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Human exposure data on dioxins and dioxin-like compounds (DLCs) in Ghana are limited. Based on health risks associated with dioxins and DLCs, the impact of maternal body burdens on foetal exposure is significant. This is the first study that assesses polychlorinated, polybrominated and mixed halogenated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, PBDD/Fs and PXDD/Fs), and dioxin-like polychlorinated biphenyls (dlPCBs) in sera of primiparous Ghanaians. Our sample selection includes 34 participants from two municipalities (Accra and Tema), and explores contributions from environmental and dietary exposures using questionnaire data. Sample preparation involved C 18 solid phase extraction, purification with acidified silica and lipid removal cartridges, and detection with gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. The calculated average toxic equivalent concentration was 5.3 pg TEQ/g lw, with contributions from dlPCBs (1.25 pg TEQ/g lw), PCDD/Fs (3.10 pg TEQ/g lw), PBDD/Fs (0.49 pg TEQ/g lw) and PXDD/Fs (0.50 pg TEQ/g lw). The calculated total TEQ concentration was lower than background TEQ concentrations reported in sera of pregnant women globally. Positive correlations were obtained for total dioxins and DLC concentrations with age and Body Mass Index (BMI). Dietary intake of seafood and dairy products had a strong influence on PCDD/F and dlPCB concentrations. Statistically significant differences were observed for dioxins and DLCs in participants from Accra (in close proximity to Agbogbloshie e-waste site) and Tema. Given the significant TEQ contribution of PBDD/Fs and PXDD/Fs (~20%), it is essential to explore these classes of dioxins and DLCs in future biomonitoring studies as they may pose health risks, and add extra diagnostic information in source exposure investigations., (Copyright © 2019. Published by Elsevier B.V.)

A large and complex suite of 295 legacy and new halogenated persistent organic pollutants (POPs) were investigated in fat or liver tissue samples of polar bears collected in 2013-2014 from Southern (SHB) and Western (WHB) subpopulations of the Canadian Arctic contaminants hotspot of Hudson Bay. A total of 210 POPs were detected and/or quantifiable with some frequency in all fat or liver samples. POP profile and concentration differences were investigated both within (e.g. age and sex) and between the two subpopulations. Two time-point comparisons were made relative to POPs reported for Hudson Bay polar bears harvested in 2007-2008. ΣPolychlorinated biphenyl (PCB) concentrations at both time points were the most concentrated of the POP groups, and were spatially uniform with no detectable influence of sex or age, as were concentrations of the dominant congener CB153. ΣChlordanes (ΣCHLs, 74-79% oxychlordane) and the Σperfluoroalkyl substances (ΣPFASs, ≈60% perfluorooctane sulfonate (PFOS)) had the second greatest POP group concentrations in SHB and WHB respectively, with ΣPFASs and ΣCHLs being significantly influenced by age and/or sex. ΣCHLs were spatially uniform but ΣPFASs were greater in the SHB bears, as were e.g. some flame retardants, due to e.g. local contamination and/or changes in bear behavior and diet. Endosulfans and hexabromocyclododecane were detectable in samples from 2007-2008 but not from 2013-2014, which is consistent with their global POP regulations. ΣPolychlorinated naphthalenes (ΣPCNs) were consistently detected at relatively high concentrations compared to other arctic wildlife, however these concentrations were low relative to legacy POPs. ΣShort-chain chlorinated paraffins (ΣSCCPs) were major contributors to the overall POPs burden with concentrations comparable to other legacy POPs, though there was no significant difference between or within subpopulations for PCNs or SCCPs. Except for octachlorostyrene, POPs concentrations were generally lower in female and male bears from SHB in 2013-2014 relative to 2007-2008, however those of WHB males were greater over the same timeframe for almost all POPs., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate whether bevacizumab compromises early response assessment after Transarterial Chemoembolization (TACE) in patients with hepatocellular carcinoma by 3D quantitative European Association for the Study of the Liver (qEASL) criteria in comparison to other imaging-based criteria., Materials and Methods: Each of 14 patients receiving TACE and bevacizumab was matched with two patients receiving TACE alone. Baseline and Follow-up MRI was retrospectively analyzed regarding qEASL and other imaging-based criteria., Results: Percentage-based qEASL achieved significant separation in both therapy arms (p=0.046 and p=0.015). Response and Overall Survival showed similar association among treatment groups (p=0.749)., Conclusions: Anti-angiogenic therapy with bevacizumab does not impede early response assessment by qEASL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

