA) and VMA (in the presence of HVA) in optimum medium of Britton-Robinson buffer (0.04 mol L, pH 3.0). Calibration dependences consist of two linear parts for both biomarkers, the first one being in the concentration range from 1 to 10 μmol L and the second one from 10 to 100 μmol L (with obtained LODs 0.44 μmol L for HVA and 0.34 μmol L for VMA, respectively). To minimize any negative effects related to the passivation of the working electrode, suitable cleaning pulses (+2.4 V for 30 s) were imposed on the working electrode after each measurement. An attempt to use FIA with multiple pulse amperometric detection to determine both analytes in one run was not successful. Changing potentials in short intervals in multiple pulse detection probably results in mutual interaction of analytes and/or products of their electrochemical oxidation, thus preventing the application of this approach.
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http://dx.doi.org/10.1016/j.aca.2019.08.062DOI Listing
December 2019

The impact of co-morbidities on a 6-year survival after methanol mass poisoning outbreak: possible role of metabolic formaldehyde.

Clin Toxicol (Phila) 2020 04 12;58(4):241-253. Epub 2019 Jul 12.

Department of Occupational Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

The influence of co-morbid conditions on the outcome of acute methanol poisoning in mass poisoning outbreaks is not known. The objective of this is to study the impact of burden of co-morbidities, complications, and methanol-induced brain lesions on hospital, follow-up, and total mortality. All patients hospitalized with methanol poisoning during a mass poisoning outbreak were followed in a prospective cohort study until death or final follow-up after 6 years. The age-adjusted Charlson co-morbidity index (ACCI) score was calculated for each patient. A multivariate Cox regression model was used to calculate the adjusted hazards ratio (HR) for death. The survival was modeled using the Kaplan-Meier method. Of 108 patients (mean age with SD 50.9 ± 2.6 years), 24 (54.4 ± 5.9 years) died during hospitalization (mean survival with SD 8 ± 4 days) and 84 (49.9 ± 3.0 years;  = .159) were discharged, including 27 with methanol-induced brain lesions. Of the discharged patients, 15 (56.3 ± 6.8 years) died during the follow-up (mean survival 37 ± 11 months) and 69 (48.5 ± 3.3 years;  = .044) survived. The hospital mortality was 22%, the follow-up mortality was 18%; the total mortality was 36%. Cardiac/respiratory arrest, acute respiratory failure, multiorgan failure syndrome, and arterial hypotension increased the HR for hospital and total (but not follow-up) mortality after adjustment for age, sex, and arterial pH (all  < .05). All patients who died in the hospital had at least one complication. A higher ACCI score was associated with greater total mortality (HR 1.22; 1.00-1.48 95% CI;  = .046). Of those who died, 35 (90%) had a moderate-to-high ACCI. The Kaplan-Meier curve demonstrated that patients with a high ACCI had greater follow-up mortality compared to ones with low ( = .027) or moderate ( = .020) scores. For the patients who died during follow-up, cancers of different localizations were responsible for 7/15 (47%) of the deaths. The character and number of complications affected hospital but not follow-up mortality, while the burden of co-morbidities affected follow-up mortality. Methanol-induced brain lesions did not affect follow-up mortality. Relatively high cancer mortality rate may be associated with acute exposure to metabolic formaldehyde produced by methanol oxidation.
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http://dx.doi.org/10.1080/15563650.2019.1637525DOI Listing
April 2020

NanoTiO Sunscreen Does Not Prevent Systemic Oxidative Stress Caused by UV Radiation and a Minor Amount of NanoTiO is Absorbed in Humans.

Nanomaterials (Basel) 2019 Jun 17;9(6). Epub 2019 Jun 17.

Czech University of Life Sciences, Kamycka 129, 165 00 Prague 6, Czech Republic.

