Diagnostic Tests in the Prediction of Neonatal Outcome in Early Placental Fetal Growth Restriction.

Background and Objectives: Monitoring pregnancies with fetal growth restriction (FGR) presents a challenge, especially concerning the time of delivery in cases of early preterm pregnancies below 32 weeks. The aim of our study was to compare different diagnostic parameters in growth-restricted preterm neonates with and without morbidity/mortality and to determine sensitivity and specificity of diagnostic parameters for monitoring preterm pregnancies with early preterm fetal growth restriction below 32 weeks. Materials and Methods: Our clinical study evaluated 120 cases of early preterm deliveries, with gestational age ≤ 32 + 0 weeks, with prenatally diagnosed placental FGR. All the patients were divided into three groups of 40 cases each based on neonatal condition,: I-Neonates with morbidity/mortality (NMM); II-Neonates without morbidity with acidosis/asphyxia (NAA); III-Neonates without neonatal morbidity/acidosis/asphyxia (NWMAA). Results: Amniotic fluid index (AFI) was lower in NMM, while NWMAA had higher biophysical profile scores (BPS). UA PI was lower in NWMAA. NWMAA had higher MCA PI and CPR and fewer cases with CPR <5th percentile. NMM had higher DV PI, and more often had ductus venosus (DV) PI > 95th‱ or absent/reversed A wave, and pulsatile blood flow in umbilical vein (UV). The incidence of pathological fetal heart rate monitoring (FHRM) was higher in NMM and NAA, although the difference was not statistically significant. ROC calculated by defining a bad outcome as NMM and a good outcome as NAA and NWMAA showed the best sensitivity in DV PIi. ROC calculated by defined bad outcome in NMM and NAA and good outcome in NWMAA showed the best sensitivity in MCA PI. Conclusions: In early fetal growth restriction normal cerebral blood flow strongly predicts good outcomes, while pathological venous blood flow is associated with bad outcomes. In fetal growth restriction before 32 weeks, individualized expectant management remains the best option for the optimal timing of delivery.

Uncovering the Reasons Behind COVID-19 Vaccine Hesitancy in Serbia: Sentiment-Based Topic Modeling.

BACKGROUND: Since the first COVID-19 vaccine appeared, there has been a growing tendency to automatically determine public attitudes toward it. In particular, it was important to find the reasons for vaccine hesitancy, since it was directly correlated with pandemic protraction. Natural language processing (NLP) and public health researchers have turned to social media (eg, Twitter, Reddit, and Facebook) for user-created content from which they can gauge public opinion on vaccination. To automatically process such content, they use a number of NLP techniques, most notably topic modeling. Topic modeling enables the automatic uncovering and grouping of hidden topics in the text. When applied to content that expresses a negative sentiment toward vaccination, it can give direct insight into the reasons for vaccine hesitancy. OBJECTIVE: This study applies NLP methods to classify vaccination-related tweets by sentiment polarity and uncover the reasons for vaccine hesitancy among the negative tweets in the Serbian language. METHODS: To study the attitudes and beliefs behind vaccine hesitancy, we collected 2 batches of tweets that mention some aspects of COVID-19 vaccination. The first batch of 8817 tweets was manually annotated as either relevant or irrelevant regarding the COVID-19 vaccination sentiment, and then the relevant tweets were annotated as positive, negative, or neutral. We used the annotated tweets to train a sequential bidirectional encoder representations from transformers (BERT)-based classifier for 2 tweet classification tasks to augment this initial data set. The first classifier distinguished between relevant and irrelevant tweets. The second classifier used the relevant tweets and classified them as negative, positive, or neutral. This sequential classifier was used to annotate the second batch of tweets. The combined data sets resulted in 3286 tweets with a negative sentiment: 1770 (53.9%) from the manually annotated data set and 1516 (46.1%) as a result of automatic classification. Topic modeling methods (latent Dirichlet allocation [LDA] and nonnegative matrix factorization [NMF]) were applied using the 3286 preprocessed tweets to detect the reasons for vaccine hesitancy. RESULTS: The relevance classifier achieved an F-score of 0.91 and 0.96 for relevant and irrelevant tweets, respectively. The sentiment polarity classifier achieved an F-score of 0.87, 0.85, and 0.85 for negative, neutral, and positive sentiments, respectively. By summarizing the topics obtained in both models, we extracted 5 main groups of reasons for vaccine hesitancy: concern over vaccine side effects, concern over vaccine effectiveness, concern over insufficiently tested vaccines, mistrust of authorities, and conspiracy theories. CONCLUSIONS: This paper presents a combination of NLP methods applied to find the reasons for vaccine hesitancy in Serbia. Given these reasons, it is now possible to better understand the concerns of people regarding the vaccination process.

