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Following a request from the European Commission, the EFSA Panel on Plant Health performed a quantitative risk assessment for the EU of Phlyctinus callosus (Coleoptera: Curculionidae), a polyphagous pest occurring in Australia, New Zealand and South Africa. The current risk assessment focused on potential pathways for entry, the climatic conditions allowing establishment, the expected spread capacity and the impact considering a time horizon of 10 years (2023-2032). The Panel identified the import of apples, cut flowers and table grapes as the most relevant entry pathways. Over the next 10 years, an annual median estimate of approximately 49.5 (90% certainty range, CR, ranging from 4.0 to 881.2) potential P. callosus founder populations are expected. When the probability of establishment is considered and climatic indicators are used to define the areas in the EU where establishment is possible, the model estimated a median of 1 founder population every 1.3 years (90% CR: 1 every 30.8 years to 23.3 per year) in the scenario where the areas are defined by the union of all the climatic indicators and 1 founder population every 11.9 years (90% CR: 1 every 256.6 years to 2.5 per year) in the scenario where establishment is possible only in the areas defined by the climatic indicator of minimum soil temperature. The estimated number of founder populations per year is mostly driven by the probability of establishment in the rural areas, infestation rate in table grapes and the probability of transfer to a suitable host in the rural area. The risk of entry for cut flowers and apples is substantially lower than the risk from the table grapes. If such founder populations were to establish, P. callosus is estimated to spread by natural dispersal and common agricultural practices at a rate of 15.5 m/year (90% CR 5.1-46.8 m/year) after a lag phase of 4.0 years (90% CR 1.3-8.7 years). The impact, expressed as percentage loss of the production directly attributable to P. callosus in the areas where establishment is possible and assuming farmers do not apply specific control measures was estimated at 0.5% (90% CR 0.01%-2.8%) for cut flowers/foliage, 5.2% (90% CR 2.2%-11.7%) for apples and 2% (90% CR 1.3%-5.2%) for table grapes. Options for risk reduction are discussed, but their effectiveness is not quantified.

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The European Commission requested the EFSA Panel on Plant Health to deliver a risk assessment on the likelihood of pest freedom from Union quarantine pests and pests subject to measures adopted pursuant to Article 30 of Regulation (EU) No 2016/2031 for the maple veneer sheets manufactured according to the process set out by Canada, with emphasis on the freedom from Davidsoniella virescens and Phytophthora ramorum (non-EU isolates). The assessment was conducted for veneer sheets of up to 0.7 mm and up to 6 mm thickness, taking into account the different phases in the veneer production in a systems approach. Some of those phases, taken alone, including the heat treatment of logs in a water bath, the cutting into thin veneer sheets and the final high heat drying of veneer sheets are expected to be effective against some of the pests, without uncertainties, making the system approach fully effective. The panel considers that no insects would survive cutting of logs into thin veneer sheets of 0.7 mm and that Xylella fastidiosa will not survive the temperatures in the water bath and final drying of veneers. The degree of pest freedom for the different groups of organisms is generally very high with slightly lower degree of pest freedom for veneer sheets of 6 mm thickness because of lower temperatures reached in the final drying of veneer sheets compared to thinner sheets. P. ramorum is not expected to survive the high heat drying of thin veneer sheets, but it may survive the lower temperatures inside thicker veneer sheets. The Expert Knowledge Elicitation (EKE) indicated, with 95% certainty, that between 9989 and 10,000 veneer sheets (thickness 6 mm) per 10,000 will be free from living P. ramorum. For D. virescens, the EKE indicated, with 95% certainty, that between 9984 and 10,000 veneer sheets (0.7 mm) per 10,000 and that between 9954 and 10,000 veneer sheets (6 mm) per 10,000 will be free from living inoculum. For other relevant groups of pests, the greatest likelihood of pest presence was observed for wood decay fungi. The EKE indicated, with 95% certainty, that between 9967 and 10,000 veneer sheets (0.7 mm) per 10,000 and that between 9911 and 10,000 veneer sheets (6 mm) per 10,000 will be free from living wood decay fungi.