The present pilot study tested the efficiency of nanoTiO sunscreen to prevent the oxidative stress/inflammation caused by ultraviolet (UV) radiation using biomarkers in subjects' blood, urine, and exhaled breath condensate (EBC). In addition, the skin absorption of nanoTiO was studied. Six identical subjects participated in three tests: (A) nanoTiO sunscreen, (B) UV radiation, and (C) sunscreen + UV. The first samples were collected before the test and the second after sunscreen application and/or UV exposure. On day 4, the third samples were collected, and the sunscreen was washed off, and the fourth samples were collected on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy--hexenal, 4-hydroxy--nonenal, aldehydes C6-C12, 8--Prostaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes, using liquid chromatography-electrospray ionisation-tandem mass spectrometry. Titania was measured using inductively coupled plasma mass spectrometry and TiO nanoparticles by transmission and scanning electron microscopy. Sunscreen alone did not elevate the markers, but UV increased the biomarkers in the plasma, urine, and EBC. The sunscreen prevented skin redness, however it did not inhibit the elevation of oxidative stress/inflammatory markers. Titania and nanoTiO particles were found in the plasma and urine (but not in the EBC) in all sunscreen users, suggesting their skin absorption.
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http://dx.doi.org/10.3390/nano9060888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631994PMC
June 2019

Decreasing litterfall mercury deposition in central European coniferous forests and effects of bark beetle infestation.

Sci Total Environ 2019 Sep 10;682:213-225. Epub 2019 May 10.

Global Change Research Centre of the Czech Academy of Sciences, Poříčí 3b, 60 300 Brno, Czech Republic.

We evaluated a 14-year trend (2003-2017) in mercury (Hg) concentrations and fluxes in six litterfall categories (needles, bark, twigs, cones, lichen, and a mixture of unidentified fragments) at six research plots situated in two central European unmanaged mountain forest stands, dominated by mature Norway spruce. One of the stands (catchment of Plešné Lake, PL) was infested by bark beetle and all mature spruces died at three of four research plots during the study. One PL plot and two plots in the second stand (catchment of Čertovo Lake, CT) were intact and used as a control. At the intact plots, the litterfall Hg deposition averaged 45 and 32 μg/m/year in the PL and CT catchments, respectively, while bulk precipitation Hg deposition was an order of magnitude lower (2.6 μg/m/year). In the individual litter categories, Hg concentrations averaged 223, 195, 126, 81, 79 and 30 μg/kg in lichen, unidentified fragments, bark, twigs, needles and cones, respectively. As a result of decreasing European Hg emissions, Hg concentrations in most litter categories decreased from 2003 to 2017. Consequently, the litter-associated Hg flux to the forest floor decreased from 66 to 23 μg/m/year during 2003-2017. The litterfall mass fluxes exhibited no trends at the intact plots. In contrast, the litter-associated Hg flux increased 5-fold after tree dieback due to elevated litterfall, averaging 218 μg/m/year Hg at the PL infested plots during 2004-2009. The relative contribution of individual litter categories to the total Hg flux shifted from needle to bark and twig dominance. Starting in 2010, Hg flux decreased to pre-disturbance levels for the following decade. The tree mortality in the PL catchment provided a unique opportunity to evaluate changes in litter-associated Hg fluxes to the forest floor during and after natural tree dieback.
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http://dx.doi.org/10.1016/j.scitotenv.2019.05.093DOI Listing
September 2019

Clinical and genetic determinants of chronic visual pathway changes after methanol - induced optic neuropathy: four-year follow-up study.

Clin Toxicol (Phila) 2019 06 17;57(6):387-397. Epub 2018 Nov 17.

a Toxicological Information Centre, Department of Occupational Medicine, First Faculty of Medicine , Charles University and General University Hospital , Prague , Czech Republic.

Context: Methanol poisoning induces acute optic neuropathy with possible long-term visual damage.

Objective: To study the dynamics and key determinants of visual pathway functional changes during 4 years after acute methanol poisoning.

Methods: A total of 42 patients with confirmed methanol poisoning (mean age 45.7 ± 4.4 years) were examined 4.9 ± 0.6, 25.0 ± 0.6, and 49.9 ± 0.5 months after discharge. The following tests were performed: visual evoked potential (VEP), retinal nerve fiber layer (RNFL) measurement, brain magnetic resonance imaging (MRI), complete ocular examination, biochemical tests, and apolipoprotein E (ApoE) genotyping.

Results: Abnormal VEP P1 latency was registered in 18/42 right eyes (OD) and 21/42 left eyes (OS), abnormal N1P1 amplitude in 10/42 OD and OS. Mean P1 latency shortening during the follow-up was 15.0 ± 2.0 ms for 36/42 (86%) OD and 14.9 ± 2.4 ms for 35/42 (83%) OS, with maximum shortening up to 35.0 ms. No significant change of mean N1P1 amplitude was registered during follow-up. A further decrease in N1P1 amplitude ≥1.0 mcV in at least one eye was observed in 17 of 36 patients (47%) with measurable amplitude (mean decrease -1.11 ± 0.83 (OD)/-2.37 ± 0.66 (OS) mcV versus -0.06 ± 0.56 (OD)/-0.83 ± 0.64 (OS) mcV in the study population; both p < .001). ApoE4 allele carriers had lower global and temporal RNFL thickness and longer initial P1 latency compared to the non-carriers (all p < .05). The odds ratio for abnormal visual function was 8.92 (3.00-36.50; 95%CI) for ApoE4 allele carriers (p < .001). The presence of ApoE4 allele was further associated with brain necrotic lesions (r = 0.384; p = .013) and brain hemorrhages (r = 0.395; p = .011).

Conclusions: Improvement of optic nerve conductivity occurred in more than 80% of patients, but evoked potential amplitude tended to decrease during the 4 years of observation. ApoE4 allele carriers demonstrated lower RNFL thickness, longer P1 latency, and more frequent methanol-induced brain damage compared to non-carriers.
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http://dx.doi.org/10.1080/15563650.2018.1532083DOI Listing
June 2019

Larch Tree Rings as a Tool for Reconstructing 20th Century Central European Atmospheric Mercury Trends.

Environ Sci Technol 2018 10 24;52(19):11060-11068. Epub 2018 Sep 24.

University of Maine , Orono , Maine 04469 , United States.

We propose the tree rings of European Larch ( Larix decidua) as a widely available and reliable geochemical archive of local and regional changes in atmospheric mercury (Hg). Mean Hg concentrations in larch tree rings from 8 background sites across the Czech Republic ranged from 2.2 to 4.8 μg kg; the maximum concentrations occurred in the period 1951-1970. At 3 sites impacted by Hg-emission sources [gold amalgamation processing, caustic soda production, and lead (Pb) ore smelting] mean larch tree ring Hg concentrations were significantly elevated relative to background sites. Changes in larch tree ring Hg concentrations were temporally coherent with known activities at the sites that would alter Hg emissions; the nearly simultaneous response in tree rings indicated little or no translocation of Hg within the larch bole. Based on the present-day atmospheric Hg concentration of 1.63 ng m at the intensively monitored Czech Global Mercury Observation System site and the most recent mean tree ring Hg concentration of 2.8 μg kg in co-located larch trees, we developed a simple distribution model of Hg between the atmosphere and larch tree rings. We applied the model using observed changes of Hg in larch tree rings from the countrywide background sites to reconstruct past atmospheric Hg concentrations in central Europe. Modeled Hg concentrations were in agreement with annual means from the European Monitoring and Evaluation Programme observatories.
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http://dx.doi.org/10.1021/acs.est.8b02117DOI Listing
October 2018

Stability of mercury concentration measurements in archived soil and peat samples.

Chemosphere 2018 Oct 5;208:707-711. Epub 2018 Jun 5.

Institute of Geochemistry, Mineralogy and Mineral Resources, Faculty of Science, Charles University, Albertov 6, Praha 2, 128 43, Czech Republic.

Archived soil samples can provide important information on the history of environmental contamination and by comparison with recently collected samples, temporal trends can be inferred. Little previous work has addressed whether mercury (Hg) concentrations in soil samples are stable with long-term storage under standard laboratory conditions. In this study, we have re-analyzed using cold vapor atomic absorption spectroscopy a set of archived soil samples that ranged from relatively pristine mountainous sites to a polluted site near a non-ferrous metal smelter with a wide range of Hg concentrations (6.7-6485 μg kg). Samples included organic and mineral soils and peats with a carbon content that ranged from 0.2 to 47.7%. Soil samples were stored in polyethylene bags or bottles and held in laboratory rooms where temperature was not kept to a constant value. Mercury concentrations in four subsets of samples were originally measured in 2000, 2005, 2006 and 2007, and re-analyzed in 2017, i.e. after 17, 12, 11 and 10 years of storage. Statistical analyses of either separated or lumped data yielded no significant differences between the original and current Hg concentrations. Based on these analyses, we show that archived soil and peat samples can be used to evaluate historical soil mercury contamination.
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http://dx.doi.org/10.1016/j.chemosphere.2018.06.033DOI Listing
October 2018

Neuroinflammation markers and methyl alcohol induced toxic brain damage.

