Evaluation of the chemical composition and in vitro antimicrobial activity of Rosmarinus officinalis, Zataria multiflora, Anethum graveolens and Eucalyptus globulus against Streptococcus iniae; the cause of zoonotic disease in farmed fish

There is a growing interest of industry to replace synthetic chemicals by natural products with bioactive properties from plant origin. The purpose of this study was to elucidate the factors affecting antimicrobial effectiveness of essential oils Rosmarinus officinalis, Zataria multiflora, Anethum graveolens and Eucalyptus globulus against food spoilage and pathogenic bacteria, Streptococcus iniae; the cause of zoonotic streptococcosis in fish. Food conservation is based on an intermittent search for foods with a high nutritional quality and microbial stability and it has been reached by the control of the growth/survival of spoiling and pathogen foodborne microorganisms. Based on several reports, fish streptococcosis is currently considered as one of the main limiting factors in the aquaculture industry, due to the significant economic losses (annually more than $150 million) that these infections cause in different cultured fresh and seawater fish species worldwide. The sensitivity of S. iniae to antibacterial activity of the essential oils was determined using well diffusion assays and paper disc diffusion method. The ranges of minimum inhibitory concentration (MIC) of the oils and extracts were 3.9-250 and 7.8-500 µg/ml and the ranges of minimum bactericidal concentration (MBC) values for the oils and extracts were found to be in the range of 7.8-250 and 15.6-500 µg/ml, respectively. The essential oils exhibited antibacterial activity against S. iniae. The essential oil of rosemary showed the strongest antimicrobial activity

Polymeric Nanosuspensions for Enhanced Dissolution of Water Insoluble Drugs

The aim of the present research is to formulate and evaluate polymeric nanosuspensions containing three model water insoluble drugs, nifedipine (NIF), carbamazepine (CBZ), and ibuprofen (IBU) with various physicochemical properties. The nanosuspensions were prepared from hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) by a cosolvent technique with polyethylene glycol (PEG-300) and water as the cosolvents. Physicochemical and morphological characteristics of the nanosuspensions (particle size, polydispersity index, and crystallinity) have been correlated with the drug release behaviour. The effects of polymer, drug ratio on the physical, morphological, and dissolution characteristics of the drugs are reported. Drug release is significantly enhanced from the nanosuspensions; for example, the maximum NIF, IBU, and CBZ concentrations after 8-hour dissolution are increased approximately 37, 2, and 1.2 times, respectively, in comparison with the pure powdered drugs. Based on this solubilization enhancement performance, the nanosuspensions have potential for increasing the orally dosed bioavailability of NIF, IBU, and CBZ

Developing a Machine Learning-Based Clinical Decision Support Tool for Uterine Tumor Imaging

Uterine leiomyosarcoma (LMS) is a rare but aggressive malignancy. On imaging, it is difficult to differentiate LMS from, for example, degenerated leiomyoma (LM), a prevalent but benign condition. We curated a data set of 115 axial T2-weighted MRI images from 110 patients (mean [range] age=45 [17-81] years) with UTs that included five different tumor types. These data were randomly split stratifying on tumor volume into training (n=85) and test sets (n=30). An independent second reader (reader 2) provided manual segmentations for all test set images. To automate segmentation, we applied nnU-Net and explored the effect of training set size on performance by randomly generating subsets with 25, 45, 65 and 85 training set images. We evaluated the ability of radiomic features to distinguish between types of UT individually and when combined through feature selection and machine learning. Using the entire training set the mean [95% CI] fibroid DSC was measured as 0.87 [0.59-1.00] and the agreement between the two readers was 0.89 [0.77-1.0] on the test set. When classifying degenerated LM from LMS we achieve a test set F1-score of 0.80. Classifying UTs based on radiomic features we identify classifiers achieving F1-scores of 0.53 [0.45, 0.61] and 0.80 [0.80, 0.80] on the test set for the benign versus malignant, and degenerated LM versus LMS tasks. We show that it is possible to develop an automated method for 3D segmentation of the uterus and UT that is close to human-level performance with fewer than 150 annotated images. For distinguishing UT types, while we train models that merit further investigation with additional data, reliable automatic differentiation of UTs remains a challenge

