Toxins, Vol. 7, Pages 4935-4966: Qualitative and Quantitative Detection of Botulinum Neurotoxins from Complex Matrices: Results of the First International Proficiency Test

In the framework of the EU project EQuATox, a first international proficiency test (PT) on the detection and quantification of botulinum neurotoxins (BoNT) was conducted. Sample materials included BoNT serotypes A, B and E spiked into buffer, milk, meat extract and serum. Different methods were applied by the participants combining different principles of detection, identification and quantification. Based on qualitative assays, 95% of all results reported were correct. Successful strategies for BoNT detection were based on a combination of complementary immunological, MS-based and functional methods or on suitable functional in vivo/in vitro approaches (mouse bioassay, hemidiaphragm assay and Endopep-MS assay). Quantification of BoNT/A, BoNT/B and BoNT/E was performed by 48% of participating laboratories. It turned out that precise quantification of BoNT was difficult, resulting in a substantial scatter of quantitative data. This was especially true for results obtained by the mouse bioassay which is currently considered as "gold standard" for BoNT detection. The results clearly demonstrate the urgent need for certified BoNT reference materials and the development of methods replacing animal testing. In this context, the BoNT PT provided the valuable information that both the Endopep-MS assay and the hemidiaphragm assay delivered quantitative results superior to the mouse bioassay.

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Toxins, Vol. 7, Pages 4906-4934: Characterization of Ricin and R. communis Agglutinin Reference Materials

Ricinus communis intoxications have been known for centuries and were attributed to the toxic protein ricin. Due to its toxicity, availability, ease of preparation, and the lack of medical countermeasures, ricin attracted interest as a potential biological warfare agent. While different technologies for ricin analysis have been established, hardly any universally agreed-upon "gold standards" are available. Expert laboratories currently use differently purified in-house materials, making any comparison of accuracy and sensitivity of different methods nearly impossible. Technically challenging is the discrimination of ricin from R. communis agglutinin (RCA120), a less toxic but highly homologous protein also contained in R. communis. Here, we established both highly pure ricin and RCA120 reference materials which were extensively characterized by gel electrophoresis, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI MS/MS), and matrix-assisted laser desorption ionization–time of flight approaches as well as immunological and functional techniques. Purity reached >97% for ricin and >99% for RCA120. Different isoforms of ricin and RCA120 were identified unambiguously and distinguished by LC-ESI MS/MS. In terms of function, a real-time cytotoxicity assay showed that ricin is approximately 300-fold more toxic than RCA120. The highly pure ricin and RCA120 reference materials were used to conduct an international proficiency test.

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Toxins, Vol. 7, Pages 4967-4986: Recommended Immunological Assays to Screen for Ricin-Containing Samples

Ricin, a toxin from the plant Ricinus communis, is one of the most toxic biological agents known. Due to its availability, toxicity, ease of production and absence of curative treatments, ricin has been classified by the Centers for Disease Control and Prevention (CDC) as category B biological weapon and it is scheduled as a List 1 compound in the Chemical Weapons Convention. An international proficiency test (PT) was conducted to evaluate detection and quantification capabilities of 17 expert laboratories. In this exercise one goal was to analyse the laboratories' capacity to detect and differentiate ricin and the less toxic, but highly homologuous protein R. communis agglutinin (RCA120). Six analytical strategies are presented in this paper based on immunological assays (four immunoenzymatic assays and two immunochromatographic tests). Using these immunological methods "dangerous" samples containing ricin and/or RCA120 were successfully identified. Based on different antibodies used the detection and quantification of ricin and RCA120 was successful. The ricin PT highlighted the performance of different immunological approaches that are exemplarily recommended for highly sensitive and precise quantification of ricin.