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Acute thrombosis and thromboembolisms are one of the leading causes of mortality and morbidity in both developed and developing countries, placing a huge burden on health and economic systems. Early diagnosis is critical but currently limited in accuracy and hampered by a narrow time frame, where the short therapeutic window also severely restricts treatment options. Additionally, clinically used antithrombotics and thrombolytics suffer from severe side effects and are limited in efficacy by a short half-life and susceptibility to degradation. The use of systems containing both diagnostic and therapeutic moieties, known as theranostics, can potentially improve patient outcomes by increasing the precision and efficacy of diagnosis and treatment, enabling personalised and precision medicine. Leveraging nanomedicine may further improve treatment by improving the system's pharmacokinetic properties including controlled drug delivery. This review provides an overview of the development of such theranostic nanoparticle systems, with a focus on approaches that may be utilised to usher this field towards clinical use.

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Thrombosis is characterized by the formation of in vivo blood clots that are localized within arterial or venous blood vessels. These thrombi form beyond the need for physiologically healthy hemostatic responses and can lead to significant medical issues for affected individuals. Unfortunately, the existing standard-of-care therapies for treating thrombosis are systemic in their therapeutic design; therefore, they interfere with the patient's physiological hemostasis. Examples of the severe clinical side effects commonly associated with currently available therapies include, but are not limited to, bleeding complications. Therefore, there is a profound demand for novel therapeutic interventions that can circumvent these debilitating complications, while offering improved therapeutic efficacy. Recent advancements in nanotechnology present an opportunity to develop novel and improved drug delivery systems to meet this clinical demand. Preclinical investigations have begun to uncover the potential of nanotechnology, particularly in the treatment of thrombosis and also in nonhemostatic cardiovascular diseases. This article reviews recent preclinical studies aimed at developing a diverse array of different nanotechnologies for treating thrombosis as well as heart diseases. This review will also outline the limitations with current nanotechnologies and what challenges need to be overcome to translate these novel therapies to the clinic.

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The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL-PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre- and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005-TEQ/g fat in blood sampled at age 9 years based on PCDD/F-TEQs. No association was observed when including DL-PCB-TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F-TEQ only was on average 2.4- and 2.7-fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL-PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.

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BACKGROUND: Thrombolytic therapy for acute thrombosis is limited by life-threatening side effects such as major bleeding and neurotoxicity. New treatment options with enhanced fibrinolytic potential are therefore required. Here, we report the development of a new thrombolytic molecule that exploits key features of thrombosis. We designed a recombinant microplasminogen modified to be activated by the prothrombotic serine-protease thrombin (HtPlg), fused to an activation-specific anti-glycoprotein IIb/IIIa single-chain antibody (SCE5), thereby hijacking the coagulation system to initiate thrombolysis. METHODS AND RESULTS: The resulting fusion protein named SCE5-HtPlg shows in vitro targeting towards the highly abundant activated form of the fibrinogen receptor glycoprotein IIb/IIIa expressed on activated human platelets. Following thrombin formation, SCE5-HtPlg is activated to contain active microplasmin. We evaluate the effectiveness of our targeted thrombolytic construct in two models of thromboembolic disease. Administration of SCE5-HtPlg (4 µg/g body weight) resulted in effective thrombolysis 20 minutes after injection in a ferric chloride-induced model of mesenteric thrombosis (48±3% versus 92±5% for saline control, P<0.01) and also reduced emboli formation in a model of pulmonary embolism (P<0.01 versus saline). Furthermore, at these effective therapeutic doses, the SCE5-HtPlg did not prolong bleeding time compared with saline (P=0.99). CONCLUSIONS: Our novel fusion molecule is a potent and effective treatment for thrombosis that enables in vivo thrombolysis without bleeding time prolongation. The activation of this construct by thrombin generated within the clot itself rather than by a plasminogen activator, which needs to be delivered systemically, provides a novel targeted approach to improve thrombolysis.

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RATIONALE: The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans. OBJECTIVE: Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis. METHODS AND RESULTS: On the basis of flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of apolipoprotein E-deficient mice on high-fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ≈50% of mice, as well as disruption of fibrous caps, intraluminal thrombosis, neovascularization, and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and downregulation of monocyte chemoattractant protein-1 and ubiquitin. Microarray profiling of mRNA and microRNA (miR) and, in particular, its combined analysis demonstrated major differences in the hierarchical clustering of genes and miRs among nonatherosclerotic arteries, stable, and unstable plaques and allows the identification of distinct genes/miRs, potentially representing novel therapeutic targets for plaque stabilization. The feasibility of the described animal model as a discovery tool was established in a pilot approach, identifying a disintegrin and metalloprotease with thrombospondin motifs 4 (ADAMTS4) and miR-322 as potential pathogenic factors of plaque instability in mice and validated in human plaques. CONCLUSIONS: The newly described mouse model reflects human atherosclerotic plaque instability and represents a discovery tool toward the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and miRs can be linked to plaque instability.

