Effects of the Protein Kinase Inhibitor PKC412 on Gene Expression and Link to Physiological Effects in Zebrafish Danio rerio Eleuthero-Embryos

To identify molecular effects of the antineoplastic agent protein kinase C inhibitor 412 (PKC412) (midostaurin), we applied gene expression profiling in zebrafish using whole-genome microarrays. Behavioral, developmental, and physiological effects were investigated in order to analyze for correlations between altered gene expression profiles with effects on development and physiology. Zebrafish blastula-stage embryos were exposed for 6 days postfertilization to nominal levels of 2 and 40 μg/l PKC412. Among the 259 and 511 altered transcripts at both concentrations, respectively, the expressions of genes involved in the circadian rhythm were further investigated. Alteration of swimming behavior was not observed. Pathways of interest affected by PKC412 were angiogenesis, apoptosis, DNA damage response, and response to oxidative stress. Angiogenesis was analyzed in double-transgenic zebrafish embryos Tg(fli1a:EGFP)y1;Tg(gata1:dsRed)sd2; no major defects were induced by PKC412 treatment at both concentrations. Apoptosis occurred in olfactory placodes of embryos exposed to 40 μg/l, and DNA damage was induced at both PKC412 concentrations. However, there were no significant effects on reactive oxygen species formation. This study leads to the conclusion that PKC412-induced alterations of gene transcripts are partly paralleled by physiological effects at high, but not at low PKC412 concentrations expected to be of environmental relevanc

The cardiac complications of COVID-19; many publications, multiple uncertainties

Since the first description of COVID-19 in December 2019, more than 63,000 publications have described its virology, clinical course, management, treatment and prevention. Most physicians are now encountering, or will soon encounter, patients with COVID-19 and must attempt to simultaneously assimilate this avalanche of information while managing an entirely novel disease with few guiding precedents. It is increasingly clear that, although primarily a respiratory illness, COVID-19 is associated with cardiovascular complications. However, the true incidence of direct cardiac complications remains unclear, as all complications thus far reported can also occur in patients without COVID19. In this review, we briefly summarise and critically appraise the data on cardiac complications associated with COVID-19 and describe some cases from our own experience. We identify unresolved questions and highlight the many uncertainties in this developing field

Removal processes for tributyltin during municipal wastewater treatment

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Springer.The fate and behaviour of tributyltin (TBT) at two wastewater treatment works was examined. Both sites had two inlet streams, and each utilised high rate biological filters (biofilters) on one the streams, before treatment of the combined flows on trickling filters, with one having additional tertiary processes, installed to remove ammonia and solids. The study was designed to determine if these processes enhanced the removal of TBT. Degradation of TBT was observed in one of the biofilters, possibly as a result of temperature and hydraulic loading. At the treatment works with tertiary processes, the mass flux showed the overall removal of TBT was 68 %, predominantly due to removal with solids in the primary settlement processes. However, overall removal of 95 % was observed in the conventional trickling filter works with 94 % of this due to biodegradation in the trickling filter. The two works both removed TBT, but at different treatment stages and by different processes. Differences in the form (solubility) of TBT in the influent may have attributed to this, although further understanding of factors controlling degradation would allow for a more complete assessment of the potential of biological processes to remove hazardous compounds from wastewaters.United Utilities PL

On the Common Support of Workflow Type and Instance Changes under Correctness Constraints

The capability to rapidly adapt in-progress workflows (WF) is an essential requirement for any workflow system. Adaptations may concern single WF instances or a WF type as a whole. Especially for long-running business processes it is indispensable to propagate WF type changes to in-progress WF instances as well. Very challenging in this context is to correctly adapt a (potentially large) collection of WF instances, which may be in different states and to which various ad-hoc changes may have been previously applied. This paper presents a generic framework for the common support of both WF type and WF instance changes. We establish fundamental correctness principles, position formal theorems, and show how WF instances can be automatically and efficiently migrated to a modified WF schema. The adequate treatment of conflicting WF type and WF instance changes adds to the overall completeness of our approach. By offering more flexibility and adaptability the so promising WF technology will finally deliver

Toxic metal enrichment and boating intensity: sediment records of antifoulant copper in shallow lakes of eastern England

Tributyltin (TBT), an aqueous biocide derived from antifouling paint pollution, is known to have impacted coastal marine ecosystems, and has been reported in the sediment of the Norfolk and Suffolk Broads, a network of rivers and shallow lakes in eastern England. In the marine environment, the 1987 TBT ban has resulted in expanded use of alternative biocides, raising the question of whether these products too have impacted the Broads ecosystem and freshwaters in general. Here we examine the lake sediment record in the Norfolk and Suffolk Broads for contamination by copper (Cu) (as an active biocide agent) and zinc (Zn) (as a component of booster biocides), to assess their occurrence and potential for causing environmental harm in freshwater ecosystems. We find that, after the introduction of leisure boating, there is a statistically significant difference in Cu enrichment between heavily and lightly boated sites, while no such difference exists prior to this time. At the heavily boated sites the onset of Cu enrichment coincides with a period of rapid increase in leisure boating. Such enrichment is maintained to the present day, with some evidence of continued increase. We conclude that Cu-based antifouling has measurably contaminated lakes exposed to boating, at concentrations high enough to cause ecological harm. Similar findings can be expected at other boated freshwater ecosystems elsewhere in the world

An Effective Strategy for the Synthesis of Biocompatible Gold Nanoparticles Using Cinnamon Phytochemicals for Phantom CT Imaging and Photoacoustic Detection of Cancerous Cells

