Search

Chronic copper toxicosis in cattle has never been reported in Israel and very rarely abroad. Chronic copper toxicity in cattle results mostly from the ingestion of high copper containing feeds, or due to accidental administration of excessive amounts of soluble copper salts. In February of 2015, the complete feed for lactating Holstein-Friesian dairy herd was accidently supplemented with 250 mg copper /kg complete feed. By June of 2015, clinical signs of copper intoxication occurred in several cows followed by sudden death of twenty cows within 4 days. The mean liver and kidney copper level was 405±120 mg/kg and 29±16 mg/kg, respectively. The remaining herd was treated with 200 mg/cow/day of sodium molybdenum for 7 days added to the new feed from which the copper supplement has been removed. Subsequently, sodium molybdenum supplement was terminated and the herd was further fed on complete feed lacking any copper supplements for several months. About 2-3 months after the remedial management of the dairy herd, a full recovery of the animals was observed, with milk production and body condition returning to normal. The molybdenum therapy achieved a 50% reduction in mean liver copper level. In contrast, the mean kidney copper level was reduced to normal levels only 2-3 months post treatment. It was concluded that chronic copper poisoning of dairy cows can be successfully treated by the removal of all copper supplements from feed and oral administration of 200 mg molybdenum/cow/day, thereby reducing liver and kidney levels within 2-3 months to normal values. [ABSTRACT FROM AUTHOR]

Inspection of feed and animal derived food products is of utmost importance in providing safe feed and food products. Chemical as well as microbial contaminants are frequently encountered in various food and feed commodities thereby potentially endangering public health as well as animal well-being. In February 2014 a new law, namely the Control of Animal Feed Law, was approved by the Israeli parliament and which will come into force in 2017. The law regulates the production, safety and marketing of animal feed and animal derived products. In the present review, we have summarized the major feed and animal-derived food product contaminants most frequently encountered in Israel. The need for a governmental regulated feed safety laboratory, is crucial for ensuring public and animal health, thereby guarantying the safety of animal feed and consequently the quality of animal-derived food products. [ABSTRACT FROM AUTHOR]

Clove (Syzygium aromaticum) oil is primarily a mixture of monoterpenes, allylphenols and its major component is eugenol. A study was conducted to determine the stability and sustainability of clove oil components in beeswax samples under semi-field conditions. Five wooden hives with ten comb foundations of frames were used; none of the hives contained bees. For the assays in the four hives, 50 ml of 1% clove oil was tested using different emulsifiers and modes of application. Tween 80 and paraffin oil emulsifiers were used via both evaporation from cups and the spraying method on each of the separate hives. One hive containing blank beeswax was kept as control. Characterization of clove oil and contamination levels of its components in beeswax on days 1, 2, 5, 7, 14 and 28 were determined via gas chromatography/mass spectrophotometry analysis. Eugenol was detected and identified as the major component; its level in beeswax was determined to be stable for up to three weeks with three of the dispensers, but it was not stable when used with paraffin oil using the cup method application. As a result of these studies, we found that if clove oil is used for honeybee Varroosis with different dispensers, eugenol can be stable for a minimum of two weeks in beeswax. As a result, this period should be considered during treatment of Varroosis and before honey harvesting. Absorption and accumulation of eugenol and other effective volatile essential oils and monoterpenes into beeswax may make honeycombs as a secondary, sustain release source. [ABSTRACT FROM AUTHOR]