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BACKGROUND, AIM, AND SCOPE: Biowaste contains compounds of agricultural value such as organic carbon, nutrients, and trace elements and can partially replace mineral fertilizer (MIN) and improve the physical properties of the soil. However, the obvious benefits of land spreading need to be carefully evaluated against potential adverse effects on the environment and human health. Environmental contamination resulting from biowaste application is one of the key variables when assessing cost/benefits. This study provides data on the resulting concentration of polychlorinated dibenzodioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) in the soil column as a result of the different types of fertilizers. MATERIALS AND METHODS: In a long-term field experiment established in 1962, we investigated the influence of the application of biowaste-derived fertilizers such as sewage sludge (SSL), compost (COM), and farmyard manure (FYM) to a luvisol derived from loess on the contents of PCDD/Fs and DL-PCBs. Control plots amended only with MIN served as a basis to compare the biowaste-amended soils with soils affected only by atmospheric deposition, thus experimentally separating the two pathways of soil contamination. Samples of the soil column down to a depth of 90 cm were taken in 2001 and analyzed for PCDD/Fs and dioxin-like PCBs according to US-EPA methods 1613 and 1668, respectively. RESULTS: Thirty-nine years of experimental SSL and COM applications exceeding four times the maximal amount as laid down in German legislation resulted in a doubling of the international toxicity equivalent (I-TEQ) budget for PCDD/Fs and a threefold increase for DL-PCBs as compared to test plots amended with MIN only. As compared to MIN, the application of FYM had no effect on the PCDD/F and PCB content in soil. The average contribution of the DL-PCBs to the WHO-TEQ was 19% in the MIN and FYM plots and somewhat higher in the COM (23%) and in the SSL (27%) plots. DISCUSSION: Although the test plots received four times the maximum application of SSL as laid down in the German SSL ordinance and the investigated region represents the upper end of the topsoil concentrations typically found in Germany, the soils treated with SSL and COM were still a factor of 4 below the German guideline value of PCDD/Fs for arable land. No enhancement of translocation of PCDD/Fs and PCBs into the corresponding subsoils due to the presence of dissolved humic matter or other surfactants potentially present in the biowaste was observed. The similarity of congener patterns in all soils, irrespective of the type of fertilizer applied, points towards atmospheric deposition of PCDD/Fs and DL-PCBs as the main intake route in the soils. The higher levels in the SSL- and COM-amended soils can be explained by the fact that both biowastes are subject to atmospheric deposition occurring at their origin. In the case of COM, it is accumulation in the foliage, while in the case of SSL, atmospheric particulate from wet and dry deposition is collected in the wastewater treatment system via urban runoff. CONCLUSIONS: It appears that the common practice of SSL applications in Germany does not pose a current threat to the agro-environment with regard to PCDD/Fs and DL-PCBs. However, time trend data on PCDD/Fs in SSL-amended soils will be needed to obtain a prognosis about the long-term effect of biowaste applications on soil quality.

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BACKGROUND, AIM, AND SCOPE: The aim of the study was to identify the impact of polychlorinated dibenzo-p-dioxin and furan (PCDD/F) emission sources on ambient air concentrations in the Malopolska Region, southern Poland. Three sites were selected: the city center of Krakow (Aleje), an industrial area (Nova Huta), and a rural site (Zakopane). In order to investigate the annual variations of PCDD/F sources, summer and winter time samples were taken. MATERIALS AND METHODS: Ambient air particulate matter (PM10) was collected using an Anderson High-Volume sampler during June and December 2002 in the three mentioned sites. Analysis of PCDD/Fs was based on isotope dilution using high-resolution gas chromatography-high-resolution mass spectrometry for quantification. RESULTS AND DISCUSSION: Total concentrations of 2,3,7,8-PCDD/Fs in air particulate phase from Malopolska region ranged from 0.6 to 37 pg m(-3) (0.04-3.2 pg WHO(98)-TEQ per cubic meter, 0.037-2.9 pg I-TEQ per cubic meter). Higher PCDD/F concentrations were measured at all three sites during winter. A linear correlation among PCDD/F concentrations, benzo(a)pyrene (B(a)P) and PM10 concentrations, was found in Aleje and Zakopane, which suggested that all compounds were originating from the same source, solid fuel domestic heating. Instead, PCDD/F levels in Nova Huta did not correlate with the seasonality of B(a)P or PM10 levels and 2,3,7,8-PCDD/F congener patterns for this site were significantly different from the other sites. CONCLUSIONS: Domestic solid fuel combustion is likely the main PCDD/F source in winter in this part of Poland for urban and rural sites. PCDD/F fingerprints in the industrial site remained almost identical during summer and winter, confirming the yearly prevalence of the emissions from the nearby metal industry. RECOMMENDATIONS AND PERSPECTIVES: PCDD/F concentrations found in Malopolska Region are in the upper range of ambient air concentrations of PCDD/Fs reported worldwide. However, further research is needed in order to study the impact of the deposition of these PCDD/F emissions on the region. A more extended study is being conducted in the area to analyze soil samples, such as sink of atmospheric deposition, and spruce needles, as indicator of PCDD/F availability.