An isotope dilution congener-specific method for the determination of the most abundant and most toxic polychlorinated naphthalenes (PCNs) was developed using gas chromatography with high resolution mass spectrometry (GC-HRMS). The method was used to determine the concentration of 24 target congeners and total PCN concentrations in fish and sediment samples. Tissue samples were extracted using pressurized liquid extraction (PLE) and sediment samples were extracted using Soxhlet extraction. Sample extracts were cleaned up using either a manual two-stage open column procedure or an automated FMS Power Prep System with multi-analyte and multi-sample capability using a three-column cleanup procedure. Sediment extracts were cleaned up with a dual open column cleanup technique involving the use of both a multi-layered silica (silver nitrate/acid/base/neutral silica) column followed by column containing carbon-activated silica. Fish tissue extracts were cleaned up on the automated system involving the use of a high capacity ABN (acid/base/neutral column), carbon celite column, and a basic alumina column. The method is capable of producing instrument detection limits (IDLs) between 0.06 and 0.13pg for each PCN (on column), with method detection limits (MDLs) for the fish extracts ranging from 1.3 to 3.4pg/g (wet weight) and 0.46 to 1.2pg/g (dry weight) for sediments. The average accuracy of 34 spiked fish samples analysed over a period of several months was 100% with a precision (%RSD) of 12%. Similarly, the average accuracy for 28 spiked sediment samples was 104% with a precision (%RSD) of 12%. The application of the method to environmental samples was demonstrated through the analysis of sediment and fish samples obtained from Lake Ontario, Canada. The method is used both for the determination of 24 PCNs and to perform non-targeted screening for the remaining 51 PCN congeners, which are included in the total PCN quantification result. It is currently one of the most comprehensive and accurate congener-specific methods available and was developed from the existing techniques used for the determination of polychlorinated dioxins and furans to produce high quality data with only minor modifications in the clean-up procedure. It can therefore be readily adopted by other laboratories performing dioxin and POP analyses., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To evaluate the effects of statin therapy on augmentation index (AIx) as a measure of arterial stiffness using a meta-analysis of clinical trials., Methods: The search included PubMed-Medline, Embase, SCOPUS, Web of Science and Google Scholar databases to identify randomized controlled trials investigating the effects of statin therapy on arterial stiffness measured as AIx. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential confounders., Results: 18 trials examining the effects of statin therapy on arterial stiffness were included. A significant reduction in aortic AIx following statin therapy was proven (WMD: -2.40%, 95% CI: -4.59, -0.21, p=0.032; I(2): 51.20%). HR-adjusted AIx 75% values also revealed a significant improvement by statin therapy (WMD: -5.04%, 95% CI: -7.81, -2.27, p<0.001; I(2): 0%), but not when analysis was restricted to unadjusted AIx values (WMD: -2.30%, 95% CI: -4.83, 0.23, p=0.075; I(2): 53.83%). There was no significant change in carotid (WMD: -2.75%, 95% CI: -8.06, 2.56, p=0.309; I(2): 26.86%) and peripheral (WMD: 0.25%, 95% CI: -3.31, 3.82, p=0.889; I(2): 72.19%) AIx due to statin treatment. There was also