Detecting unilateral phrenic paralysis by acoustic respiratory analysis

The consequences of phrenic nerve paralysis vary from a considerable reduction in respiratory function to an apparently normal state. Acoustic analysis of lung sound intensity (LSI) could be an indirect non-invasive measurement of respiratory muscle function, comparing activity on the two sides of the thoracic cage. Lung sounds and airflow were recorded in ten males with unilateral phrenic paralysis and ten healthy subjects (5 men/5 women), during progressive increasing airflow maneuvers. Subjects were in sitting position and two acoustic sensors were placed on their back, on the left and right sides. LSI was determined from 1.2 to 2.4 L/s between 70 and 2000 Hz. LSI was significantly greater on the normal (19.3±4.0 dB) than the affected (5.7±3.5 dB) side in all patients (p = 0.0002), differences ranging from 9.9 to 21.3 dB (13.5±3.5 dB). In the healthy subjects, the LSI was similar on both left (15.1±6.3 dB) and right (17.4±5.7 dB) sides (p = 0.2730), differences ranging from 0.4 to 4.6 dB (2.3±1.6 dB). There was a positive linear relationship between the LSI and the airflow, with clear differences between the slope of patients (about 5 dB/L/s) and healthy subjects (about 10 dB/L/s). Furthermore, the LSI from the affected side of patients was close to the background noise level, at low airflows. As the airflow increases, the LSI from the affected side did also increase, but never reached the levels seen in healthy subjects. Moreover, the difference in LSI between healthy and paralyzed sides was higher in patients with lower FEV1 (%). The acoustic analysis of LSI is a relevant non-invasive technique to assess respiratory function. This method could reinforce the reliability of the diagnosis of unilateral phrenic paralysis, as well as the monitoring of these patients.Peer ReviewedPostprint (published version

Extracellular NAD and ATP: Partners in immune cell modulation

Extracellular NAD and ATP exert multiple, partially overlapping effects on immune cells. Catabolism of both nucleotides by extracellular enzymes keeps extracellular concentrations low under steady-state conditions and generates metabolites that are themselves signal transducers. ATP and its metabolites signal through purinergic P2 and P1 receptors, whereas extracellular NAD exerts its effects by serving as a substrate for ADP-ribosyltransferases (ARTs) and NAD glycohydrolases/ADPR cyclases like CD38 and CD157. Both nucleotides activate the P2X7 purinoceptor, although by different mechanisms and with different characteristics. While ATP activates P2X7 directly as a soluble ligand, activation via NAD occurs by ART-dependent ADP-ribosylation of cell surface proteins, providing an immobilised ligand. P2X7 activation by either route leads to phosphatidylserine exposure, shedding of CD62L, and ultimately to cell death. Activation by ATP requires high micromolar concentrations of nucleotide and is readily reversible, whereas NAD-dependent stimulation begins at low micromolar concentrations and is more stable. Under conditions of cell stress or inflammation, ATP and NAD are released into the extracellular space from intracellular stores by lytic and non-lytic mechanisms, and may serve as ‘danger signals–to alert the immune response to tissue damage. Since ART expression is limited to naïve/resting T cells, P2X7-mediated NAD-induced cell death (NICD) specifically targets this cell population. In inflamed tissue, NICD may inhibit bystander activation of unprimed T cells, reducing the risk of autoimmunity. In draining lymph nodes, NICD may eliminate regulatory T cells or provide space for the preferential expansion of primed cells, and thus help to augment an immune response

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience

Introduction: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicentre observational study evaluating bendamustine toxicity in real-world practice. Methods: Patients receiving at least one dose of bendamustine (B) +/- rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details and grade 3-5 adverse events (AEs) were analysed. Results: 323 patients were enrolled from 9 NHS hospitals. Most patients (96%) received BR and 46% R maintenance. 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%), and the relative risk highest during maintenance (54%), induction (34%) and follow-up (28%). Toxicity led to permanent treatment discontinuation in 13% of patients, and 2.8% died of bendamustine-related infections (n=5), myelodysplastic syndrome (n=3), and cardiac disease (n=1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor pre-induction PS, poor pre-maintenance PS, abnormal pre-induction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3/10 opportunistic infections occurred despite prophylaxis. Conclusion: In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to trial populations of younger, fitter patients. Poor PS, mantle cell histology and maintenance rituximab were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death warranting extended antimicrobial prophylaxis and infectious surveillance, especially in maintenance-treated patients