This is a post-print version of the Pharmaceutical Research Article. The original publication is available at www.springerlink.com. DOI 10.1007/s11095-010-0276-6Purpose: The purpose of the present study was to explore the utilization of cinnamon coated gold nanoparticles (Cin-AuNPs) as CT/optical contrast enhancement agent for detection of cancer cells. Methods: Cin-AuNPs were synthesized by a “Green” procedure and the detailed characterization has been performed by physic-chemical analysis. Cytotoxicity and cellualar uptake studies were carried out in normal human fibroblast and cancerous (PC-3 and MCF-7) cells respectively. The efficacy of detecting cancerous cells was monitored using photoacoustic technique. In vivo biodistribution was studied after IV injection of Cin-AuNPs in mice and a CT phantom model was generated. Results: Biocompatible Cin-AuNPs were synthesized with high purity. Significant uptake of these gold nanoparticles was observed in PC-3 and MCF-7 cells. Cin-AuNPs internalized in cancerous cells facilitate detectable photoacoustic signals. In vivo biodistribution in normal mouse shows steady accumulation of gold nanoparticles in lungs and rapid clearance from blood. Quantitative analysis of CT values in phantom model reveals that the cinnamon phytochemicals coated AuNPs has reasonable attenuation efficiency. Conclusions: The results indicate that these non-toxic Cin-AuNPs can serve as excellent CT/ photoacoustic contrast enhancement agents and may provide a novel approach toward the tumor detection through nanopharmaceuticals.This work has been supported by grants from the National Institutes of Health/National Cancer Institute under the Cancer Nanotechnology Platform program (grant number: 5R01CA119412-01), NIH - 1R21CA128460-01; NIH-SBIR-Contract no. 241, and University of Missouri-Research Board - Program C8761 RB 06-030

The patient's perspective of placebo use in daily practice: a qualitative study

QUESTIONS UNDER STUDY: The use of placebo outside of randomised controlled trials raises ethical and legal issues. So far, patients' perspectives have been considered only in quantitative studies. These studies did not distinguish between pure placebos (no pharmacological effect) and impure placebos (pharmacological ingredient, but no disease-specific effect). The aim of our study was to explore patients' conceptualisation, experiences and attitudes regarding the use of placebos in daily clinical practice. METHODS: Qualitative study with a convenience sample of 12 patients and semistructured interviews. The interviews were digitally recorded; full transcripts were obtained. The information was analysed in accordance with the qualitative content analysis method. RESULTS: The definition of placebo given by the participants mostly matched the common understanding of a pure placebo. Most participants supposed that placebos were mainly effective in diseases in which psychological influences play an important role. Furthermore, most participants believed that placebos themselves mainly worked via psychological effects. The acceptance of a hypothetical earlier use of a placebo depended on the success of the therapy. CONCLUSION: Patients were not aware of the differences between pure and impure placebos. Even regarding pure placebos, patients were more open than many physicians would expect. Trust between the patient and the general practitioner is an important element of the acceptance of a placebo. Appropriate communication could further increase the acceptance. Further research is needed to adapt the information given to the patient about possible placebo therapy

The Liquid Argon Jet Trigger of the H1 Experiment at HERA

We report on a novel trigger for the liquid argon calorimeter which was installed in the H1 Experiment at HERA.This trigger, called the “Jet Trigger”, was running at level 1 and implemented a real-time cluster algorithm. Within only 800 ns, the Jet Trigger algorithm found local energy maxima in the calorimeter, summed their immediate neighbors, sorted the resulting jets by energy, and applied topological conditions for the final level 1 trigger decision. The Jet Trigger was in operation from the year 2006 until the end of the HERA running in the summer of 2007. With the Jet Trigger it was possible to substantially reduce the thresholds for triggering on electronsand jets, giving access to a largely extended phase space for physical observables which could not have been reached in H1 before. The concepts of the Jet Trigger may be an interesting upgrade option for the LHC experiments

A novel and practical screening tool for the detection of silent myocardial infarction in patients with type 2 diabetes

Silent myocardial infarction (MI) is a prevalent finding in patients with type 2 diabetes and is associated with significant mortality and morbidity. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) is the most validated technique for detection of silent MI but is time consuming, costly and requires administration of intravenous contrast. We therefore planned to develop a simple and low cost population screening tool to identify those at highest risk of silent MI validated against the CMR reference standard.100 asymptomatic patients with type 2 diabetes underwent electrocardiogram (ECG), echocardiography, biomarker assessment and CMR at 3.0T including assessment of left ventricular ejection fraction and LGE. Global longitudinal strain (GLS) from 2 and 4 chamber cines was measured using feature tracking.17/100 patients with no history of cardiovascular disease had silent MI defined by LGE in an infarct pattern on CMR. Only 4 silent MI patients had Q waves on ECG. Patients with silent MI were older (65 vs 60, p=0.05), had lower E/A ratio (0.75 vs 0.89, p=0.004), lower GLS (-15.2% vs -17.7%, p=0.004) and higher NT-proBNP (106ng/L vs 52ng/L, p=0.003). A combined risk score derived from these 4 factors had an area under the receiver operating characteristic (ROC) curve of 0.823 (0.734-0.892), P<0.0001. A score of ?3/5 had 82% sensitivity and 72% specificity for silent MI.Using measures that can be derived in an outpatient clinic setting, we have developed a novel screening tool for the detection of silent MI in type 2 diabetes. The screening tool had significantly superior diagnostic accuracy than current ECG criteria for the detection of silent MI in asymptomatic patients

The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme