Microphysiological Systems for Studying Cellular Crosstalk During the Neutrophil Response to Infection

Neutrophils are the primary responders to infection, rapidly migrating to sites of inflammation and clearing pathogens through a variety of antimicrobial functions. This response is controlled by a complex network of signals produced by vascular cells, tissue resident cells, other immune cells, and the pathogen itself. Despite significant efforts to understand how these signals are integrated into the neutrophil response, we still do not have a complete picture of the mechanisms regulating this process. This is in part due to the inherent disadvantages of the most-used experimental systems: in vitro systems lack the complexity of the tissue microenvironment and animal models do not accurately capture the human immune response. Advanced microfluidic devices incorporating relevant tissue architectures, cell-cell interactions, and live pathogen sources have been developed to overcome these challenges. In this review, we will discuss the in vitro models currently being used to study the neutrophil response to infection, specifically in the context of cell-cell interactions, and provide an overview of their findings. We will also provide recommendations for the future direction of the field and what important aspects of the infectious microenvironment are missing from the current models. &nbsp;</p

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview.

The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Notes for genera: basal clades of Fungi (including Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota)

Compared to the higher fungi (Dikarya), taxonomic and evolutionary studies on the basal clades of fungi are fewer in number. Thus, the generic boundaries and higher ranks in the basal clades of fungi are poorly known. Recent DNA based taxonomic studies have provided reliable and accurate information. It is therefore necessary to compile all available information since basal clades genera lack updated checklists or outlines. Recently, Tedersoo et al. (MycoKeys 13:1--20, 2016) accepted Aphelidiomycota and Rozellomycota in Fungal clade. Thus, we regard both these phyla as members in Kingdom Fungi. We accept 16 phyla in basal clades viz. Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota. Thus, 611 genera in 153 families, 43 orders and 18 classes are provided with details of classification, synonyms, life modes, distribution, recent literature and genomic data. Moreover, Catenariaceae Couch is proposed to be conserved, Cladochytriales Mozl.-Standr. is emended and the family Nephridiophagaceae is introduced

Hemodynamic Predictors of Early Neurological Worsening in Acute Ischemic Stroke

Introduction: Early neurological worsening is common in acute ischemic stroke (AIS) and associated with increased morbidity. Hypothesis: We tested the hypothesis that early hemodynamic factors are associated with early neurological worsening in AIS. Methods: Prospective, observational study of AIS patients with a NIHSS \u3e 3. Patients were enrolled in the emergency department as soon as AIS was suspected. Exclusion criteria were: time of onset \u3e 12 hours and hemorrhagic stroke. We performed baseline non-invasive, continuous hemodynamic monitoring and measured cerebral blood flow velocity with transcranial Doppler insonation of the middle cerebral arteries. We limited analysis to patients with confirmed stroke. Early neurological worsening was defined by any increase in the NIHSS over the first 24 hours. Results: We enrolled 77 patients, 57 of whom had AIS confirmed on imaging. The mean age was 67 ± 13 years, 53% were female and 78% were African American. The median NIHSS was 6 (IQR 4,8) and baseline SBP was 151 ± 35 mmHg. Fifteen (26%) patients had neurological worsening. Blood pressure, age, and presenting NIHSS were not predictive of neurological worsening. Low stroke volume index was associated with neurological worsening (OR 5.2, 95% CI 1.5 - 18.3). There was no significant difference in baseline MCA mean flow velocity (MFV) between patients with or without neurological worsening (42 vs 41 cm/sec, p=0.8). There was a trend towards higher MFV in patients with normal stroke volume vs. those with low stroke volume (43 ± 14 vs 37 ± 9 cm/sec, p=0.07). Conclusion: In this sample of low to moderate severity AIS patients, low stroke volume index was predictive of early neurological worsening, suggesting a hemodynamic effect on the ischemic penumbra

Representative images of rat mesenteric arterioles and venules 5 seconds after injection of 200 nM kg^-1 FITC-N/OFQ into the mesenteric artery with (C,D) and without (A,B) N/OFQ (added 15 sec prior to FITC-N/OFQ and labelled T₁₅) competing for the same NOP receptor site.

<p>The areas highlighted by arrows indicate binding of FITC-N/OFQ to NOP (FITC-N/OFQ-NOP) and thus sparse distribution of NOP receptors on the endothelium in this animal.</p

Characterisation of FITC-N/OFQ (F-N/OFQ) at recombinant NOP and classical opioid receptors on CHO cells.

<p><b>A</b>: Binding affinity of F-N/OFQ and a range of opioid receptor subtype selective reference compounds. F-N/OFQ shows high selectivity for NOP over classical opioid receptors (mean (range) of up to 4 experiments.) *curves did not saturate K_i estimated between 1 and 10µM. <b>B</b>: Both N/OFQ and F-N/OFQ behave as full agonists on recombinant human NOP. These data are stimulation factor = agonist stimulated specific binding / basal specific binding (mean <u>+</u>SEM, <i>n</i>=8).</p

The effect of UFP-101 on cardiovascular variables: mean arterial pressure (MAP, mmHg; upper panel) and heart rate (beats per minute, bpm; lower panel) were measured in anesthetised rats at baseline (T₀), this being 24 hours after i.v. injection with 1 mg kg^-1 + 0.5 mg kg^-1 (LPS, n=6; LPS + UFP-101, n=6) or saline (control, n=6; UFP-101, n=6).

<p>Measurements were repeated 40 minutes after baseline (T₄₀) in response to i.v. injection of 150 nM kg^-1 UFP-101 (LPS + UFP-101, UFP-101 groups) or saline (control; LPS, groups). Values are median, with open bars representing the 50^th-75^th percentile, grey bars the 25^th-50^th percentile and upper and lower error bars representing the maximum and minimum respectively.</p

The effect of UFP-101 on macromolecular leak and leukocyte rolling <i>in vivo</i>: macromolecular leak (percentage change in interstitial FITC-BSA fluorescence from baseline, upper panel) and leukocyte rolling (per minute, baseline and after treatment, lower panel) in post capillary venules (<40 µm) within the anesthetised rat mesentery preparation.

<p>Measurements were taken in response to i.v. injection of 150 nM kg^-1 UFP-101 (LPS + UFP-101 and UFP-101 groups) or saline (control and LPS groups). Values are median, with open bars representing the 50^th-75^th percentile, grey bars the 25^th-50^th percentile and upper and lower error bars representing the maximum and minimum respectively. ^*increased compared to control.</p