Curcumin Loaded PEGylated Nanoemulsions Designed for Maintained Antioxidant Effects and Improved Bioavailability: A Pilot Study on Rats.

The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of -40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078-0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.

A New Photocatalyst Bismuth Oxo Citrate: Synthesis, Characterization, and Photocatalytic Performance.

A new photocatalyst bismuth oxo citrate was synthesized by facile precipitation process with calcination at 200 °C. The photocatalyst was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, N2 sorptometry, and elemental analysis. Morphologically, it is composed of polyhedral particles with different, irregular shapes and sizes. The specific surface area (SSA) of the photocatalyst was 8.92 m2 g-1. It showed very good photocatalytic performance and reusability. Total decolorization of Reactive Blue 19 (RB19) was achieved in less than 10 minutes, which is much faster in comparison with TiO2 P25. Also, bismuth oxo citrate showed higher photocatalytic activity than other photocatalysts based on bismuth compounds reported by other authors. Optimal photocatalysis parameters were pH 2 and photocatalyst dose of 250 mg dm-3. The decolorization rate was found to decrease as initial dye concentration increased. The photocatalytic data best fitted to L-H kinetic model with pseudo-first order reaction rate. Chrastil diffusion model showed that diffusion has not influence on the process.

A Novel Biosorbent Lagenaria vulgaris Shell - ZrO2for the Removal of Textile Dye From Water.

A new biosorbent, abbreviated as LVB-ZrO2, was synthesized by chemically modifying Lagenaria vulgaris shell with ZrO2. The removal of textile dye RB19 from aqueous solution by LVB-ZrO2was studied. Characterization by SEM, FTIR and XRD confirmed the chemical modification of the biomaterial, which showed significant improvement of removal efficiency compared with unmodified Lagenaria vulgaris shell. LVB-ZrO2point of zero charge is 5.49. The biosorption process is highly pH dependent and the optimal pH is 2.0, at which complete dye removal was attained. The results are the best by a pseudo-second order kinetic model. The optimal adsorbent dosage is 4 mg/dm³.The RB19 biosorption follows the Langmuir isotherm model (R² = 0.9978), with the maximum sorption capacity of 75.12 mg/g. LVB-ZrO2is a mechanically stable, easy to synthesize, cost-effective, biocompatible and environmentally-friendly biosorbent with the high potential for the removal of RB19 from aqueous solution.

Identification of intermediates and ecotoxicity assessment during the UV/H2O2 oxidation of azo dye Reactive Orange 16.

Degradation of azo dye Reactive Orange 16, a widely used textile dye, was carried out with UV light in the presence of H2O2. The experiments were conducted in the batch mode using low-pressure mercury lamps, emitting at 253.7 nm. Liquid-chromatography tandem mass spectrometry (LC/MS/MS) and high resolution mass spectrometry (FT-ICR) were employed in order to identify some of degradation products as well as to suggest possible degradation pathways. According to the mass spectrum characterization of RO16 dye and MS(n) fragmentation (up to MS(4)), its possible fragmentation pattern was proposed. The results revealed that degradation occurred mainly via hydroxylation, cleavage of the C‒S bond between the aromatic ring and the sulfonate group, cleavage of the azo bond, cleavage of the C‒N bond between azo group and naphthalene ring and aromatic ring opening. Toxicity test with marine photobacterium Vibrio Fisheri was performed to consider whether or not the UV/H2O2 treatment of RO16 dye results in the products with enhanced toxicity for aquatic life.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 µM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1ß3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

Pericardial syndromes: an update after the ESC guidelines 2004.

