Successful Management of Valproate Overdose by a Combination of Extracorporeal Therapies

Valproic acid toxicity is not infrequent and is difficult to treat, as there is no specific antidote. In the past, this drug was considered unremovable by extracorporeal methods because of the highly protein bound state (90–95%). However, recent reports suggest that the toxicokinetics of valproate vary considerably from the pharmacokinetics at therapeutic levels, and at higher concentrations protein‐binding sites become saturated. The drug's relatively low molecular weight (144 Da), small volume of distribution (0.13–0.23 L/kg), and saturable protein binding render it potentially amenable to extracorporeal removal, but published experience is scant and there are only a few reported instances in which patients were successfully treated with extracorporeal methods. Here we report the case of a patient with serious valproate toxicity treated with simultaneous “in series” hemodialysis and hemoperfusion followed by continuous veno‐venous hemodiafiltration. A 35‐year‐old homeless male presented to the emergency department after ingesting 120 pills of valproic acid. Initial valproic acid level was 59 µg/mL. Urine drug screen was negative and serum chemistries including LFTs were normal. He was treated with activated charcoal and admitted to the intensive care unit. 4 h later, he developed respiratory failure and became hemodynamically unstable. He was intubated and successfully resuscitated. Subsequently, the valproic acid level was found to be 553 µg/mL and a decision was made to employ extracorporeal methods for drug removal. “In series” hemodialysis and hemoperfusion were done for 4 h and simultaneous blood samples for measurement of valproic acid levels were obtained as blood entered the hemoperfusion column (arterial) and as it exited the hemodialysis membrane (venous). Extraction ratio, whole blood, and plasma clearances were calculated and they compared substantially with the published data. The above measures decreased valproate levels from 572.6 (pre‐dialysis level) to 203.2 µg/mL. This was followed by continuous veno‐venous hemodiafiltration for 18 h, which sustained the drug removal and prevented significant post‐dialytic rebound. This is the first reported instance in which these three methods were administered together successfully in the management of valproic acid toxicity.     

Waveguiding through a two-dimensional metallic photonic crystal

We present a two‐dimensional (2D) finite‐difference time domain simulation of the propagation of light through linear and bent channels in metallic photonic crystals. We took as a starting point the Bozhevolnyi experiment, consisting of the scattering of surface plasmons by a 2D structure of finitely sized periodic gold dots arranged in a triangular lattice of 400‐nm period. We model injection and propagation of light through linear channels of different widths. We also study the behaviour of light in the presence of a 90° bent line defect made in the structure. We show that the confinement depends on the orientation of the input and output line defects. The two cases of ΓM and ΓK orientations are considered and a spectral study for five different wavelengths is carried out.     

Automatic symbolic derivation of order conditions for two-stage complex Rosenbrock schemes

Rosenbrock methods are known to be good in numerical modeling of stiff problems. In this work, a new symbolic algorithm is proposed for automating the derivation of order conditions for two-stage Rosenbrock schemes with complex coefficients. Software implementation of the proposed algorithm is discussed in detail.     

Automatic verification of reduction techniques in Higher Order Logic

In this paper we propose an automatic methodology to verify the soundness of model checking reduction techniques. The idea is to use the consistency of the specifications to verify if the reduced model is faithful to the original one. The user provides the reduction technique, the specification and the system under verification. Then, using Higher Order Logic he verifies automatically if the reduction technique is soundly applied. The method is completely defined in an MDG–HOL special integration platform that combines an automatic high level model checking tool Multiway Decision Graphs (MDGs) within the HOL theorem prover. We provide two case studies, the first one is the reduction using SAT–MDG of an Island Tunnel Controller and the second one is the MDG–HOL assume-guarantee reduction of the Look-Aside Interface. The obtained results of our approach offer a considerable gain in terms of the correctness of heuristics and reduction techniques as applied to commercial model checking, however a small penalty is paid in terms of CPU time and memory usage.     

Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia

Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the hypothesis that aspirin at a dose sufficient to inhibit COX-2 would reduce inflammatory responses in preeclampsia neutrophils. Neutrophils were isolated from normal pregnant and preeclamptic women at approximately 30 weeks’ gestation. Normal pregnancy neutrophils were treated with elastase, a protease elevated in preeclampsia, or elastase plus aspirin to inhibit COX-2, or elastase plus pinane thromboxane, a biologically active structural analog of thromboxane and a thromboxane synthase inhibitor. Preeclamptic pregnancy neutrophils were treated with the same doses of aspirin or pinane thromboxane. Confocal microscopy with immunofluorescence staining was used to determine the cellular localization of the p65 subunit of nuclear factor-kappa B (NF-κB) and media concentrations of thromboxane were measured to evaluate the inflammatory response. In untreated neutrophils of normal pregnant women, p65 was localized to the cytosol. Upon stimulation with elastase, p65 translocated from the cytosol to the nucleus coincident with increased thromboxane production. When neutrophils were co-treated with aspirin or pinane thromboxane, elastase was not able to cause nuclear translocation of p65 or increase thromboxane. In untreated neutrophils of preeclamptic women, the p65 subunit was present in the nucleus and thromboxane production was elevated, but when preeclamptic neutrophils were treated with aspirin or pinane thromboxane, p65 was cleared from the nucleus and returned to the cytosol along with decreased thromboxane production. These findings suggest that COX-2 is a downstream mediator of PAR-1 and demonstrate that PAR-1- mediated inflammation can be inhibited by aspirin. Given the extensive and ubiquitous expression of PAR-1 and COX-2 in preeclamptic women, consideration should be given to treating women with preeclampsia using a dose of aspirin sufficient to inhibit COX-2.     