Toxicol Lett 2018 Dec 4;298:60-69. Epub 2018 May 4.

Toxicological Information Centre, General University Hospital, Na Bojisti 1, 12000, Prague, Czech Republic; Department of Biomimetic Electrochemistry, J. Heyrovský Institute of Physical Chemistry of the AS CR, v.v.i, Dolejskova 2155/3, 18200, Prague, Czech Republic.

Methyl alcohol intoxication is a global problem with high mortality and long-term visual sequelae and severe brain damage in survivors. The role of neuroinflammation in the mechanisms of methyl alcohol-induced toxic brain damage has not been well studied. We measured the acute concentrations and dynamics of lipoxins LxA4 and LxB4 and the interleukins IL-4, IL-5, IL-9, IL-10, and IL-13 in the serum of patients treated with methyl alcohol poisoning and the follow-up concentrations in survivors two years after discharge from the hospital. A series of acute measurements was performed in 28 hospitalized patients (mean age 54.2 ± 5.2 years, mean observation time 88 ± 20 h) and the follow-up measurements were performed in 36 subjects who survived poisoning (including 12/28 survivors from the acute group). Visual evoked potentials (VEP) and magnetic resonance imaging of the brain (MRI) were performed to detect long-term visual and brain sequelae of intoxication. The acute concentrations of inflammatory mediators were higher than the follow-up concentrations: LxA4, 62.0 ± 6.0 vs. 30.0 ± 5.0 pg/mL; LxB4, 64.0 ± 7.0 vs. 34.0 ± 4.0 pg/mL; IL-4, 29.0 ± 4.0 vs. 15.0 ± 1.0 pg/mL; IL-5, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-9, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-10, 38.0 ± 5.0 vs. 16.0 ± 1.0 pg/mL; IL-13, 35.0 ± 4.0 vs. 14.0 ± 1.0 pg/mL (all p < 0.001). The patients with higher follow-up IL-5 concentration had prolonged latency P1 (r = 0.413; p = 0.033) and lower amplitude N1P1 (r = -0.498; p = 0.010) of VEP. The higher follow-up IL-10 concentration was associated with MRI signs of brain necrotic damage (r = 0.533; p = 0.001) and brain hemorrhage (r = 0.396; p = 0.020). Our findings suggest that neuroinflammation plays an important role in the mechanisms of toxic brain damage in acute methyl alcohol intoxication.
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http://dx.doi.org/10.1016/j.toxlet.2018.05.001DOI Listing
December 2018

Progressive Chronic Retinal Axonal Loss Following Acute Methanol-induced Optic Neuropathy: Four-Year Prospective Cohort Study.

Am J Ophthalmol 2018 07 28;191:100-115. Epub 2018 Apr 28.

Toxicological Information Centre, Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic. Electronic address:

Purpose: To study the dynamics and clinical determinants of chronic retinal nerve fiber layer thickness (RNFL) loss after methanol-induced optic neuropathy.

Design: Prospective cohort study.

Methods: All patients underwent complete ophthalmic evaluation including spectral-domain optical coherence tomography 3 times during 4 years of observation: 4.9 (±0.6), 25.0 (±0.6), and 49.9 (±0.5) months after discharge.

Participants: Eighty-four eyes of 42 survivors of methanol poisoning, mean age (standard deviation) of 45.7 (±4.4) years; and 82 eyes of 41 controls, mean age 44.0 (±4.2) years.

Main Outcome Measures: Global and temporal RNFL loss.

Results: Abnormal RNFL thickness was registered in 13 of 42 (31%) survivors of methanol poisoning and chronic axonal loss in 10 of 42 (24%) patients. Significant decrease of global/temporal RNFL thickness during the observation period was found in the study population compared to the controls (P < .001). The risk estimate of chronic global RNFL loss for arterial blood pH < 7.3 at admission was 11.65 (95% confidence interval 1.91-71.12) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated progressive visual loss in 7 of 10 cases. The patients with abnormal RNFL thickness had magnetic resonance signs of brain damage in 10 of 13 vs 8 of 29 cases with normal RNFL thickness (P = .003). Signs of brain hemorrhages were present in 7 of 13 patients with abnormal RNFL thickness vs 5 of 29 cases with normal RNFL thickness (P = .015).