Background: In recent years, hydroponically cultivated basil has gained extensive popularity over soil-based cultivation. Evidence for potential differences between both cultivation methods, in terms of resistance to biotic and abiotic stress factors, storage properties and shelf-life, is still lacking and the potential effect of cultivation method on the antioxidant capacity has not yet been fully explored. This study aimed to determine which of the two basil cultivation methods produces plants that are more resilient to downy mildew and external heat treatment and that exhibit better storage and shelf-life performance., Results: Hydroponically grown basil was significantly more affected by browning than the soil-grown basil at the end of the storage and end of the shelf-life period. Under both cultivation methods, the extent of browning increased significantly between the end of the storage and end of the shelf-life period, by a factor of 1.4. Moreover, hydroponically grown plants were significantly more sensitive to heat treatment than soil-grown basil. However, the soil-grown basil exhibited significantly greater susceptibility to downy mildew than the hydroponically grown basil. At harvest, and at the end of the storage period, the antioxidant capacity of hydroponically cultivated basil was significantly greater than that of soil-grown basil., Conclusions: Hydroponically cultivated basil exhibited greater resistance to downy mildew, but less resilience to heat and browning during storage and a shelf-life period, resulting in poorer storage and shelf-life performance as compared to soil-cultivated basil. The greater total antioxidant capacity of the hydroponically cultivated basil seems to be the major cause for the observed phenomena. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Cannabis sativa L. is used to treat a wide variety of medical conditions, in light of its beneficial pharmacological properties of its cannabinoids and terpenes. At present, the quantitative chemical analysis of these active compounds is achieved through the use of laborious, expensive, and time-consuming technologies, such as high-pressure liquid-chromatography- photodiode arrays, mass spectrometer detectors (HPLC-PDA or MS), or gas chromatography-mass spectroscopy (GC-MS). Hence, we aimed to develop a simple, accurate, fast, and cheap technique for the quantification of major cannabinoids and terpenes using Fourier transform near infra-red spectroscopy (FT-NIRS). FT-NIRS was coupled with multivariate classification and regression models, namely partial least square-discriminant analysis (PLS-DA) and partial least squares regression (PLS-R) models. The PLS-DA model yielded an absolute major class separation (high-THC, high-CBD, hybrid, and high-CBG) and perfect class prediction. Using only three latent variables (LVs), the cross-validation and prediction model errors indicated a low probability of over-fitting the data. In addition, the PLS-DA model enabled the classification of chemovars with genetic-chemical similarities. The classification of high-THCA chemovars was more sensitive and more specific than the classifications of the remaining chemovars. The prediction of cannabinoid and terpene concentrations by PLS-R yielded 11 robust models with high predictive capabilities (R 2 CV and R 2 pred > 0.8, RPD >2.5 and RPIQ >3, RMSECV/RMSEC ratio <1.2) and additional 15 models whose performance was acceptable for initial screening purposes (R 2 CV  > 0.7 and R 2 pred < 0.8, RPD >2 and RPIQ <3, 1.2 < RMSECV/RMSEC ratio <2). Our results confirm that there is sufficient information in the FT-NIRS to develop cannabinoid and terpene prediction models and major-cultivar classification models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Varroa control is essential for the maintenance of healthy honey bee colonies. Overuse of acaricides has led to the evolution of resistance to those substances. Studies of the short-term acaricidal effects and safety of various lithium (Li) salts recently have been reported. This study examined the long-term in vitro and in vivo bee toxicities, short-term motor toxicity to bees and long-term anti-Varroa field efficacy of several Li salts., Results: In an in vitro chronic-toxicity assay, lithium citrate (18.8 mm) was the most toxic of the examined salts, followed by lithium lactate (29.5 mm), and lithium formate (32.5 mm). In terms of acute locomotor toxicity to bees, all of the Li salts were well-tolerated and none of the treatment groups differed from the negative control group. In an in vitro survival study, all of the Li treatments significantly reduced bee life spans by a factor of 1.8-7.2, as compared to the control. In terms of life expectancy, lithium citrate was the most toxic salt, with no significant differences noted between lithium formate and lithium lactate. In the bee-mortality field study, none of the examined treatments differed from the negative control. Amitraz and lithium formate exhibited similar acaricide effects, which were significantly different from those observed for lithium lactate and the negative control., Conclusion: In light of lithium formate's honey bee safety and efficacy as an acaricide, additional sublethal toxicity studies in brood, drones and queens, as well as tests aimed at the optimization of administration frequency are warranted. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the superoxide dismutase (SOD1) gene, causing protein misfolding and aggregation, were suggested as the pathogenic mechanisms involved in familial ALS cases. In the present study, we investigated the potential therapeutic effect of C4 and C5, two derivatives of the chemical chaperone 4-phenylbutyric acid (4-PBA). By combining in vivo and in vitro techniques, we show that, although C4 and C5 successfully inhibited amyloid aggregation of recombinant mutant SOD1 in a dose-dependent manner, they failed to suppress the accumulation of misfolded SOD1. Moreover, C4 or C5 daily injections to SOD1 G93A mice following onset had no effect on either the accumulation of misfolded SOD1 or the neuroinflammatory response in the spinal cord and, consequently, failed to extend the survival of SOD1 G93A mice or to improve their motor symptoms. Finally, pharmacokinetic (PK) studies demonstrated that high concentrations of C4 and C5 reached the brain and spinal cord but only for a short period of time. Thus, our findings suggest that use of such chemical chaperones for ALS drug development may need to be optimized for more effective results.