ONT-Based Alternative Assemblies Impact on the Annotations of Unique versus Repetitive Features in the Genome of a Romanian Strain of Drosophila melanogaster

To date, different strategies of whole-genome sequencing (WGS) have been developed in order to understand the genome structure and functions. However, the analysis of genomic sequences obtained from natural populations is challenging and the biological interpretation of sequencing data remains the main issue. The MinION device developed by Oxford Nanopore Technologies (ONT) is able to generate long reads with minimal costs and time requirements. These valuable assets qualify it as a suitable method for performing WGS, especially in small laboratories. The long reads resulted using this sequencing approach can cover large structural variants and repetitive sequences commonly present in the genomes of eukaryotes. Using MinION, we performed two WGS assessments of a Romanian local strain of Drosophila melanogaster, referred to as Horezu_LaPeri (Horezu). In total, 1,317,857 reads with a size of 8.9 gigabytes (Gb) were generated. Canu and Flye de novo assembly tools were employed to obtain four distinct assemblies with both unfiltered and filtered reads, achieving maximum reference genome coverages of 94.8% (Canu) and 91.4% (Flye). In order to test the quality of these assemblies, we performed a two-step evaluation. Firstly, we considered the BUSCO scores and inquired for a supplemental set of genes using BLAST. Subsequently, we appraised the total content of natural transposons (NTs) relative to the reference genome (ISO1 strain) and mapped the mdg1 retroelement as a resolution assayer. Our results reveal that filtered data provide only slightly enhanced results when considering genes identification, but the use of unfiltered data had a consistent positive impact on the global evaluation of the NTs content. Our comparative studies also revealed differences between Flye and Canu assemblies regarding the annotation of unique versus repetitive genomic features. In our hands, Flye proved to be moderately better for gene identification, while Canu clearly outperformed Flye for NTs analysis. Data concerning the NTs content were compared to those obtained with ONT for the D. melanogaster ISO1 strain, revealing that our strategy conducted to better results. Additionally, the parameters of our ONT reads and assemblies are similar to those reported for ONT experiments performed on various model organisms, revealing that our assembly data are appropriate for a proficient annotation of the Horezu genome.     

The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.     

Bacillus subtilis: As an Efficient Bacterial Strain for the Reclamation of Water Loaded with Textile Azo Dye,Orange II

The azo dye orange II is used extensively in the textile sector for coloring fabrics. High concentrations of it are released into aqueous environments through textile effluents. Therefore, its removal from textile wastewater and effluents is necessary. Herein, initially, we tested 11 bacterial strains for their capabilities in the degradation of orange II dye. It was revealed in the preliminary data that B. subtilis can more potently degrade the selected dye, which was thus used in the subsequent experiments. To achieve maximum decolorization, the experimental conditions were optimized whereby maximum degradation was achieved at: a 25 ppm dye concentration, pH 7, a temperature of 35 °C, a 1000 mg/L concentration of glucose, a 1000 mg/L urea concentration, a 666.66 mg/L NaCl concentration, an incubation period of 3 days, and with hydroquinone as a redox mediator at a concentration of 66.66 mg/L. The effects of the interaction of the operational factors were further confirmed using response surface methodology, which revealed that at optimum conditions of pH 6.45, a dye concentration of 17.07 mg/L, and an incubation time of 9.96 h at 45.38 °C, the maximum degradation of orange II can be obtained at a desirability coefficient of 1, estimated using the central composite design (CCD). To understand the underlying principles of degradation of the metabolites in the aliquot mixture at the optimized condition, the study steps were extracted and analyzed using GC-MS(Gas Chromatography Mass Spectrometry), FTIR(Fourier Transform Infrared Spectroscopy), ¹H and carbon 13 NMR(Nuclear Magnetic Resonance Spectroscopy). The GC-MS pattern revealed that the original dye was degraded into o-xylene and naphthalene. Naphthalene was even obtained in a pure state through silica gel column isolation and confirmed using ¹H and ¹³C NMR spectroscopic analysis. Phytotoxicity tests on Vigna radiata were also conducted and the results confirmed that the dye metabolites were less toxic than the parent dye. These results emphasize that B. subtilis should be used as a potential strain for the bioremediation of textile effluents containing orange II and other toxic azo dyes.