Increased oxidative/nitrosative stress markers measured non- invasively in patients with high 2,3,7,8-tetrachloro-dibenzo-p-dioxin plasma level.

OBJECTIVES: 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) is a highly toxic persistent environmental contaminant, classified as a human carcinogen affecting any target organ. The mechanism of carcinogenesis by TCDD is unclear as TCDD shows a lack of direct genotoxicity. Experimental studies also support the role of oxidative stress in TCDD neurotoxicity and vascular dysfunction. The aim was to investigate markers of oxidative/nitrosative stress and inflammation using non-invasive methods in subjects who got ill due to severe occupational exposure to TCDD in the years 1965-1968. METHODS: In 11 TCDD-exposed patients, and 16 controls, the analysis of following oxidative products of lipids, proteins and nucleic acids in plasma, urine and exhaled breath condensate (EBC) was performed: 8-iso-prostaglandin F2α (8-isoprostane), 4-hydroxy-trans-2-nonenale (HNE), malondialdehyde (MDA), o-tyrosine (o-Tyr), 8-hydroxyguanosine (8-OHG), 8-hydroxy-2´-deoxy-guanosine (8-OHdG), 5-hydroxymethyluracil (5-OHMeU). In addition, nitric-oxide-tyrosine (NO-Tyr) and leukotriene (LT) B4, C4, D4, and E4 were detected by liquid chromatography-mass spectrometry/mass spectrometry (LC-ESI-MS/MS). TCDD was measured by HRGC/HRMS, body lipid content by densitometry. Single-photon emission spectrometry (SPECT) of the brain was performed and compared with the findings of the patients in 2008. RESULTS: Mean TCDD plasma level in 2010 was 175 ± 162 pg/g lipids (population level about 2 pg/g), total TCDD content in the body 5.16 ± 4.62 mg. Reduction of cerebral blood flow in SPECT progressed in 8 patients, finding was stable in 2 subjects, and improvement occurred in 1 patient. In the EBC, 10 from 12 markers (all except LT D4 and LT E4), were significantly increased in the patients (p<0.05). In the urine, 7 markers were significantly higher than in the controls (p<0.05): 8-isoprostane, MDA, HNE, LT C4, LT E4, o-Tyr and NO-Tyr. In plasma, only NO-Tyr and 8-OHG were elevated (p<0.05). CONCLUSION: NO-Tyr was increased in all matrices in dioxin-exposed patients. EBC is not limited to lung disorders as the markers of oxidative stress and inflammation were elevated in EBC of patients with normal lung functions. TCDD-induced oxidative stress and inflammation markers can be detected non-invasively in the EBC and urine in the follow-up of the highly-exposed patients. Their prognostic value, however, needs to be elucidated.

Efficiency of 123I-ioflupane SPECT as the marker of basal ganglia damage in acute methanol poisoning: 6-year prospective study.

CONTEXT: Investigate whether 123I-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 DaTQUANTTM 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 (r = 0.665; p < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I (p < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH (r = 0.574; p < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations (p < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness (p < 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; p = 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.

MRI-guided voxel-based automatic semi-quantification of dopamine transporter imaging.

PURPOSE: Functional imaging with 123I-FP-CIT SPECT suffers from poor spatial resolution resulting in partial-volume effect, which affects the subsequent semi-quantification. Definition of regions of interest for semi-quantification is further subject to user's experience and inter-observer variability. The aim of this work has been to develop an automatic method for definition of volumes of interest and partial-volume correction using patient-specific MRI and providing complete contrast recovery in striatal region. METHOD: The method consists of spatial pre-processing (image segmentation and multi-modality registration), partial-volume correction (performed by region-based voxel-wise technique), and calculation of uptake indices in striatal structures. Anthropomorphic striatal phantom was used to optimize the method and to assess linearity, accuracy, and reproducibility. The method was tested on 58 patient datasets and compared with clinical assessment and BasGan software. RESULTS: The method works automatically. The output is highly linear regarding changing striatal uptake. Complete contrast recovery is achieved using 6.5 mm FWHM. Accuracy is better than 0.15 in terms of RMSE between measured and true uptake indices. Reproducibility is better than 5% for normal uptake ratio. The method outperformed clinical assessment in all measures. With patient data, it provided results closer to BasGan (RMSE 0.9) than to clinical assessment (RMSE 1.9) and fairly correlated with both. CONCLUSION: The proposed method provides complete recovery of striatal contrast under given acquisition and reconstruction conditions. It reduces intra- and inter-observer variability, accurately defines volumes of interest, and effectively suppresses partial-volume effect. It can be reproduced using publicly available software.

