Protective Effects of Non-Anticoagulant Activated Protein C Variant (D36A/L38D/A39V) in a Murine Model of Ischaemic Stroke

Ischaemic stroke is caused by occlusive thrombi in the cerebral vasculature. Although tissue-plasminogen activator (tPA) can be administered as thrombolytic therapy, it has major limitations, which include disruption of the blood-brain barrier and an increased risk of bleeding. Treatments that prevent or limit such deleterious effects could be of major clinical importance. Activated protein C (APC) is a natural anticoagulant that regulates thrombin generation, but also confers endothelial cytoprotective effects and improved endothelial barrier function mediated through its cell signalling properties. In murine models of stroke, although APC can limit the deleterious effects of tPA due to its cell signalling function, its anticoagulant actions can further elevate the risk of bleeding. Thus, APC variants such as APC(5A), APC(Ca-ins) and APC(36-39) with reduced anticoagulant, but normal signalling function may have therapeutic benefit. Human and murine protein C (5A), (Ca-ins) and (36-39) variants were expressed and characterised. All protein C variants were secreted normally, but 5-20% of the protein C (Ca-ins) variants were secreted as disulphide-linked dimers. Thrombin generation assays suggested reductions in anticoagulant function of 50- to 57-fold for APC(36-39), 22- to 27-fold for APC(Ca-ins) and 14- to 17-fold for APC(5A). Interestingly, whereas human wt APC, APC(36-39) and APC(Ca-ins) were inhibited similarly by protein C inhibitor (t½ - 33 to 39 mins), APC(5A) was inactivated ~9-fold faster (t½ - 4 mins). Using the murine middle cerebral artery occlusion ischaemia/repurfusion injury model, in combination with tPA, APC(36-39), which cannot be enhanced by its cofactor protein S, significantly improved neurological scores, reduced cerebral infarct area by ~50% and reduced oedema ratio. APC(36-39) also significantly reduced bleeding in the brain induced by administration of tPA, whereas wt APC did not. If our data can be extrapolated to clinical settings, then APC(36-39) could represent a feasible adjunctive therapy for ischaemic stroke

Methylome of human skeletal muscle after acute & chronic resistance exercise training, detraining & retraining

DNA methylation is an important epigenetic modification that can regulate gene expression following environmental encounters without changes to the genetic code. Using Infinium MethylationEPIC BeadChip Arrays (850,000 CpG sites) we analysed for the first time, DNA isolated from untrained human skeletal muscle biopsies (vastus lateralis) at baseline (rest) and immediately following an acute (single) bout of resistance exercise. In the same participants, we also analysed the methylome following a period of muscle growth (hypertrophy) evoked via chronic (repeated bouts-3 sessions/wk) resistance exercise (RE) (training) over 7-weeks, followed by complete exercise cessation for 7-weeks returning muscle back to baseline levels (detraining), and finally followed by a subsequent 7-week period of RE-induced hypertrophy (retraining). These valuable methylome data sets described in the present manuscript and deposited in an open-access repository can now be shared and re-used to enable the identification of epigenetically regulated genes/ networks that are modified after acute anabolic stimuli and hypertrophy, and further investigate the phenomenon of epigenetic memory in skeletal muscle

Quantification of bedform dynamics and bedload sediment flux in sandy braided rivers from airborne and satellite imagery

 This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record Images from specially‐commissioned aeroplane sorties (manned aerial vehicle, MAV), repeat unmanned aerial vehicles (UAVs) surveys, and Planet CubeSat satellites are used to quantify dune and bar dynamics in the sandy braided South Saskatchewan River, Canada. Structure‐from‐Motion (SfM) techniques and application of a depth‐brightness model are used to produce a series of Digital Surface Models (DSMs) at low and near‐bankfull flows. A number of technical and image processing challenges are described that arise from the application of SfM in dry and submerged environments. A model for best practice is outlined and analysis suggests a depth‐brightness model approach can represent the different scales of bedforms present in sandy braided rivers with low‐turbidity and shallow (< 2 m deep) water. The aerial imagery is used to quantify the spatial distribution of unit bar and dune migration rate in an 18 km reach and three ~1 km long reaches respectively. Dune and unit bar migration rates are highly variable in response to local variations in planform morphology. Sediment transport rates for dunes and unit bars, obtained by integrating migration rates (from UAV) with the volume of sediment moved (from DSMs using MAV imagery) show near‐equivalence in sediment flux. Hence, reach‐based sediment transport rate estimates can be derived from unit bar data alone. Moreover, it is shown that reasonable estimates of sediment transport rate can be made using just unit bar migration rates as measured from 2D imagery, including from satellite images, so long as informed assumptions are made regarding average bar shape and height. With recent availability of frequent, repeat satellite imagery, and the ease of undertaking repeat MAV and UAV surveys, for the first time, it may be possible to provide global estimates of bedload sediment flux for large or inaccessible low‐turbidity rivers that currently have sparse information on bedload sediment transport rates.Natural Environment Research Council (NERC