Conclusions: Methanol-induced optic neuropathy may lead to chronic retinal axonal loss during the following years. Arterial blood pH on admission is the strongest predictor of chronic RNFL thickness decrease. Chronic retinal neurodegeneration is associated with the progressive loss of visual functions and necrotic brain lesions.
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http://dx.doi.org/10.1016/j.ajo.2018.04.015DOI Listing
July 2018

Role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning

Clin Toxicol (Phila) 2018 10 2;56(10):893-903. Epub 2018 Apr 2.

a Toxicological Information Centre , General University Hospital in Prague , Prague , Czech Republic.

Context: The role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning has not been studied.

Objective: We measured the concentrations of lipid peroxidation markers in acutely intoxicated patients with known serum concentrations of methanol and leukotrienes.

Methods: Blood serum samples were collected from 28 patients hospitalized with acute intoxication and from 36 survivors 2 years after discharge. In these samples, concentrations of 4-hydroxy-trans-2-hexenal (HHE), 4-hydroxynonenal (HNE), and malondialdehyde (MDA) were measured using the method of liquid chromatography-electrospray ionization-tandem mass spectrometry.

Results: The maximum acute serum concentrations of all three lipid oxidative damage markers were higher than the follow-up serum concentrations: HNE 71.7 ± 8.0 ng/mL versus 35.4 ± 2.3 ng/mL; p < .001; HHE 40.1 ± 6.7 ng/mL versus 17.7 ± 4.1 ng/mL; p < .001; MDA 80.0 ± 7.2 ng/mL versus 40.9 ± 1.9 ng/mL; p < .001. The survivors without methanol poisoning sequelae demonstrated higher acute serum concentrations of the markers than the patients with sequelae. A correlation between measured markers and serum leukotrienes was present: HNE correlated with LTC4 (r = 0.663), LTD4 (r = 0.608), LTE4 (r = 0.771), LTB4 (r = 0.717), HHE correlated with LTC4 (r = 0.713), LTD4 (r = 0.676), LTE4 (r = 0.819), LTB4 (r = 0.746), MDA correlated with LTC4 (r = 0.785), LTD4 (r = 0.735), LTE4 (r = 0.814), LTB4 (r = 0.674); all p < .001. Lipid peroxidation markers correlated with anion gap (r= -0.428, -0.388, -0.334; p = .026, .045, .080 for HNE, HHE, MDA, respectively). The follow-up serum concentrations of lipid oxidation markers measured in survivors with and without visual/neurological sequelae 2 years after discharge did not differ.

Conclusion: Our results demonstrate that lipid peroxidation plays a significant role in the mechanisms of acute methanol poisoning. The acute concentrations of three measured biomarkers were elevated in comparison with the follow-up concentrations. Neuronal membrane lipid peroxidation seems to activate leukotriene-mediated inflammation as a part of the neuroprotective mechanisms. No cases of persistent elevation were registered among the survivors 2 years after discharge.
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http://dx.doi.org/10.1080/15563650.2018.1455980DOI Listing
October 2018

Diabetes, Cardiovascular Disorders and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Body Burden in Czech Patients 50 Years After the Intoxication.

Basic Clin Pharmacol Toxicol 2018 Sep 7;123(3):356-359. Epub 2018 May 7.

Department of Occupational Medicine, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.