Cannabis is used to treat various medical conditions, and lines are commonly classified according to their total concentrations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Based on their ratio of total THC to total CBD, cannabis cultivars are commonly classified into high-THC, high-CBD, and hybrid classes. While cultivars from the same class have similar compositions of major cannabinoids, their levels of other cannabinoids and their terpene compositions may differ substantially. Therefore, a more comprehensive and accurate classification of medicinal cannabis cultivars, based on a large number of cannabinoids and terpenes is needed. For this purpose, three different chemometric-based classification models were constructed using three sets of chemical profiles. We examined those models to determine which provides the most accurate "chemovar" classification. This was done by analyzing profiles of cannabinoids, terpenes, and the combination of these substances using the partial least square-discriminant analysis multivariate (PLS-DA) technique. The chemical profiles were selected from the three major classes of medicinal cannabis that are most commonly prescribed to patients in Israel: high-THC, high-cannabigerol (CBG), and hybrid. We studied the correlations between cannabinoids and terpenes to identify major bio-indicators representing the plant's terpene and cannabinoid content. All three PLS-DA models provided highly accurate classifications, utilizing six to nine latent variables with an overall accuracy ranging from 2 to 11% CV. The PLS-DA model applied to the combined cannabinoid-and-terpene profile did the best job of differentiating between the chemovars in terms of misclassification error, sensitivity, specificity, and accuracy. The combined cannabinoid-and-terpene PLS-DA profile had cross-validation and prediction misclassification errors of 4% and 0%, respectively. This is the first study to demonstrate the highly accurate classification of samples of medicinal cannabis based on their cannabinoid and terpene profiles, as compared to cannabinoid profiles alone. Furthermore, our correlation analysis indicated that 11 cannabinoids and terpenes might serve as bio-indicators for 32 different active compounds. These findings suggest that the use of multivariate statistics could assist in breeding studies and serve as a tool for minimizing the mislabeling of cannabis inflorescences., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Fractional exhaled nitric oxide (FeNO) is a cost-effective, noninvasive point-of-care test that has proven valuable in identifying patients with lower airway inflammation and predicting the likelihood of responsiveness to inhaled corticosteroid therapy in asthma. The utility of FeNO in upper airway disease, specifically in CRS, remains to be determined., Objective: The goal of this study was to test whether FeNO could serve as a noninvasive marker of sinonasal mucosal inflammation in CRS patients., Methods: FeNO was obtained using a nitric oxide analyzer (NIOX VERO) as well as nasal mucus, the 22-item Sinonasal Outcome Test (SNOT-22), University of Pennsylvania Smell Identification Test (UPSIT), and Lund-Kennedy endoscopic scores concurrently in 112 CRS patients. Nasal mucus was analyzed for cytokine expression using solid-phase sandwich ELISA. Linear regression with Spearman correlation coefficient was used to determine strength of relationship between variables., Results: CRS patients showed elevated FeNO levels with asthma (47.12 ± 5.21 ppb) or without asthma (43.24 ± 9.810 ppb). Elevated FeNO levels correlated with sinonasal mucosal inflammation, as determined by increased levels of CCL26 and TNFα in nasal mucus obtained from CRS patients. Furthermore, elevated FeNO levels selectively correlated with worsened SNOT-22 nasal symptoms (P = 0.03) and Lund-Kennedy endoscopic scores (P = 0.007), but did not correlate with UPSIT scores., Conclusions: FeNO levels correlated with increased sinonasal mucosal inflammation and symptom severity in CRS regardless of asthma status. FeNO measurements may serve as a quick and noninvasive marker in evaluating CRS patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SEL: Clinical trial funding: Sanofi Aventis Regeneron, GlaxoSmithKline, AstraZeneca, Genentech, Optinose. Advisory board: Sanofi Aventis Regeneron, GlaxoSmithKline, AstraZeneca, Genentech Novartis. JAM: Clinical Trial Salary Support: Sanofi Aventis Regeneron, GlaxoSmithKline, AstraZeneca, Genentech, Optinose.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons. About 20% of familial ALS cases are caused by dominant mutations in SOD1. It has been suggested that toxicity of mutant SOD1 results from its misfolding, however, it is unclear why misfolded SOD1 accumulates within specific tissues. We have demonstrated that macrophage migration inhibitory factor (MIF), a multifunctional protein with cytokine/chemokine and chaperone-like activity, inhibits the accumulation and aggregation of misfolded SOD1. Although MIF homolog, D-dopachrome tautomerase (D-DT/MIF-2), shares structural and genetic similarities with MIF, its biological function is not well understood. In the current study, we investigated, for the first time, the mechanism of action of D-DT in a model of ALS. We show that D-DT inhibits mutant SOD1 amyloid aggregation in vitro, promoting the formation of amorphous aggregates. Moreover, we report that D-DT interacts with mutant SOD1, but does not inhibit misfolded mutant SOD1 accumulation and toxicity in neuronal cells. Finally, we show that D-DT is expressed mainly in liver and kidney, with extremely low expression in brain and spinal cord of adult mice. Our findings contribute to better understanding of D-DT versus MIF function in the context of ALS., (© 2022. The Author(s).)