Chronic health impairment due to 2,3,7,8-tetrachloro-dibenzo-p-dioxin exposure.

OBJECTIVES: The aim of this study, performed in 2008, was to evaluate the consequences of severe occupational intoxication with 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) that occurred during production of the herbicide trichlorophenoxyacetic acid in the period 1965-1968. DESIGN: Examination of 11 men, mean age 64.4+/-1.5 years, included: internal and neurological examination, eye fundus examination, TCDD in plasma, thyroid-stimulating hormone (TSH), testosterone and serum lipids, ultrasonography of the carotid artery, nerve conduction study (NCS), electroencephalography (EEG), visual evoked potential (VEP), Lanthony test of acquired visual impairment, single photon emission computer tomography (SPECT) of the brain, neuropsychological examination and carbohydrate-deficient transferrin (CDT), a marker of chronic ethanol intake. RESULTS: Mean TCDD level in 2008 was still 274.0+/-181.2 pg/g blood lipids (reference level is 2-3 pg/g). All (100%) patients had residues of chloracne/chloracne consequences, atherosclerotic changes on the eye fundus and plaques in the carotid arteries. Progression of intima-media thickness (IMT) from a mean of 0.84+/-0.14 mm in 2003 to 1.09+/-0.18 mm in 2008 was observed. Ninety-one per cents of patients had impairment in SPECT of the brain; and 55% of patients had hyperfixation of the perfusion indicator as a measure of increased neuronal activity. Additionally, 91 % of patients were treated for hyperlipidaemia, 73 % for hypertension, 55 % for diabetes type 2, 45 % for ischemic heart disease, and 36 % for psychological disorders. The Lanthony test demonstrated acquired dyschromatopsia in 80 % of patients. Mean colour confusion index (CCI) was 1.438, which indicates impairment since 2003, when the index was 1.302. CDT was in the normal range and did not correlate with CCI. Neuropsychological status appeared stabilized in all 8 patients examined, with impairment in one or more parameter (memory, attention, verbal fluency, psychomotor speed, motorics) in comparison to the norm. CONCLUSION: Forty years after intoxication, the blood level of TCDD is still 100 times higher than in the general population. Other PCDD/Fs were not elevated. A high percentage of subjects suffer from neurological and vascular disorders. No association of alcohol consumption with neurological impairment was seen, and the highly significant correlation between CCI and TCDD blood concentration suggests that acquired colour impairment was associated with TCDD but not with alcohol consumption. IMT significantly increased during past 5 years. The patients obviously need complex treatment, including intense hypolipidaemic and antidepressant therapy.

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

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.

Prospective memory impairment in idiopathic REM sleep behavior disorder.

OBJECTIVE: The aim of the present study was to investigate if prospective memory (PM) is impaired in idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). RBD is a parasomnia characterized by dream enactment and by REM sleep without muscle atonia. iRBD is considered as the initial stage of neurodegeneration with pathological storage of alpha-synuclein. METHOD: Sixty iRBD patients with polysomnography-confirmed RBD without parkinsonism and dementia and 30 demographically matched normal controls (NC) were enrolled in the present study. Clinical assessment included Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), dopamine transporter single-photon emission computed tomography (DaT-SPECT) for imaging synapses of dopaminergic neurons in the striatum and a neuropsychological battery with embedded time-based and event-based PM measures. RESULTS: iRBD differed significantly from NC in event-based PM, a number of event-based failures to recall intention and total PM performance (all p < .001) but did not differ in time-based PM and recognition. PM did not contribute to impairment of instrumental activities of daily living in iRBD. Despite being preserved in iRBD in comparison to NC, time-based PM correlated significantly with dopaminergic neuronal loss measured by DaT-SPECT. CONCLUSIONS: We show evidence for a differential pattern of PM impairment in iRBD with severe impairment of event-based and concurrent preservation of time-based PM. We theorize that event-based PM impairment in iRBD is caused by severe impairment of retention and recognition mechanisms in episodic memory whereas time-based PM seems to be affected by reduced striatal dopaminergic synapses.