The correlation between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication and the parameters of metabolic impairment was examined in the last eight male survivors of 80 workers exposed to TCDD during the production of herbicides in a chemical factory in 1965-1967. Their median TCDD blood level was 112 (46-390) pg/g lipids, and the median TCDD body deposit was 3.9 (0.8-11.7) μg. This puts these patients into the most severely intoxicated group of subjects, according to back-calculated levels of TCDD. The median TCDD blood level in eight controls was 12 pg/g (<0.10 to 22.2 pg/g). Markers of metabolic impairment - diabetes, dyslipidaemia, arterial hypertension, carotid artery plaque, skin microvascular reactivity, eye fundus hypertensive angiopathy and history of coronary heart disease - were assessed and compared to a general male population of comparable age. Measured parameters compared with a population of comparable age were as follows: prevalence of diabetes (62.5% versus 17.6%), arterial hypertension (87.5% versus 71.8%), dyslipidaemia (87.5% versus 88.8%), history of coronary heart disease (62.5% versus 26.0%) and eye fundus hypertension angiopathy (50% versus 14%). All eight patients (100% versus 43%) developed plaques in carotid arteries, six had stenosis >50% and two had a carotid intervention (stenting or endarterectomy). Total cholesterol levels decreased compared to the earlier study this patient group in 2008, most likely due to a more intensive use of lipid-lowering drugs. Several metabolic parameters were higher (diabetes as much as 3.5-fold) in the group of severely TCDD-intoxicated subjects than in a general population of comparable age. This suggests that TCDD plays a role in the development of metabolic impairment and vascular changes.
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http://dx.doi.org/10.1111/bcpt.13013DOI Listing
September 2018

Comparison Study of Voltammetric Behavior of Muscle Relaxant Dantrolene Sodium on Silver Solid Amalgam and Bismuth Film Electrodes.

J Anal Methods Chem 2017 13;2017:3627428. Epub 2017 Sep 13.

Faculty of Chemical Technology, Institute of Environmental and Chemical Engineering, University of Pardubice, Studentská 573, 53210 Pardubice, Czech Republic.

Voltammetric behavior of muscle relaxant dantrolene sodium (DAN) was studied and the voltammetric methods for its determination using polished and mercury meniscus modified silver solid amalgam electrodes (p-AgSAE and m-AgSAE) as well as using bismuth film electrode (BiFE, ex situ plating on GCE) have been proposed. These working electrodes represent the most commonly used alternatives to mercury ones which come wrongfully into disfavor because of alleged toxicity of mercury. Within this work, the obtained results of DAN determination have been completed by corresponding statistical parameters and also some electrochemical characteristics of AgSAEs and BiFE were assessed, especially in comparison with the mercury electrodes.
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http://dx.doi.org/10.1155/2017/3627428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615959PMC
September 2017

Neurological and Neurophysiological Findings in Workers with Chronic 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Intoxication 50 Years After Exposure.

Basic Clin Pharmacol Toxicol 2018 Feb 27;122(2):271-277. Epub 2017 Sep 27.

Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

The last eight survivors of 80 workers accidentally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during production of herbicides based on trichlorophenoxyacetic acid in 1965-1967 in a chemical factory were followed. All were men, mean age 72.4 ± 1.3 years. Their current median TCDD blood level was 112 (46-390) pg/g lipids. Neurological examination revealed central nervous system impairment in all individuals and signs of polyneuropathy in 87.5%, which was confirmed by a nerve conduction study (NCS) in 75%. A Lanthony test demonstrated acquired dyschromatopsia in 87.5% of the patients, with deterioration of mean colour confusion index (CCI) from 1.52 ± 0.39 in 2010 to 1.73 ± 0.41 in 2016. Single-photon emission computer tomography (SPECT) of the brain showed focal reduction of perfusion in various brain locations in all patients and worsening in six patients. Visual-evoked potentials (VEP) was abnormal in 62.6% of individuals. Most patients complained of psychological problems. The neuropsychological test battery showed most positive impairments in the Trail Making Test evaluating processing speed (average level in the range of mild neurocognitive impairment), which correlated with mean CCI (p < 0.05).

Conclusion: Fifty years after exposure, blood levels of TCDD are still 10 times higher than the general population. NCS, VEP, Lanthony test and SPECT findings deteriorated from examination of these patients in 2004 and in 2010. The total of abnormal tests per patient in 2016 is very high. Minor differences among patients and their reduced count may explain why the number of impairments in 2016 does not correlate with TCDD blood level.
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http://dx.doi.org/10.1111/bcpt.12899DOI Listing
February 2018

Intermittent versus continuous renal replacement therapy in acute methanol poisoning: comparison of clinical effectiveness in mass poisoning outbreaks.

Ann Intensive Care 2017 Dec 20;7(1):77. Epub 2017 Jul 20.

The Norwegian CBRNE Centre of Medicine, Department of Acute Medicine, Oslo University Hospital, Oslo, Norway.

Background: Intermittent hemodialysis (IHD) is the modality of choice in the extracorporeal treatment (ECTR) of acute methanol poisoning. However, the comparative clinical effectiveness of intermittent versus continuous modalities (CRRT) is unknown. During an outbreak of mass methanol poisoning, we therefore studied the effect of IHD versus CRRT on mortality and the prevalence of visual/central nervous system (CNS) sequelae in survivors.

Methods: The study was designed as prospective observational cohort study. Patients hospitalized with a diagnosis of acute methanol poisoning were identified for the study. Exploratory factor analysis and multivariate logistic regression were applied to determine the effect of ECTR modality on the outcome.

Results: Data were obtained from 41 patients treated with IHD and 40 patients with CRRT. The follow-up time in survivors was two years. Both groups of patients were comparable by age, time to presentation, laboratory data, clinical features, and other treatment applied. The CRRT group was more acidemic (arterial blood pH 6.96 ± 0.08 vs. 7.17 ± 0.07; p < 0.001) and more severely poisoned (25/40 vs. 9/41 patients with Glasgow Coma Scale (GCS) ≤ 8; p < 0.001). The median intensive care unit length of stay (4 (range 1-16) days vs. 4 (1-22) days; p = 0.703) and the number of patients with complications during the treatment (11/41 vs. 13/40 patients; p = 0.576) did not differ between the groups. The mortality was higher in the CRRT group (15/40 vs. 5/41; p = 0.008). The number of survivors without sequelae of poisoning was higher in the IHD group (23/41 vs. 10/40; p = 0.004). There was a significant association of ECTR modality with both mortality and the number of survivors with visual and CNS sequelae of poisoning, but this association was not present after adjustment for arterial blood pH and GCS on admission (all p > 0.05).

Conclusions: In spite of the faster correction of the acidosis and the quicker removal of the toxic metabolite in intermittent dialysis, we did not find significant differences in the treatment outcomes between the two groups after adjusting for the degree of acidemia and the severity of poisoning on admission. These findings support the strategy of "use what you have" in situations with large outbreaks and limited dialysis capacity.
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http://dx.doi.org/10.1186/s13613-017-0300-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519513PMC
December 2017

Nonclinical Development of ENV905 (Difluprednate) Ophthalmic Implant for the Treatment of Inflammation and Pain Associated with Ocular Surgery.

J Ocul Pharmacol Ther 2018 Jan/Feb;34(1-2):161-169. Epub 2017 Jun 26.

1 Envisia Therapeutics, Durham, North Carolina.

Purpose: Topical corticosteroids are widely used in the treatment of inflammation and pain after ocular surgery, but they possess several shortcomings, including frequent dosing and low patient adherence. We evaluated the efficacy and pharmacokinetics of ENV905 (difluprednate or DFBA) Ophthalmic Implant, a single-dose drug delivery system, compared with 0.05% Durezol.

Methods: PRINT technology was used to fabricate ENV905 implants for either intracameral (IC) or subconjunctival (SCJ) delivery of extended-release DFBA. A postoperative inflammation model and ocular pharmacokinetics studies of ENV905 or Durezol were conducted in albino rabbits for a maximum of 12 weeks.

Results: Suppression of ocular inflammation was marked for both IC and SJC ENV905 compared with placebo, and it was superior or equivalent to that observed with QID Durezol. Concentrations of desacetyl difluprednate (DFB, active metabolite) peaked on day 1 and tapered over time for ENV905, with IC ENV905 delivering DFB to the target tissue at the time of greatest inflammation, whereas SJC produced a longer duration of exposure. Durezol eyes demonstrated consistent exposure over time with maximal exposure in the cornea. Although the pharmacokinetic profile differed for the two routes, efficacy was similar.

Conclusion: ENV905 was well tolerated and demonstrated a robust reduction in ocular inflammation with targeted drug delivery. The results from these studies show that ENV905 provides a sustained therapeutic effect after a single dose. By resolving low patient compliance and eliminating the peaks and troughs in drug concentration, sustained drug delivery via ENV905 may further improve the overall control of postoperative inflammation and pain.
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http://dx.doi.org/10.1089/jop.2016.0195DOI Listing
October 2019