no difference in the effect size calculated for different statins subgroups. The impact of statins on AIx was independent of LDL-cholesterol level (slope: 0.05; 95% CI: -0.02, 0.13; p=0.181)., Conclusion: Statin therapy causes a significant reduction in aortic AIx which is independent of LDL-cholesterol changes., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Cardiovascular diseases (CVD) are the major cause of premature death in the world. This study was designed to examine the physicians' knowledge and perception of CVD risk factors and perceived implementation of CVD prevention guidelines as well as barriers to their implementation., Methods: A questionnaire survey by face-to-face interviews was performed among 1382 randomly selected physicians (general practitioners/family medicine specialists, internists and cardiologists) from different regions of Croatia., Results: Most physicians believe that guidelines are useful but only 56.9% are really using some guidelines. 40.2% favour Joint European guidelines. More primary care physicians use their own personal experience in prevention while internists and cardiologists tend more to use the guidelines. 80.6% believe that they treat their patients with dyslipidemia well but only 53.3% knew the LDL-cholesterol goal value for high-risk patients and only 56.2% knew which HDL-cholesterol level is the marker of increased risk. Hypertension was perceived as the most important risk factor, particularly by primary care physicians, while cardiologists tend to favour diabetes. Although most physicians considered the lack of financial resources as the main barrier in CVD prevention, at the same time most of them believe that it could primarily be improved by better patient education., Conclusions: Although most physicians support the guidelines use, only half of them use them and in average their knowledge of guidelines is not satisfactory. This is, together with the lack of time and finances and perceived lack of patients' awareness, probably one of the main causes why they do not manage risk factors better., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Applications of recombinant DNA technology, chemical synthesis on biological templates and fluorescence detection of organophosphorylation provide unexplored avenues for development of antidotes and approaches for remote detection of organophosphate nerve agents and pesticides. We discuss here how acetylcholinesterase (AChE), through appropriate mutations, becomes more susceptible to oxime reactivation. Since the reaction between organophosphate and the mutated enzyme remains rapid, regeneration of active enzyme by oxime becomes the rate-limiting step in the process to complete a catalytic cycle for generation of active enzyme. Accordingly, "Oxime-assisted Catalysis" by AChE provides a potential means for catalyzing the hydrolysis of organophosphates in plasma prior to their reaching the cellular target site. In turn, AChE, when conjugated with organophosphate, is employed as a template for 'click-chemistry, freeze-frame' synthesis of new nucleophilic reactivating agents that could potentially prove useful in AChE reactivation at the target site as well as in catalytic scavenging of organophosphates in plasma. Finally, substituted AChE molecules can be conjugated to fluorophores giving rise to shifts in emission spectra for detection of dispersed organophosphates. Since external reagents do not have to be added to detect the fluorescence change, the modified enzyme would serve as a remote sensor.