The analysis of soil cores polluted with certain metals using the Box-Cox transformation.

To define the soil properties for a given area or country including the level of pollution, soil survey and inventory programs are essential tools. Soil data transformations enable the expression of the original data on a new scale, more suitable for data analysis. In the computer-aided interactive analysis of large data files of soil characteristics containing outliers, the diagnostic plots of the exploratory data analysis (EDA) often find that the sample distribution is systematically skewed or reject sample homogeneity. Under such circumstances the original data should be transformed. The Box-Cox transformation improves sample symmetry and stabilizes spread. The logarithmic plot of a profile likelihood function enables the optimum transformation parameter to be found. Here, a proposed procedure for data transformation in univariate data analysis is illustrated on a determination of cadmium content in the plough zone of agricultural soils. A typical soil pollution survey concerns the determination of the elements Be (16 544 values available), Cd (40 317 values), Co (22 176 values), Cr (40 318 values), Hg (32 344 values), Ni (34 989 values), Pb (40 344 values), V (20 373 values) and Zn (36 123 values) in large samples.

Assessment of the mean-value of 17-hydroxypregnenolone in the umbilical blood of newborns by the exploratory analysis of biochemical data.

The main aim of data analysis in biochemical metrology is the extraction of relevant information from biochemical data measurements. A system of extended exploratory data analysis (EDA) based on the concept of graphical tools for sample data summarization and exploration is proposed and the original EDA algorithm in S-Plus is available on the Internet at http://www.trilobyte.cz/EDA. To check basic assumptions about biochemical and medical data is to examine the independence of sample elements, sample normality and homogeneity. The exact assessment of the mean-value and the variance of steroid levels in controls is necessary for the correct assessment of the samples from patients. Data examination procedures are illustrated by a determination of the mean-value of 17-hydroxypregnenolone in the umbilical blood of newborns. For an asymmetric, strongly skewed sample distribution corrupted with outliers the best estimate of location seems to be the median. The Box-Cox transformation improves a sample symmetry. The proposed procedure gives reliable estimates of a mean-value for an asymmetric distribution of 17-hydroxypregnenolone when the arithmetic mean can not be used.

The effect of influential data, model and method on the precision of univariate calibration.

Building a calibration model with detection and quantification capabilities is identical to the task of building a regression model. Although commonly used by analysts, an application of the calibration model requires at first careful attention to the three components of the regression triplet (data, model, method), examining (a) the data quality of the proposed model; (b) the model quality; (c) the LS method to be used or a fulfillment of all least-squares assumptions. This paper summarizes these components, describes the effects of deviations from assumptions and considers the correction of such deviations: identifying influential points is the first step in least-squares model building, the calibration task depends on the regression model used, and finally the least squares LS method is based on assumptions of normality of errors, homoscedasticity, independence of errors, overly influential data points and independent variables being subject to error. When some assumptions are violated, the ordinary LS is inconvenient and robust M-estimates with the iterative method of reweighted least-squares must be used. The effects of influential points, heteroscedasticity and non-normality on the calibration precision limits are also elucidated. This paper also considers the proper construction of the statistical uncertainty expressed as confidence limits predicting an unknown concentration (or amount) value, and its dependence on the regression triplet. The authors' objectives were to provide a thorough treatment that includes pertinent references, consistent nomeclature, and related mathematical formulae to show by theory and illustrative examples those approaches best suited to typical problems in analytical chemistry. Two new algorithms, calibration and linear regression written in s-plus and enabling regression triplet analysis, the estimation of calibration precision limits, critical levels, detection limits and quantification limits with the statistical uncertainty of unknown concentrations, form the goal of this paper.