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Inactivation of testosterone by specific hydroxylations is a main function of cytochrome P450 (P450, CYP) in the brain. Recent data imply that induction of brain P450s by neuroactive drugs alters steroid hormone levels and endocrine signalling, giving rise to endocrine disorders. In this study, we investigated this drug-hormone crosstalk in mouse brain. Phenytoin led to a significant increase of 2alpha-, 2beta-, 6beta-, 16alpha- and 16beta-hydroxytestosterones, while 6alpha- and 15alpha-hydroxytestosterones showed no significant alteration of their metabolism compared with untreated controls. Inhibition of testosterone hydroxylation using the chemical inhibitors orphenadrine, chloramphenicol, ketoconazole and nifedipine as well as antibodies against CYP3A- and 2B-isoforms pointed to major role of Cyp3a11 and an only minor function of Cyp2b9/10 in mouse brain. Cyp3a11 revealed to be the major isoform affected by phenytoin. There was considerable overlap of Cyp3a11 and AR expression in neuronal structures of the limbic system, namely the hippocampus, amygdala, hypothalamus and thalamus. Phenytoin treatment led to an increase of both, Cyp3a11 and AR expression in the limbic system. Additionally, the coherence between CYP3A and AR expression was analysed in PC-12 cells. Inhibition of phenytoin-induced endogenous CYP3A2 and AR by ketoconazole led a reduction of their expression to basal levels. We conclude that Cyp3a11 plays a crucial role in directing drug action to hormonal response within the limbic system of mouse brain in a so-called drug-hormone crosstalk.

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Trace elements and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were analyzed in soils from rural and light-industrialized sites (n = 168) of Province of Pavia (Northern Italy). Most of the trace element values fit in typical ranges of concentrations in soils and are similar to the ones reported for rural sites in Italy or sites with no direct anthropogenic impact. Total concentrations of 2,3,7,8 chlorine substituted PCDD/Fs in superficial soils ranged between 24.4 and 1287 pg g(-1) dw (0.5-28.9 pg WHO98-TEQ g(-1) dw). The North Eastern part of the Province presented significantly higher levels (p < 0.001) than the rest of the Province for As, Cd, Hg, Pb, Zn and PCDD/Fs. While the existence of a defined heavy metal polluting source for this specific site has been suggested, in the case of PCDD/Fs, profiles were not linked to any specific emission source fingerprint. In the whole extension of Pavia Province, OCDD/F dominated the 2,3,7,8 chlorine substituted congener soil pattern, followed by the 1,2,3,4,6,7,8 hepta-CDD/F congener. Principal Component Analysis (PCA) showed that this profile could not be associated to any described PCDD/F emission source fingerprint and was relatively similar to the baseline deposition of sites with no direct impact of PCDD/F emission sources independently of land use.

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C7-C11 perfluorinated carboxylates (PFACs) and perfluorooctansulfonate (PFOS) were analysed in selected stretches of the River Po and its major tributaries. Analyses were performed by solid-phase extraction (SPE) with Oasis HLB cartridges and methanol elution followed by LC-MS-MS detection using 13C-labelled internal standards. High concentration levels ( approximately 1.3 microg l(-1)) of perfluorooctanoate (PFOA) were detected in the Tánaro River close to the city Alessandria. After this tributary, levels between 60 and 337 ng l(-1) were measured in the Po River on several occasions. The PFOA concentration close to the river mouth in Ferrara was between 60 and 174 ng l(-1). Using the river discharge flow data in m3 s(-1) at this point (average approximately 920 m3 s(-1) for the year 2006), a mass load of approximately 0.3 kg PFOA per hour or approximately 2.6 tons per year discharged in the Adriatic Sea has been calculated. PFOS concentration levels in the Po River at Ferrara were approximately 10 ng l(-1).

