Simultaneous Venous-Arterial Doppler Ultrasound During Early Fluid Resuscitation to Characterize a Novel Doppler Starling Curve: A Prospective Observational Pilot Study.

The likelihood of a patient being preload responsive-a state where the cardiac output or stroke volume (SV) increases significantly in response to preload-depends on both cardiac filling and function. This relationship is described by the canonical Frank-Starling curve. : We hypothesize that a novel method for phenotyping hypoperfused patients (ie, the "Doppler Starling curve") using synchronously measured jugular venous Doppler as a marker of central venous pressure (CVP) and corrected flow time of the carotid artery (ccFT) as a surrogate for SV will refine the pretest probability of preload responsiveness/unresponsiveness.

ProGlide entrapment of the occlusive balloon during repair of an iatrogenic subclavian artery injury.

The insertion of any central venous catheter (CVC) is associated with a risk of damage to neurovascular structures, pneumothorax, cardiac arrhythmias, and infection. Unintentional arterial puncture remains rare, occurring in 6.3-9.

Simultaneous venous-arterial Doppler during preload augmentation: illustrating the Doppler Starling curve.

Providing intravenous (IV) fluids to a patient with signs or symptoms of hypoperfusion is common. However, evaluating the IV fluid 'dose-response' curve of the heart is elusive. Two patients were studied in the emergency department with a wireless, wearable Doppler ultrasound system.

Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction.

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33) and oxidized IL-33 (IL-33) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 10 M s, to effectively neutralize IL-33 following rapid release from damaged tissue.

Designing a neuroclinical assessment of empathy deficits in psychopathy based on the Zipper Model of Empathy.

The heterogeneity of the literature on empathy highlights its multidimensional and dynamic nature and affects unclear descriptions of empathy in the context of psychopathology. The Zipper Model of Empathy integrates current theories of empathy and proposes that empathy maturity is dependent on whether contextual and personal factors push affective and cognitive processes together or apart. This concept paper therefore proposes a comprehensive battery of physiological and behavioral measures to empirically assess empathy processing according to this model with an application for psychopathic personality.

The time cost of physiologically ineffective intravenous fluids in the emergency department: an observational pilot study employing wearable Doppler ultrasound.

Background: Little data exist on the time spent by emergency department (ED) personnel providing intravenous (IV) fluid to 'responsive' versus 'unresponsive' patients.

Methods: A prospective, convenience sample of adult ED patients was studied; patients were enrolled if preload expansion was indicated for any reason. Using a novel, wireless, wearable ultrasound, carotid artery Doppler was obtained before and throughout a preload challenge (PC) prior to each bag of ordered IV fluid.

Cellular Analysis and Chemotherapeutic Potential of a Bi-Functionalized Halloysite Nanotube.

The surface of halloysite nanotubes (HNTs) was bifunctionalized with two ligands-folic acid and a fluorochrome. In tandem, this combination should selectively target cancer cells and provide a means for imaging the nanoparticle. Modified bi-functionalized HNTs (bi-HNTs) were then doped with the anti-cancer drug methotrexate.

Time course images of cellular injury and recovery in murine brain with high-resolution GRIN lens system.

Time course, in vivo imaging of brain cells is crucial to fully understand the progression of secondary cellular damage and recovery in murine models of injury. We have combined high-resolution gradient index lens technology with a model of diffuse axonal injury in rodents to enable repeated visualization of fine features of individual cells in three-dimensional space over several weeks. For example, we recorded changes in morphology in the same axons in the external capsule numerous times over 30 to 60 days, before and after induced traumatic brain injury.

PICS: a platform for planar imaging of curved surfaces of brain and other tissue.

Optical imaging of wholemount tissue samples provides greater understanding of structure-function relationships as the architecture of these specimens is generally well preserved. However, difficulties arise when attempting to stitch together images of multiple regions of larger, oddly shaped specimens. These difficulties include (1) maintaining consistent signal-to-noise ratios when the overlying sample surface is uneven, (2) ensuring sample viability when live samples are required, and (3) stabilizing the specimen in a fixed position in a flowing medium without distorting the tissue sample.

Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity.

Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4 T cells.

Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment.

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule.

Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses.

Objective: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development.

Methods: VIB9600 was humanised and optimised from the IV.

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection.

C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection.

TRIO Platform: A Novel Low Profile In vivo Imaging Support and Restraint System for Mice.

High resolution, in vivo optical imaging of the mouse brain over time often requires anesthesia, which necessitates maintaining the animal's body temperature and level of anesthesia, as well as securing the head in an optimal, stable position. Controlling each parameter usually requires using multiple systems. Assembling multiple components into the small space on a standard microscope stage can be difficult and some commercially available parts simply do not fit.

Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation.

In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site.

Evaluation of strategies to control Fab light chain dimer during mammalian expression and purification: A universal one-step process for purification of correctly assembled Fab.

Fabs are an important class of antibody fragment as both research reagents and therapeutic agents. There are a plethora of methods described for their recombinant expression and purification. However, these do not address the issue of excessive light chain production that forms light chain dimers nor do they describe a universal purification strategy.

Generation of potent mouse monoclonal antibodies to self-proteins using T-cell epitope "tags".

Immunization of mice or rats with a "non-self" protein is a commonly used method to obtain monoclonal antibodies, and relies on the immune system's ability to recognize the immunogen as foreign. Immunization of an antigen with 100% identity to the endogenous protein, however, will not elicit a robust immune response. To develop antibodies to mouse proteins, we focused on the potential for breaking such immune tolerance by genetically fusing two independent T-cell epitope-containing sequences (from tetanus toxin (TT) and diphtheria toxin fragment A (DTA)) to a mouse protein, mouse ST2 (mST2).

S cysteine-rich (SCR) binding domain analysis of the Brassica self-incompatibility S-locus receptor kinase.

Brassica self-incompatibility, a highly discriminating outbreeding mechanism, has become a paradigm for the study of plant cell-cell communications. When self-pollen lands on a stigma, the male ligand S cysteine-rich (SCR), which is present in the pollen coat, is transmitted to the female receptor, S-locus receptor kinase (SRK). SRK is a membrane-spanning serine/threonine receptor kinase present in the stigmatic papillar cell membrane.

cDNA-AFLP reveals genes differentially expressed during the hypersensitive response of cassava.

SUMMARY The tropical staple cassava is subject to several major diseases, such as cassava bacterial blight, caused by Xanthomonas axonopodis pv. manihotis. Disease-resistant genotypes afford the only practical solution, yet despite the global importance of this crop, little is known about its defence mechanisms.

Just how complex is the Brassica S-receptor complex?

Of the plant self-incompatibility (SI) systems investigated to date, that possessed by members of the Brassicaceae is currently the best understood. Whilst the recent demonstrations of interactions between the male determinant (S-locus cysteine rich protein, SCR) and the female determinant (S-locus receptor kinase, SRK) indicate the minimal requirement for SI in Brassica, no consensus exists as to the nature of these molecules in vivo and the potential involvement of accessory molecules in establishing the active S-receptor complex. Variation between S haplotypes appears to be present in the molecular composition of the receptor complex, the regulation of downstream signalling and the requirement for accessory molecules.