Background: Terpene, eugenol and polyphenolic contents of basil are major determinants of quality, which is affected by genetics, weather, growing practices, pests and diseases. Here, we aimed to develop a simple predictive analytical method for determining the polyphenol, eugenol and terpene content of the leaves of major Israeli sweet basil cultivars grown hydroponically, as a function of harvest time, through the use of near-infrared (NIR) spectroscopy, liquid/gas chromatography, and chemometric methods. We also wanted to identify the harvest time associated with the highest terpene, eugenol and polyphenol content., Results: Six different cultivars and four different harvest times were analyzed. Partial least square regression (PLS-R) analysis yielded an accurate, predictive model that explained more than 93% of the population variance for all of the analyzed compounds. The model yielded good/excellent prediction (R 2  > 0.90, R 2 cv and R 2 pre  > 0.80) and very good residual predictive deviation (RPD > 2) for all of the analyzed compounds. Concentrations of rosmarinic acid, eugenol and terpenes increased steadily over the first 3 weeks, peaking in the fourth week in most of the cultivars. Our PLS-discriminant analysis (PLS-DA) model provided accurate harvest classification and prediction as compared to cultivar classification. The sensitivity, specificity and accuracy of harvest classification were larger than 0.82 for all harvest time points, whereas the cultivar classification, resulted in sensitivity values lower than 0.8 in three cultivars., Conclusion: The PLS-R model provided good predictions of rosmarinic acid, eugenol and terpene content. Our NIR coupled with a PLS-DA demonstrated reasonable solution for harvest and cultivar classification. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Although amitraz is one of the acaricides most commonly applied within beehives, to date, its time-dependent oral toxicity in honeybees has not been investigated, due to amitraz's instability in aqueous media. In aqueous media such as honey, amitraz rapidly forms a continuously changing tertiary mixture with two of its major hydrolysis products, DMF and DMPF. The contribution of each hydrolysis product to the overall oral toxicity of this acaricide is not known. Therefore, we aimed to characterize the depletion and formation kinetics of amitraz and its hydrolysis products in 50% sucrose solution provided to caged honeybees, including the calculation of the 50% lethal oral concentration (LC 50 ) of amitraz. We sought to determine the contribution of each component of the mixture to the overall observed toxicity. We also investigated the time- and concentration-dependent toxicity of the amitraz mixture and its hydrolysis products. A novel approach based on the analysis of the areas under the depletion and formation curves of amitraz and its hydrolysis products revealed that DMPF, amitraz and DMF accounted for 92%, 7% and 1% (respectively) of the overall toxicity of the mixture. The chronic oral LC 50 of amitraz was 3300 μmol/L, of similar magnitude as that of the non-toxic hydrolysis product DMF. The toxicity of DMPF and the mixture decreased over time; whereas the toxicity of DMF increased over time. Amitraz's instability in aqueous media and the highly toxic profile of DMPF, suggest that DMPF is the actual toxic entity responsible for amitraz's toxicity toward honeybees., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Honeybees are exposed to a wide range of pesticides for long periods via contaminated water, pollen and nectar. Some of those pesticides might constitute health hazards in a time- and dose-dependent manner. Time-dependent toxicity profiles for many applied pesticides are lacking, despite the fact that such profiles are crucial for toxicological evaluations. Therefore, we sought to determine the time-dependent toxicities of pesticides/pesticide metabolites frequently found in Israeli beehives, namely, amitraz metabolites, N'-(2,4-dimethylphenyl)-N-methylformamidine (DMPF) and N-(2,4-dimethylphenyl)-formamide (DMF), coumaphos, imidacloprid, thiacloprid, acetamiprid and dimethoate (toxic reference). By applying accepted methodological approaches such as the modified Haber's rule (product of concentration and exposure duration leads to a constant effect) and comparisons between cumulative doses at different time points, we determined the time-dependent toxicities of these pesticides. We also studied the mixture toxicities of frequently occurring pesticide combinations and estimated their potential contributions to the overall toxicities of neonicotinoids. Thiacloprid was the only pesticide that complied with Haber's rule. DMPF, dimethoate and imidacloprid exhibited time-diminished -toxicities. In contrast, DMF and acetamiprid exhibited time-reinforced toxicities. Neither the binary mixtures nor the tertiary mixtures of DMF, DMPF and coumaphos at 10 times their environmentally relevant concentrations potentiated the neonicotinoids' toxicities. DMPF and imidacloprid were found to present the greatest hazard to honeybees, based on their 50% lethal cumulative dose and 50% lethal time. Amitraz's instability, its low detection frequency and high toxicity profile of its metabolite, DMPF, lead us to the conclusion that DMPF constitutes the actual toxic entity responsible for amitraz's toxic effect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pyrrolizidine alkaloids (PAs) are genotoxic carcinogenic phytotoxins mostly prevalent in the Boraginaceae, Asteraceae and Fabaceae families. Heliotropium species (Boraginaceae) are PA-producing weeds, widely distributed in the Mediterranean region, that have been implicated with lethal intoxications in livestock and humans. In Israel, H. europaeum , H. rotundifolium and H. suaveolens are the most prevalent species. The toxicity of PA-producing plants depends on the PA concentration and composition. PAs occur in plants as mixtures of dozens of various PA congeners. Hence, the risk arising from simultaneous exposure to different congeners has to be evaluated. The comparative risk evaluation of the three Heliotropium species was based on recently proposed interim relative potency (iREP) factors, which take into account certain structural features as well as in vitro and in vivo toxicity data obtained for several PAs of different classes. The aim of the present study was to determine the PA profile of the major organ parts of H. europaeum , H. rotundifolium and H. suaveolens in order to assess the plants' relative toxic potential by utilizing the iREP concept. In total, 31 different PAs were found, among which 20 PAs were described for the first time for H. rotundifolium and H. suaveolens . The most prominent PAs were heliotrine- N -oxide, europine- N -oxide and lasiocarpine- N -oxide. Europine- N -oxide displayed significant differences among the three species. The PA levels ranged between 0.5 and 5% of the dry weight. The flowers of the three species were rich in PAs, while the PA content in the root and flowers of H. europaeum was higher than that of the other species. H. europaeum was found to pose a higher risk to mammals than H. rotundifolium , whereas no differences were found between H. europaeum and H. suaveolens as well as H. suaveolens and H. rotundifolium .