Despite a myriad of causes, pericardial diseases present in few clinical syndromes. Acute pericarditis should be differentiated from aortic dissection, myocardial infarction, pneumonia/pleuritis, pulmonary embolism, pneumothorax, costochondritis, gastroesophageal reflux/neoplasm, and herpes zoster. High-risk features indicating hospitalization are: fever >38 °C, subacute onset, large effusion/tamponade, failure of non-steroidal anti-inflammatory drugs (NSAIDs), previous immunosuppression, trauma, anticoagulation, neoplasm, and myopericarditis. Treatment comprises 10-14-days NSAID plus 3 months colchicine (2 × 0.5 mg; 1 × 0.5 mg in patients <70 kg). Corticosteroids are avoided, except for autoimmunity, as they facilitate the recurrences. Echo-guided pericardiocentesis (±fluoroscopy) is indicated for tamponade and effusions >2 cm. Smaller effusions are drained if neoplastic, purulent or tuberculous etiology is suspected. In recurrent pericarditis, repeated testing for autoimmune and thyroid disease is appropriate. Pericardioscopy and pericardial/epicardial biopsy may clarify the etiology. Familial clustering was recently associated with tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A gene mutation). Treatment includes 10-14 days NSAIDs with colchicine 0.5 mg bid for up to 6 months. In non-responders, low-dose steroids, intrapericardial steroids, azathioprine, and cyclophosphamide can be tried. Successful management with interleukin-1 receptor antagonist (anakinra) was recently reported. Pericardiectomy remains the last option in >2 years severely symptomatic patients. In constriction, expansion of the heart is impaired by the rigid, chronically inflamed/thickened pericardium (no thickening ~20 %). Chest radiography, echocardiography, computerized tomography, magnetic resonance imaging, hemodynamics, and endomyocardial biopsy indicate the diagnosis. Pericardiectomy is the only treatment for permanent constriction. Predictors of poor survival are prior radiation, renal dysfunction, high pulmonary artery pressures, poor left ventricular function, hyponatremia, age, and simultaneous HIV and tuberculous infection.

Performance analysis of large language models in the domain of legal argument mining.

Generative pre-trained transformers (GPT) have recently demonstrated excellent performance in various natural language tasks. The development of ChatGPT and the recently released GPT-4 model has shown competence in solving complex and higher-order reasoning tasks without further training or fine-tuning. However, the applicability and strength of these models in classifying legal texts in the context of argument mining are yet to be realized and have not been tested thoroughly. In this study, we investigate the effectiveness of GPT-like models, specifically GPT-3.5 and GPT-4, for argument mining via prompting. We closely study the model's performance considering diverse prompt formulation and example selection in the prompt via semantic search using state-of-the-art embedding models from OpenAI and sentence transformers. We primarily concentrate on the argument component classification task on the legal corpus from the European Court of Human Rights. To address these models' inherent non-deterministic nature and make our result statistically sound, we conducted 5-fold cross-validation on the test set. Our experiments demonstrate, quite surprisingly, that relatively small domain-specific models outperform GPT 3.5 and GPT-4 in the F1-score for premise and conclusion classes, with 1.9% and 12% improvements, respectively. We hypothesize that the performance drop indirectly reflects the complexity of the structure in the dataset, which we verify through prompt and data analysis. Nevertheless, our results demonstrate a noteworthy variation in the performance of GPT models based on prompt formulation. We observe comparable performance between the two embedding models, with a slight improvement in the local model's ability for prompt selection. This suggests that local models are as semantically rich as the embeddings from the OpenAI model. Our results indicate that the structure of prompts significantly impacts the performance of GPT models and should be considered when designing them.

The chemical characterisation of nettle (Urtica dioica L.) seed oil.

The past decade has seen increasing interest in plant oils in the food, pharmaceutical, and cosmetic industries due to their diverse functional and nutritional properties, as well as the high levels of consumer acceptance. As a result, there has been a spike in research interest in finding new sources of oils with good potential for industrial use. In this paper, the chemical characterisation (saponification, iodine, acid and ester numbers, as well as fatty acid composition) of nettle seed oil was given. Oil was analysed for its thermooxidative stability by differential scanning calorimetry. The kinetic parameters of oxidation (Ea, A, and k) were also determined. The results showed that nettle seed oil belongs to the group of edible oils of the linoleic type and it is nutritionally highly valuable, it has pronounced thermooxidative stability and could be an alternative source of raw material for the food, cosmetics, and other non-food industries.

Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation.

Contemporary trends in combinatorial chemistry and the design of pharmaceuticals targeting brain disorders have favored the development of drug candidates with increased lipophilicity and poorer water solubility, with the expected improvement in delivery across the blood-brain barrier (BBB). The growing availability of innovative excipients/ligands allowing improved brain targeting and controlled drug release makes the lipid nanocarriers a reasonable choice to overcome the factors impeding drug delivery through the BBB. However, a wide variety of methods, study designs and experimental conditions utilized in the literature hinder their systematic comparison, and thus slows the advances in brain-targeting by lipid-based nanoparticles. This review provides an overview of the methods most commonly utilized during the preclinical testing of liposomes, nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers intended for the treatment of various CNS disorders via the parenteral route. In order to fully elucidate the structure, stability, safety profiles, biodistribution, metabolism, pharmacokinetics and immunological effects of such lipid-based nanoparticles, a transdisciplinary approach to preclinical characterization is mandatory, covering a comprehensive set of physical, chemical, in vitro and in vivo biological testing.

Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study.

Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7­methoxy-2-(4­methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 µm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.

High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances.

Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3-2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nanoparticles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior.

'Candidatus Phytoplasma convolvuli', a new phytoplasma taxon associated with bindweed yellows in four European countries.

Plants of Convolvulus arvensis exhibiting symptoms of undersized leaves, shoot proliferation and yellowing, collectively defined as bindweed yellows, were sampled in different regions of Europe and assessed for phytoplasma infection by PCR amplification using phytoplasma universal rRNA operon primer pairs. Positive results were obtained for all diseased plants. RFLP analysis of amplicons comprising the16S rRNA gene alone or the16S rRNA gene and 16-23S intergenic spacer region indicated that the detected phytoplasmas were distinguishable from all other previously described rRNA gene sequences. Analysis of 16S rRNA gene sequences derived from seven selected phytoplasma strains (BY-S57/11, BY-S62/11, BY-I1015, BY-I1016, BY-BH1, BY-BH2 and BY-G) showed that they were nearly identical (99.9-100% gene sequence similarity) but shared less than 97.5% similarity with comparable sequences of other phytoplasmas. Thus, BY phytoplasmas represent a new taxon whose closest relatives are stolbur phytoplasma strains and 'Candidatus Phytoplasma fragariae' with which they share 97.2% and 97.1% 16S rRNA gene sequence similarity, respectively. Phylogenetic analysis of 16S rRNA gene sequences confirmed that bindweed yellows phytoplasma strains collectively represent a distinct lineage within the phytoplasma clade and share a common ancestor with previously published or proposed 'Candidatus Phytoplasma' taxa within a major branch including aster yellows and stolbur phytoplasmas. On the basis of unique 16S rRNA gene sequences and biological properties that include a single host plant species and a geographical distribution limited to parts of Europe, the bindweed yellows (BY) phytoplasmas represent a coherent but discrete taxon, 'Candidatus Phytoplasma convolvuli', with strain BY-S57/11 (GenBank accession no. JN833705) as the reference strain.

Current view on phytoplasma genomes and encoded metabolism.

Phytoplasmas are specialised bacteria that are obligate parasites of plant phloem tissue and insects. These bacteria have resisted all attempts of cell-free cultivation. Genome research is of particular importance to analyse the genetic endowment of such bacteria. Here we review the gene content of the four completely sequenced 'Candidatus Phytoplasma' genomes that include those of 'Ca. P. asteris' strains OY-M and AY-WB, 'Ca. P. australiense,' and 'Ca. P. mali'. These genomes are characterized by chromosome condensation resulting in sizes below 900 kb and a G + C content of less than 28%. Evolutionary adaption of the phytoplasmas to nutrient-rich environments resulted in losses of genetic modules and increased host dependency highlighted by the transport systems and limited metabolic repertoire. On the other hand, duplication and integration events enlarged the chromosomes and contribute to genome instability. Present differences in the content of membrane and secreted proteins reflect the host adaptation in the phytoplasma strains. General differences are obvious between different phylogenetic subgroups. 'Ca. P. mali' is separated from the other strains by its deviating chromosome organization, the genetic repertoire for recombination and excision repair of nucleotides or the loss of the complete energy-yielding part of the glycolysis. Apart from these differences, comparative analysis exemplified that all four phytoplasmas are likely to encode an alternative pathway to generate pyruvate and ATP.

Characterization of free and insoluble-bound phenolics of chia (Salvia hispanica L.) seeds.

The content, antioxidant activity and composition of free and bound phenolics from chia seeds were investigated. The free phenolics were extracted by using ethanol and methanol of analytical purity, 70% v/v ethanol and by 70% v/v methanol. The bound phenolics were extracted from seeds after alkaline hydrolysis was done. The phenolics content obtained by aqueous-alcoholic solutions was higher than the content obtained by using the pure alcoholic solution (for 20.8% by 70% methanol and 41.2% by 70% ethanol). The content of bound phenolics was 932 µg g-1. Among the identified phenolic compounds the apigenin 4'-O-glucoside was the most abundant, and among the acids, a rosmarinic was the most abundant in free phenolic extract and caffeic acid in bound. The correlation coefficients indicated the DPPH method and reducing power were more suitable for assessing the antioxidant activity than the FRAP method.

Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature.

Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague-Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.

The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions.

A nanotechnology-based approach to drug delivery presents one of the biggest trends in biomedical science that can provide increased active concentration, bioavailability, and safety compared to conventional drug-delivery systems. Nanoemulsions stand out amongst other nanocarriers for being biodegradable, biocompatible, and relatively easy to manufacture. For improved drug-delivery properties, longer circulation for the nanoemulsion droplets should be provided, to allow the active to reach the target site. One of the strategies used for this purpose is PEGylation. The aim of this research was assessing the impact of the oil phase selection, soybean or fish oil mixtures with medium chain triglycerides, on the physicochemical characteristics and injectability of curcumin-loaded PEGylated nanoemulsions. Electron paramagnetic resonance spectroscopy demonstrated the structural impact of the oil phase on the stabilizing layer of nanoemulsions, with a more pronounced stabilizing effect of curcumin observed in the fish oil nanoemulsion compared to the soybean oil one. The design of the experiment study, employed to simultaneously assess the impact of the oil phase, different PEGylated phospholipids and their concentrations, as well as the presence of curcumin, showed that not only the investigated factors alone, but also their interactions, had a significant influence on the critical quality attributes of the PEGylated nanoemulsions. Detailed physicochemical characterization of the NEs found all formulations were appropriate for parenteral administration and remained stable during two years of storage, with the preserved antioxidant activity demonstrated by DPPH and FRAP assays. In vitro release studies showed a more pronounced release of curcumin from the fish oil NEs compared to that from the soybean oil ones. The innovative in vitro injectability assessment, designed to mimic intravenous application, proved that all formulations tested in selected experimental setting could be employed in prospective in vivo studies. Overall, the current study shows the importance of oil phase selection when formulating PEGylated nanoemulsions.

Assessment of expertise in morphological identification of mosquito species (Diptera, Culicidae) using photomicrographs.

Accurate identification of insect species is an indispensable and challenging requirement for every entomologist, particularly if the species is involved in disease outbreaks. The European MediLabSecure project designed an identification (ID) exercise available to any willing participant with the aim of assessing and improving knowledge in mosquito taxonomy. The exercise was based on high-definition photomicrographs of mosquitoes (26 adult females and 12 larvae) collected from the western Palaearctic. Sixty-five responses from Europe, North Africa and the Middle East were usable. The study demonstrated that the responders were better at identifying females (82% correct responses) than larvae (63%). When the responders reported that they were sure of the accuracy of their ID, the success rate of ID increased (92% for females and 88% for larvae). The top three tools used for ID were MosKeyTool (72% of responders), the ID key following Becker et al. [2010. Mosquitoes and their control, 2nd edn. Berlin: Springer] (38%), and the CD-ROM of Schaffner et al. [2001. Les moustiques d'Europe: logiciel d'identification et d'enseignement - The mosquitoes of Europe: an identification and training programme. Montpellier: IRD; EID] (32%), while other tools were used by less than 10% of responders. Responders reporting the identification of mosquitoes using the MosKeyTool were significantly better (80% correct responses) than non-MosKeyTool users (69%). Most responders (63%) used more than one ID tool. The feedback from responders in this study was positive, with the exercise being perceived as halfway between educational training and a fun quiz. It raised the importance of further expanding training in mosquito ID for better preparedness of mosquito surveillance and control programmes.

Title: Évaluation de l'expertise en identification morphologique des espèces de moustiques (Diptera, Culicidae) à l'aide de photomicrographies. Abstract: L'identification précise des espèces d'insectes est une exigence indispensable et difficile pour tout entomologiste, en particulier si l'espèce est impliquée dans des épidémies. Le projet européen MediLabSecure a conçu un exercice d'identification (ID) accessible à tout participant volontaire dans le but d'évaluer et d'améliorer les connaissances en taxonomie des moustiques. L'exercice était basé sur des photomicrographies haute définition de moustiques (26 femelles adultes et 12 larves) prélevées dans le Paléarctique occidental. Soixante-cinq réponses d'Europe, d'Afrique du Nord et du Moyen-Orient ont été utilisables. L'étude a démontré que les répondants étaient meilleurs pour identifier les femelles (82 % de réponses correctes) que les larves (63 %). Lorsque les répondants ont déclaré être sûrs de l'exactitude de leur ID, le taux de réussite de l'identification était meilleur (92 % pour les femelles et 88 % pour les larves). Les trois principaux outils utilisés pour les ID étaient MosKeyTool (72 % des répondants), la clé d'identification du livre de Becker et al. (38%) et le CD-ROM de Schaffner et al. (32 %), tandis que d'autres outils étaient utilisés par moins de 10 % des répondants. Les répondants déclarant identifier des moustiques à l'aide de MosKeyTool étaient significativement meilleurs (80 % de réponses correctes) que les non-utilisateurs de MosKeyTool (69 %). La plupart des répondants (63 %) ont utilisé plus d'un outil d'identification. Les commentaires des répondants de cette étude ont été positifs, l'exercice étant perçu comme à mi-chemin entre une formation pédagogique et un quiz amusant. Il a souligné l'importance d'étendre la formation complémentaire à l'identification des moustiques pour une meilleure préparation des programmes de surveillance et de contrôle des moustiques.

Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach.

Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.