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Nutrients, Vol. 7, Pages 9721-9733: Assessment of Diet and Physical Activity in Paediatric Non-Alcoholic Fatty Liver Disease Patients: A United Kingdom Case Control Study

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children, with prevalence rising alongside childhood obesity rates. This study aimed to characterise the habitual diet and activity behaviours of children with NAFLD compared to obese children without liver disease in the United Kingdom (UK). Twenty-four biopsy-proven paediatric NAFLD cases and eight obese controls without biochemical or radiological evidence of NAFLD completed a 24-h dietary recall, a Physical Activity Questionnaire (PAQ), a Dutch Eating Behavior Questionnaire (DEBQ) and a 7-day food and activity diary (FAD), in conjunction with wearing a pedometer. Groups were well matched for age and gender. Obese children had higher BMI z-scores (p = 0.006) and BMI centiles (p = 0.002) than participants with NAFLD. After adjusting for multiple hypotheses testing and controlling for differences in BMI, no differences in macro- or micronutrient intake were observed as assessed using either 24-h recall or 7-day FAD (p > 0.001). Under-reporting was prevalent (NAFLD 75%, Obese Control 87%: p = 0.15). Restrained eating behaviours were significantly higher in the NAFLD group (p = 0.005), who also recorded more steps per day than the obese controls (p = 0.01). In conclusion, this is the first study to assess dietary and activity patterns in a UK paediatric NAFLD population. Only a minority of cases and controls were meeting current dietary and physical activity recommendations. Our findings do not support development of specific dietary/ physical activity guidelines for children with NAFLD; promoting adherence with current general paediatric recommendations for health should remain the focus of clinical management.

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Energies, Vol. 8, Pages 13419-13441: Impact Study of PMSG-Based Wind Power Penetration on Power System Transient Stability Using EEAC Theory

Wind turbines with direct-driven permanent magnet synchronous generators (PMSGs) are widely used in wind power generation. According to the dynamic characteristics of PMSGs, an impact analysis of PMSG-based wind power penetration on the transient stability of multi-machine power systems is carried out in this paper based on the theory of extended equal area criterion (EEAC). Considering the most severe PMSG integration situation, the changes in the system's equivalent power-angle relationships after integrating PMSGs are studied in detail. The system's equivalent mechanical input power and the fault period electrical output power curves are found to be mainly affected. The analysis demonstrates that the integration of PMSGs can cause either detrimental or beneficial effects on the system transient stability. It is determined by several factors, including the selection of the synchronous generators used to balance wind power, the reactive power control mode of PMSGs and the wind power penetration level. Two different simulation systems are also adopted to verify the analysis results.

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Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male offspring

ABSTRACT

With the growing use of selective serotonin reuptake inhibitor medications (SSRIs) for the treatment of depression during the perinatal period, questions have been raised about the longterm impact of these medications on development. We aimed to investigate how developmental SSRI exposure may alter affect-related behaviors and associated molecular processes in offspring using a rodent model of maternal stress and depression. For this purpose, prenatally stressed or non-stressed male offspring were exposed to fluoxetine (5 mg/kg/day) or vehicle, via lactation, until weaning. Primary results show that postnatal fluoxetine exposure differentially altered anxiety-like behavior by increasing anxiety in non-stressed offspring and decreasing anxiety in prenatally stressed offspring. In the hippocampus, developmental fluoxetine exposure decreased BDNF IV and TrkB mRNA expression. Prenatal stress alone also decreased escape behaviors and decreased hippocampal BDNF IV mRNA expression. These data provide important evidence for the long-term programming effects of early-life exposure to SSRIs on brain and behavior. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 9999: 1–12, 2015.

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The distribution of probability values in medical abstracts: an observational study

Background: A relatively high incidence of p values immediately below 0.05 (such as 0.047 or 0.04) compared to p values immediately above 0.05 (such as 0.051 or 0.06) has been noticed anecdotally in published medical abstracts. If p values immediately below 0.05 are over-represented, such a distribution may reflect the true underlying distribution of p values or may be due to error (a false distribution). If due to error, a consistent over-representation of p values immediately below 0.05 would be a systematic error due either to publication bias or (overt or inadvertent) bias within studies. Methods: We searched the Medline 2012 database to identify abstracts containing a p value. Two thousand abstracts out of 80,649 abstracts were randomly selected. Two independent researchers extracted all p values. The p values were plotted and compared to a predicted curve. Chi square test was used to test assumptions and significance was set at 0.05. Results: 2798 p value ranges and 3236 exact p values were reported. 4973 of these (82 %) were significant (<0.05). There was an over-representation of p values immediately below 0.05 (between 0.01 and 0.049) compared to those immediately above 0.05 (between 0.05 and 0.1) (p = 0.001). Conclusion: The distribution of p values in reported medical abstracts provides evidence for systematic error in the reporting of p values. This may be due to publication bias, methodological errors (underpowering, selective reporting and selective analyses) or fraud.

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