Throughout the world, more than six billion people consume milk and milk products yearly. The safety and quality of dairy milk are regularly monitored in most countries worldwide. The Israeli monitoring program of chemical residues in milk has not changed in the last decades, focusing only on major veterinary drugs and few selected environmental contaminants such as heavy metals and persistent organic pollutants. Consequently, a knowledge gap exists regarding the potential occurrence of other chemicals such as human pharmaceuticals and non-monitored pesticides in milk. In this survey, 51 commercial bovine and goat milk samples were analysed by LC-MS/MS and pharmaceutical and pesticide residues are reported in the range of 0.1-93 µg/L. Israeli milk samples revealed at least one and up to five chemical residues simultaneously. The pesticides found in milk were below the European maximum residue limit values. The risk assessment performed, indicated negligible risk.

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase ( SCD1 ) as a key player. In vivo SCD1 overexpression increases CNS disease, whilst genetic or pharmacological inhibition of SCD1 decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically., Competing Interests: Competing interests E.G. is a Board member and a Shareholder of Metabomed Ltd Israel, J.J.K. is an employee and shareholder of Rheos Medicines Inc. All other authors declare no potential conflicts of interest.

Postharvest application of fungicides is commonly applied in order to reduce food loss. Prochloraz is currently the only postharvest fungicide registered in Israel and Europe in avocado fruits. Due to its unfavorable toxicological properties, prochloraz will be banned from the end of 2020 for future postharvest usage and therefore a substitute candidate is urgently warranted. Fludioxonil, a relatively safe, wide spectrum fungicide, is approved in Europe and Israel for postharvest use in various fruits, but not avocado. Hence, fludioxonil has been evaluated in the present study as a potential substitute for prochloraz in avocado. The objectives of the present study were to determine fludioxonil efficacy against common fungal infestations in avocado and distribution kinetics between peel and pulp in comparison to prochloraz. At the same concentration range (75-300 µg/L), fludioxonil was as effective as prochloraz in inhibiting postharvest decay, while in the early season cultivars, suffering mainly from stem-end rot, it exhibited a better decay control than prochloraz. Fludioxonil and prochloraz displayed negligible and undetected pulp levels, respectively, due to low peel penetrability. Taken altogether, fludioxonil was found to be a suitable candidate for replacing prochloraz as a postharvest fungicide in avocado., Competing Interests: The authors state no conflicts of interest.