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Samples of air (gas and particulate phases), bulk deposition, aquatic settling material and sediments were collected in Lake Maggiore (LM) in order to determine their content of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Air (gas and particulate phases) concentrations were 0.5 pg m(-3), 80 pg m(-3), 13 pg m(-3) and 106 pg m(-3) for SigmaPCDD/Fs, SigmaPCBs, Sigma dioxin-like PCBs (DL-PCBs) and SigmaPBDEs, respectively. Deposition fluxes ranged from 0.7 ng m(-2) d(-1) for SigmaPCDD/Fs to 32 ng m(-2) d(-1) for SigmaPCBs. Aquatic settling material presented concentrations of 0.4 ng g(-1) dry weight (dw) for SigmaPCDD/Fs, 13 ng g(-1) dw for SigmaPCB, 3.4 ng g(-1) dw for SigmaDL-PCBs and 5.7 ng g(-1) dw for SigmaPBDEs. Mean sediment concentrations were 0.4 ng g(-1) dw for SigmaPCDD/Fs, 11 ng g(-1) dw for SigmaPCB, 3 ng g(-1) dw for SigmaDL-PCBs and 5.1 ng g(-1) dw for SigmaPBDEs. Similar PCDD/F and DL-PCB congener patterns in all the environmental compartments of LM point to an important, if not dominant, contribution of atmospheric deposition as source of these pollutants into LM. In contrast, PBDE congener distribution was not similar in the different environmental compartments. BDE 47 dominated air and settling material, while BDE 209 was the predominant congener in the bulk atmospheric deposition. Moreover, sediments showed two distinct PBDE congener profiles. Lower PBDE concentrated sediments were dominated by congeners 47 and 99, while BDE 209 dominated in higher PBDE concentrated samples. This suggests the influence of local sources as well as atmospheric input of PBDEs into LM.

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Epilepsy is very often related to strong impairment of neuronal networks, particularly in the hippocampus. Previous studies of brain tissue have demonstrated that long-term administration of the anti-epileptic drug (AED) phenytoin leads to enhanced metabolism of testosterone mediated by cytochrome P450 (CYP) isoforms. Thus, we speculate that AEDs affect androgen signalling in the hippocampus. In the present study, we investigated how the AED phenytoin influences the levels of testosterone, 17beta-oestradiol, and androgen receptor (AR) in the hippocampus of male C57Bl/6J mice. Phenytoin administration led to a 61.24% decreased hippocampal testosterone level as compared with controls, while serum levels were slightly enhanced. 17beta-Oestradiol serum level was elevated 2.6-fold. Concomitantly, the testosterone metabolizing CYP isoforms CYP3A11 and CYP19 (aromatase) have been found to be induced 2.4- and 4.2-fold, respectively. CYP3A-mediated depletion of testosterone-forming 2beta-, and 6beta-hydroxytestosterone was significantly enhanced. Additionally, AR expression was increased 2-fold (mRNA) and 1.8-fold (protein), predominantly in the CA1 region. AR was shown to concentrate in nuclei of CA1 pyramidal neurons. We conclude that phenytoin affects testosterone metabolism via induction of CYP isoforms. The increased metabolism of testosterone leading to augmented androgen metabolite formation most likely led to enhanced expression of CYP19 and AR in hippocampus. Phenytoin obviously modulates the androgen signalling in the hippocampus.

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Trifluoroacetate (TFA) is a ubiquitous xenochemical presently increasing in concentration in some environmental compartments, especially in the plant biomass of industrialized countries. Direct anthropogenic emissions of TFA are probably low, and the major anthropogenic sources are most likely various TFA precursors. As TFA has been found in ocean waters from remote locations, the question arose whether it is also a naturally occurring environmental chemical. Determination of the depth dependence of TFA in the ocean water column should shed some light on this question. However, in environmental analytical studies, the risk of systematic errors can be high and may lead to wrong conclusions. Therefore, special attention has been paid to the fact that TFA is a common atmospheric pollutant in the urban environment and that contributions from sampling, storage, and transport potentially lead to artificially high TFA values. The results of the ocean water sampling campaigns indicate that TFA is a naturally occurring chemical, homogeneously distributed in ocean waters of all ages with a concentration of about 200 ng/L.

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