The Ellman method for assaying thiols is based on the reaction of thiols with the chromogenic DTNB (5,5'-dithiobis-2-nitrobenzoate) whereby formation of the yellow dianion of 5-thio-2-nitrobenzoic acid (TNB) is measured. The TNB molar absorption coefficient, 13.6 x 10(3)M(-1)cm(-1), as published by Ellman in 1959 has been almost universally used until now. Over the years, however, slightly different values have been published, and it has further been shown that TNB reveals thermochromic properties. This should be taken into account when the Ellman method is used for determination of enzyme activities, such as in cholinesterase assays. Our data show that the absorbance spectra of TNB are shifted to longer wavelengths when temperature increases, while absorbance maxima decrease. Our recommended molar absorption coefficients at 412 nm are 14.15 x 10(3)M(-1)cm(-1) at 25 degrees C and 13.8 x 10(3)M(-1)cm(-1) at 37 degrees C (0.1M phosphate buffer, pH 7.4). Molar absorption coefficients for other temperatures and wavelengths are included in the paper.

The effect of heparin-induced extracorporal lipid precipitation (HELP) on the activities of paraoxonase (EC 3.1.8.1) and arylesterase (EC 3.1.1.2) was studied in serum of a patient with hyperlipoproteinaemia (A) and of a patient with non-insulin dependent diabetes mellitus and hyperlipoproteinaemia (B). The enzyme activities were measured spectrophotometrically (Tris-HCl buffer, pH 7.4, 37 degrees C) with paraoxon and phenylacetate as substrates of paraoxonase and arylesterase, respectively. Both patients underwent HELP applications once a week over a period of 7 weeks. Over that period no overall change was observed either in enzyme activities or in the lipid and protein content of the sera. However, each HELP session caused an immediate decrease of EDTA-insensitive arylesterase activity (on average 56% in A and 42% in B), while EDTA-sensitive arylesterase remained almost unaltered. Paraoxonase remained unchanged in A, but decreased in B (approximately 60%). Of the atherogenic lipoprotein parameters, the most pronounced decrease was found in VLDL-cholesterol and in triglycerides (on average 45% in A and 32% in B), while the anti-atherogenic HDL-cholesterol decreased < 10%. Possible implications of the effect of HELP on the enzyme activities studied remain to be explained.

Catalysed hydrolysis of butyrylthiocholine (BTCh) by the usual (UU), fluoride-resistant (FS), AK, AJ and atypical (AA) human serum butyrylcholinesterase (EC 3.1.1.8) variants was measured in phosphate buffer pH 7.4 at 25 degrees C. pS-curves for all phenotypes were S-shaped; the activities rose to a plateau with increasing substrate concentration except at 100 mM where there was a small decrease. To obtain the catalytic constants, three equations were applied: Michaelis-Menten equation (Eq. 1), Hill equation (Eq. 2) and an equation which assumes simultaneous binding of the substrate to the catalytic site and to a peripheral site on the enzyme (Eq. 3). Over a range from 0.01 to 50 mM BTCh, the activity versus substrate concentration relationship deviated from Michaelis-Menten kinetics (Eq. 1) while data fitted well with Eqs. 2 and 3. The Michaelis-Menten equation was applied separately to two BTCh concentration ranges: the corresponding Km constants for the UU, FS, AK, AJ and AA phenotypes ranged from 0.1 to 0.2 mM (at 0.01-1.0 mM BTCh) and from 0.3 to 2.0 mM (at 1.0-50 mM BTCh). Hill coefficients (nH) calculated from Eq. 2 were similar for all phenotypes (nH approximately 0.5). The dissociation constants K1 and K2 calculated from Eq. 3 for two sites on the enzyme fell between 0.02 and 0.12 mM (K1) and 0.89 and 4.9 mM (K2) for the five phenotypes. Experimental data support the assumption that the phenotypes studied have two substrate binding sites.

Four compounds were prepared: 3-hydroxy-1-methylquinuclidinium iodide (I), 3-(N,N-dimethylcarbamoyloxy)-1-methylquinuclidinum iodide (II), and two conjugates of I and II with 2-hydroxyiminomethyl-3-methylimidazole in which two parts of the molecule were linked by -CH2-O-CH2- (III and IV). III and IV are new compounds and their synthesis and physical data were given. All compounds were tested as inhibitors of human erythrocyte acetylcholinesterase (EC 3.1.1.7, AChE). The enzyme activity was measured in 0.1 M phosphate buffer (pH 7.4) at 10 and 37 degrees C with acetylthiocholine (ATCh) as the substrate. The obtained enzyme/inhibitor dissociation constants were between 0.05 and 0.5 mM at 10 degrees C and between 0.2 and 0.6 mM at 37 degrees C. At both temperatures compounds III and IV had higher affinities for the enzyme than compounds I and II and this difference was more pronounced at 10 than at 37 degrees C. The carbamates II and IV were also progressive AChE inhibitors. For compound II the rate constants of inhibition were 6300 and 2020 M(-1) min(-1) at 37 and 10 degrees C, respectively. Compound IV was a very weak carbamoylating agent with rate constants of inhibition of 100 and 63 M(-1) min(-1) at 37 and 10 degrees C, respectively. The oxime group in compounds III and IV hydrolyzed ATCh at rates of 23 and 3.2 M(-1) min(-1) at 37 and 10 degrees C, respectively.