Beehive products are considered sentinels for environmental pollutants. The presence of trace elements and pesticides in honey and beeswax may pose a health hazard to consumers. The study's aim was to determine the profile of pesticides and trace elements in Israeli honey and beeswax samples in relation to human risk assessment. At least two pesticides contaminated the honey and beeswax samples simultaneously, in which, amitraz metabolites and coumaphos were frequently detected. The neonicotinoid insecticides and 2,4-dichlorophenoxyacetic acid, were found only in honey samples, whereas the more lipophilic pesticides were predominantly found in beeswax. In honey, chromium displayed the highest mean concentration, followed by zinc, whereas lead and molybdene occurred only in beeswax. Our findings indicate that the daily consumption of honey and beeswax together may compromise children's health. Sucrose-syrup fed honey could not be distinguished from floral honey based on sugar profile, rather by its trace elements levels., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Beehive products such as honey, beeswax and recently pollen have been regarded for many years as appropriate sentinels for environmental pesticide pollutions. However, despite yearly application of hundreds of approved pesticides in agricultural fields, only a minor fraction of these organic compounds were actually detected in honey and beeswax samples. This observation has led us to question the general suitability of beehive products as a sentinel for synthetic organic pesticides applied in the field. The aim of the present study was to experimentally determine the distribution (logarithmic ratio of beeswax to honey pesticide concentration, LogD) and depletion kinetics (half-life) of selected pesticides in honey and beeswax as a measure of the latter matrixes to serve as a pesticide sentinel. The obtained parameters were used to extrapolate to pesticide burden in honey and beeswax samples collected from German and Israeli apiaries. In addition, we aimed to establish a mathematical model, enabling us to predict distribution of selected pesticides between honey to beeswax, by utilizing simple substance descriptors, namely, octanol/water partitioning coefficient, molar weight and Henry coefficient. Based on the present results, it appears that pesticides with LogD values > 1 and half-life in beeswax > 1 day, were likely to accumulate and detected in beeswax samples, and less likely to be found in honey. On the other hand, pesticides with negative LogD values were highly likely to be found in honey and less so in beeswax samples. Finally, pesticides with LogD values between 0-1 were expected to be found in both matrixes. The developed model was successfully applied to predict LogD values, thereby identifying octanol/water partitioning and molar weight as the most prominent substance descriptors, which affect pesticide distribution between honey and beeswax., Competing Interests: We have the following interests. Roy Sperling is employed by Bilacon GMbH who provided analytical services for the study. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Pyrrolizidine alkaloids are among the most common poisonous plants affecting livestock, wildlife, and humans. Exposure of humans and livestock to toxic pyrrolizidine alkaloids through the intake of contaminated food and feed may result in poisoning, leading to devastating epidemics. During February 2014, 73 mixed breed female beef cows from the Galilee region of Israel were accidently fed pyrrolizidine alkaloid contaminated hay for 42 days, resulting in the sudden death of 24 cows over a period of 63 days. The remaining cows were slaughtered 2.5 months after the last ingestion of the contaminated hay. In this study, we report the histopathological analysis of the livers from five of the slaughtered cows and quantitation of pyrrolizidine alkaloid-derived DNA adducts from their livers and three livers of control cows fed with feed free of weeds producing pyrrolizidine alkaloids. Histopathological examination revealed that the five cows suffered from varying degrees of bile duct proliferation, fibrosis, and megalocytosis. Selected reaction monitoring HPLC-ES-MS/MS analysis indicated that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts were formed in all five livers. The livers from the three control cows did not have any liver damage nor any indication of DHP-DNA adduct formed. These results confirm that the toxicity observed in these cattle was caused by pyrrolizidine alkaloid poisoning and that pyrrolizidine alkaloid-derived DNA adducts could still be detected and quantified in the livers of the chronically poisoned cows 2.5 months after their last exposure to the contaminated feed, suggesting that DHP-derived DNA adducts can serve as biomarkers for pyrrolizidine alkaloid exposure and poisoning.

The Israeli feed safety legislation, which came to prominence in the early 1970s, has undergone a major change from simple feed safety and quality regulations to a more holistic concept of control of feed safety and quality throughout the whole feed production chain, from farm to the end user table. In February 2014, a new law was approved by the Israeli parliament, namely the Control of Animal Feed Law, which is expected to enter into effect in 2017. The law is intended to regulate the production and marketing of animal feed, guaranteeing the safety and quality of animal products throughout the production chain. The responsibility on the implementation of the new feed law was moved from the Plant Protection Inspection Service to the Veterinary Services and Animal Health. In preparation for the law's implementation, we have characterized the various sources and production lines of feed for farm and domestic animals in Israel and assessed the current feed safety challenges in terms of potential hazards or undesirable substances. Moreover, the basic requirements for feed safety laboratories, which are mandatory for analyzing and testing for potential contaminants, are summarized for each of the contaminants discussed. © 2016 Society of Chemical Industry., (© 2016 Society of Chemical Industry.)

Pyrrolizidine alkaloids (PAs) are carcinogenic and genotoxic phytochemicals found exclusively in angiosperms. The ingestion of PA-containing plants often results in acute and chronic toxicities in man and livestock, targeting mainly the liver. During February 2014, a herd of 15-18-month-old mixed-breed beef cattle (n = 73) from the Galilee region in Israel was accidently fed hay contaminated with 12% Heliotropium europaeum (average total PA intake was 33 mg PA/kg body weight/d). After 42 d of feed ingestion, sudden death occurred over a time period of 63 d with a mortality rate of 33%. Necropsy and histopathological examination revealed fibrotic livers and moderate ascites, as well as various degrees of hyperplasia and fibrosis of bile duct epithelial cells. Elevated γ-glutamyl-transferase and alkaline phosphatase levels were indicative of severe liver damage. Comprehensive PA profile determination of the contaminated hay and of native H. europaeum by LC-MS/MS revealed the presence of 30 PAs and PA-N-oxides, including several newly reported PAs and PA-N-oxides of the rinderine and heliosupine class. Heliotrine- and lasiocarpine-type PAs constituted 80% and 18% of the total PAs, respectively, with the N-oxides being the most abundant form (92%). The PA profile of the contaminated hay showed very strong resemblance to that of H. europaeum.

Dehydro pyrrolizidine alkaloids (dehydro PAs) are carcinogenic phytotoxins prevalent in the Boraginaceae, Asteraceae and Fabaceae families. Dehydro PAs enter the food and feed chain by co-harvesting of crops intended for human and animal consumption as well as by carry-over into animal-based products such as milk, eggs and honey. Recently the occurrence of dehydro PAs in teas and herbal teas has gained increasing attention from the EU, due to the high levels of dehydro PAs found in commercially available teas and herbal teas in Germany and Switzerland. Furthermore, several tropane alkaloids (TAs, e.g. scopolamine and hyoscyamine) intoxications due to the consumption of contaminated herbal teas were reported in the literature. The aim of the present study was to determine the dehydro PAs and TAs levels in 70 pre-packed teabags of herbal and non-herbal tea types sold in supermarkets in Israel. Chamomile, peppermint and rooibos teas contained high dehydro PAs levels in almost all samples analysed. Lower amounts were detected in black and green teas, while no dehydro PAs were found in fennel and melissa herbal teas. Total dehydro PAs concentrations in chamomile, peppermint and rooibos teas ranged from 20 to 1729 μg/kg. Except for black tea containing only mono-ester retrorsine-type dehydro PAs, all other teas and herbal teas showed mixed patterns of dehydro PA ester types, indicating a contamination by various weed species during harvesting and/or production. The TA levels per teabag were below the recommended acute reference dose; however, the positive findings of TAs in all peppermint tea samples warrant a more extensive survey. The partially high levels of dehydro PAs found in teas and herbal teas present an urgent warning letter to the regulatory authorities to perform routine quality control analysis and implement maximum residual levels for dehydro PAs.

The present study describes an accurate quantitative method for quantifying the adherence of conidia to the arthropod cuticle and the dynamics of conidial germination on the host. The method was developed using conidia of Metarhizium anisopliae var. anisopliae (Metschn.) Sorokin (Hypocreales: Clavicipitaceae) and engorged Rhipicephalus annulatus (Say) (Arachnida: Ixodidae) females and was also verified for M. anisopliae var. acridum Driver et Milner (Hypocreales: Clavicipitaceae) and Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) larvae. This novel method is based on using an organic solvent (dichloromethane [DCM]) to remove the adhered conidia from the tick cuticle, suspending the conidia in a detergent solution, and then counting them using a hemocytometer. To confirm the efficacy of the method, scanning electron microscopy (SEM) was used to observe the conidial adherence to and removal from the tick cuticle. As the concentration of conidia in the suspension increased, there were correlating increases in both the number of conidia adhering to engorged female R. annulatus and tick mortality. However, no correlation was observed between a tick's susceptibility to fungal infection and the amount of adhered conidia. These findings support the commonly accepted understanding of the nature of the adhesion process. The mechanism enabling the removal of the adhered conidia from the host cuticle is discussed.

Objective: To investigate the pharmacokinetics of the four stereoisomers of valnoctamide, a mild tranquilizer endowed with anticonvulsant properties., Methods: Racemic valnoctamide, 400 mg, was administered orally to seven healthy subjects and to six patients with epilepsy stabilized with long-term carbamazepine therapy. In the patients with epilepsy, valnoctamide kinetics was also reassessed after 8-day oral dosing at a dosage of 600 mg daily. Plasma samples were assayed by gas chromatography-mass spectrometry with use of a capillary column coated with chiral stationary phase that enabled baseline resolution of the four stereoisomers, designated hereafter as A, B, C, and D (where A and C, together with B and D, represent enantiomeric pairs)., Results: In healthy subjects, stereoisomers A, C, and D showed similar kinetics, with an apparent oral clearance (CL/F) of about 4 1/2 L/hr, a half-life (t1/2) of about 10 hours, and an apparent volume of distribution (VSS/F) of about 65 L. However, stereoisomer B showed a much higher clearance (8.7 +/- 0.9 L/hr) and a shorter t1/2 (5.8 hours). For all stereoisomers, CL/F values in patients with epilepsy were about tenfold higher than those found in healthy subjects. Compared with healthy subjects, patients with epilepsy also showed shorter t1/2 values and higher VSS/F values for each of the stereoisomers. After 7-day dosing, CL/F values at steady state were lower than those determined in the same patients after a single dose., Conclusions: Valnoctamide exhibits enantioselectivity and diastereoselectivity, an observation that may have important practical implications if pharmacodynamic differences between stereoisomers are also found. The observed pharmacokinetic differences between healthy subjects and patients with epilepsy are likely to be related to induction of metabolism of valnoctamide stereoisomers by carbamazepine.