Inhibition of recombinant mouse wild type AChE (EC 3.1.1.7) and BChE (EC 3.1.1.8), and AChE peripheral site-directed mutants and human serum BChE variants by 4,4'-bipyridine (4,4'-BP) and the coumarin derivative 3-chloro-7-hydroxy-4-methylcoumarin (CHMC) was studied. The enzyme activity was measured with acetylthiocholine as substrate. Enzyme-inhibitor dissociation constants for the catalytic and peripheral sites were evaluated from the apparent dissociation constants as a function of the substrate concentration. Inhibition by 4,4'-BP of AChE, BChE and the AChE mutant Y72N/Y124Q/W286A, was consistent with inhibitor binding to both catalytic and peripheral sites. The dissociation constants for the peripheral site were about 3.5-times higher than for the catalytic site. The competition between CHMC and substrate displayed two binding sites on the AChE mutants Y72N, Y124Q, W286A and W286R, and on the atypical and fluoride-resistant BChE variants. The dissociation constants for the peripheral site were on average two-times higher than for the catalytic site. CHMC displayed binding only to the catalytic site of Y72N/Y124Q/W286A mutant and only to the peripheral site of w.t. AChE and the human usual BChE. Modelling of the 4,4'-BP and CHMC binding to wild type mouse AChE substantiated the difference between the inhibitors in their mode of binding which was revealed in the kinetic studies.

Paraoxonase activities (322 healthy subjects) measured in the absence of ethylenediaminetetraacetic acid (EDTA) had a polymodal distribution profile with 60% of the subjects in the low activity mode; the activity measured in the presence of EDTA had a unimodal skewed distribution. Cholinesterase (ChE) activities (365 healthy subjects) had a unimodal, slightly skewed distribution. Patients with dementia (74) and patients with hyperlipidaemia (159) had different median paraoxonase and ChE activities than healthy subjects and all activity profiles had a higher skewness. The ChE variants usual (UU), fluoride resistant (FS) and atypical (AA) had the same affinity for the studied charged and uncharged ligands. The variants differed in rates of inhibition by the charged organophosphates and carbamates.

In patients with hyperlipaemia, serum paraoxonase activities were polymodally distributed with 75% individuals in the low activity mode. In the same patients the distribution of serum cholinesterase activities was unimodal, but asymmetrical. Patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus had slightly higher cholinesterase activities than patients with hyperlipaemia only.

The hydrolysis of four organophosphorus dichlorophenyl esters and of paraoxon was studied in hen brain homogenates and in rabbit serum. All compounds were hydrolysed by both preparations, but the rates were different in the two preparations. EDTA inhibited the hydrolysis almost completely in rabbit serum, but had only a small effect on the hydrolysis in hen brain homogenates.

The hydrolysis of paraoxon (POX), phenylacetate (PA) and beta-naphthylacetate (BNA) was studied in human serum. Based upon correlations between enzyme activities, upon reversible inhibition by EDTA and upon progressive inhibition by iso-OMPA, tabun, eserine and bis-4 nitrophenylphosphate, the following conclusions were drawn about the number and specificity of enzymes involved in the hydrolysis. Two paraxonases hydrolyse paraoxon: one sensitive and the other insensitive to EDTA. The EDTA-sensitive paraoxonase also hydrolysed BNA. The EDTA-insensitive hydrolysis of BNA and PA was attributed to a serine esterase. The EDTA-sensitive hydrolysis of PA is probably due to more than one enzyme, which might be an arylesterase and a carboxylesterase.

Two pyridinium and two imidazolium dioximes were tested as reversible inhibitors of human erythrocyte acetylcholinesterase (AChE), as protectors of the enzyme against phosphorylation and as reactivators of the phosphorylated AChE. All four dioximes reversibly inhibited AChE, protected the enzyme against phosphorylation by soman and tabun and reactivated AChE after phosphorylation by sarin, VX and tabun. From the experimental results the enzyme/dioxime dissociation constants were evaluated for the catalytically active enzyme and for phosphorylated enzyme. The evaluation constants have shown that all four dioximes have about the same affinity for the catalytically active as for the phosphylated AChE. Obtained results also indicate that imidazolium dioximes probably bind only to the allosteric, while pyridinium dioximes bind to both, the catalytic and the allosteric site of the enzyme.