The effect of fluvoxamine on the pharmacokinetics of diazepam and metabolically derived N-desmethyl-diazepam was investigated in eight healthy volunteers. Each subject received a single oral dose of diazepam (10 mg) in a control session and on the fourth day of a 16-day treatment with fluvoxamine maleate (100 to 150 mg daily). Compared with the control session, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/ml, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (from 0.40 to 0.14 ml/min/kg; p < 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p < 0.01). Although peak plasma N-desmethyldiazepam levels were similar in the two sessions, the time required for the metabolite to reach a peak was longer during fluvoxamine intake than in the control session (206 versus 62 hours; p < 0.01). N-Desmethyldiazepam area under the plasma concentration-time curve values were also significantly increased during fluvoxamine treatment. These data suggest that fluvoxamine inhibits the biotransformation of diazepam and its active N-demethylated metabolite. The magnitude of this interaction is likely to have considerable clinical significance.

The pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg-1). The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32-60% for verrucaryl glucuronides and 32-47% for verrucaryl sulphates. These urinary conjugated metabolites were analysed quantitatively following their enzymatic hydrolysis. The half-life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half-life calculated from the plasma data of the parent compound.

The pharmacokinetics of two new sustained-release (SR) products of diltiazem, Dilapress 120 mg tablets and Dilapress 240 mg tablets, was analysed and characterized in three different studies, in comparison to the following diltiazem SR formulations: Cardizem Retard, Cardizem SR, and Cardizem CD. Dilapress 120, designated for twice-daily dosing, was found to be bioequivalent to Cardizem SR and to Cardizem Retard with mean (+/- SD) relative bioavailability values of 99 +/- 27% and 113 +/- 38%, respectively. Dilapress 240, designed for once-a-day treatment, was found to have a slower absorption rate than Cardizem SR and its extent of absorption was 56 +/- 19% relative to that of Cardizem SR. However, the bioavailability of Dilapress 240 relative to that of Cardizem CD was 118 +/- 46%, indicating that the bioavailability of Cardizem CD relative to that of Cardizem SR was only 54 +/- 29%. Diltiazem is partially available due to a saturable liver first-pass effect. A high dose of Cardizem SR may partially escape this first-pass effect and, thus, achieve a higher extent of absorption than a slower SR product. Consequently, SR products of diltiazem designed for once-daily treatment may not reach the saturation stage in the liver first-pass effect process that diltiazem is susceptible to. Consequently, a twice-daily SR product of diltiazem cannot serve as a reference for extent of absorption assessments of a once-daily SR product.

HT-2 toxin was the sole metabolite formed when T-2 toxin was treated with homogenate from brain without its blood content. Homogenate from brain with its full blood content produced--besides HT-2 toxin--T-2 triol, neosolaniol, 4-deacetylneosolaniol and T-2 tetraol, i.e. the same metabolites formed by incubation of T-2 toxin with whole rat blood.

Verrucarol is a simple trichothecene which is structurally related to T-2 and HT-2 toxins. Several macrocyclic trichothecenes which are ester derivatives of verrucarol possess antitumor activity. The pharmacokinetics of verrucarol has been studied in eight dogs following iv and oral administrations (0.4 and 0.8 mg/kg, respectively). The iv study showed that verrucarol has a mean (+/- SD) clearance of 11 +/- 5.5 mL/min/kg, a volume of distribution of 1.2 +/- 0.6 L/kg, and a terminal half-life of 1.6 +/- 0.5 h. Following oral administration, the absolute bioavailability of verrucarol was 44 +/- 33%, and its terminal half-life was similar to that obtained after iv administration. In comparison with T-2 and HT-2 toxins, verrucarol has a longer half-life and a lower clearance, and its liver extraction ratio is about one third of that of T-2 and HT-2 toxins. Therefore, verrucarol is less susceptible to a liver first-pass effect and its partially absorbed after oral administration. These characteristics make verrucarol the first partially absorbed trichothecene whose pharmacokinetics was investigated following oral administration.