Surgical Treatment of Iatrogenic Ventral Glottic Stenosis Using a Mucosal Flap Technique

OBJECTIVE: To describe a novel surgical technique for correcting postoperative ventral glottic stenosis (cicatrix or web formation) and the outcome in 2 Thoroughbred racehorses. STUDY DESIGN: Retrospective case report. ANIMALS: Thoroughbreds diagnosed with ventral glottic stenosis (n=2). METHODS: Horses presenting with iatrogenic ventral glottic stenosis and resultant exercise intolerance and abnormal exercise‐related noise were anesthetized and a midline sagittal skin incision was made over the ventral larynx and between the sternohyoideus muscles overlying the cricothyroid notch. The cricothyroid ligament, attached laryngeal cicatrix, and overlying mucosa were sagittally sectioned at the dorsal aspect of the cicatrix on the left side. The laryngeal mucosa, cicatrix, and underlying cricothyroid ligament immediately rostral and caudal to the cicatrix were sectioned in a medial (axial) direction as far as the right side of the cricothyroid notch. After resection of the majority of the attached cicatrix tissue, the residual mucosal flap (attached to the right side of the larynx) was reflected ventrally and sutured to the attachment of the cricothyroid ligament on the right side of the cricothyroid notch, creating an intact mucosal layer on the right side of the ventral larynx. RESULTS: Both horses had good intralaryngeal wound healing with minimal redevelopment of ventral glottic stenosis at 5 and 9 months postoperatively and were successfully returned to racing with complete absence of abnormal respiratory noise. CONCLUSION: The unique laryngeal anatomy of horses, with a cartilage‐free ventral laryngeal area (cricothyroid notch), allowed the use of this novel surgical technique to successfully treat ventral glottic stenosis

Short acquisition time PET quantification using MRI-based pharmacokinetic parameter synthesis

Positron Emission Tomography (PET) with pharmacokinetic (PK) modelling is a quantitative molecular imaging technique, however the long data acquisition time is prohibitive in clinical practice. An approach has been proposed to incorporate blood flow information from Arterial Spin Labelling (ASL) Magnetic Resonance Imaging (MRI) into PET PK modelling to reduce the acquisition time. This requires the conversion of cerebral blood flow (CBF) maps, measured by ASL, into the relative tracer delivery parameter (R 1 ) used in the PET PK model. This was performed regionally using linear regression between population R 1 and ASL values. In this paper we propose a novel technique to synthesise R 1 maps from ASL data using a database with both R 1 and CBF maps. The local similarity between the candidate ASL image and those in the database is used to weight the propagation of R 1 values to obtain the optimal patient specific R 1 map. Structural MRI data is also included to provide information within common regions of artefact in ASL data. This methodology is compared to the linear regression technique using leave one out analysis on 32 subjects. The proposed method significantly improves regional R 1 estimation (p < 0.001), reducing the error in the pharmacokinetic modelling. Furthermore, it allows this technique to be extended to a voxel level, increasing the clinical utility of the images

The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial

BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression. OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR). METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted

Addressing the Future Burden of Cancer and Its Impact on the Oncology Workforce: Where Is Cancer Prevention and Control?

The need for cancer professionals has never been more urgent than it is today. Reports project serious shortages by 2020 of oncology health care providers. Although many plans have been proposed, no role for prevention has been described. In response, a 2-day symposium was held in 2009 at The University of Texas MD Anderson Cancer Center to capture the current status of the cancer prevention workforce and begin to identify gaps in the workforce. Five working groups were organized around the following topic areas: (a) health policy and advocacy; (b) translation to the community; (c) integrating cancer prevention into clinical practice; (d) health services infrastructure and economics; and (e) discovery, research, and technology. Along with specific recommendations on these topics, the working groups identified two additional major themes: the difficulty of defining areas within the field (including barriers to communication) and lack of sufficient funding. These interdependent issues synergistically impede progress in preventing cancer; they are explored in detail in this synthesis, and recommendations for actions to address them are presented. Progress in cancer prevention should be a major national and international goal. To achieve this goal, ensuring the health of the workforce in cancer prevention and control is imperative

Filtering of the signal of sediment export from a glacier by Its proglacial forefield

This is the final version. Available from Wiley via the DOI in this record. Data Availability Statement: The data used in this study (i.e., water discharge, suspended sediment load and bedload records for 2020 and 2021) are archivied in Zenodo. These are available in (Mancini et al., 2023; Müller & Miesen, 2022).Alpine glaciers are rapidly retreating due to global warming and this has been associated with enhanced supply of subglacially derived sediment to downstream environments. We present the first high frequency quantitative record on how the signal of sediment exported from an Alpine glacier is filtered by its proglacial forefield. The data, covering two climatically distinct glacier melt seasons, show that the signal of subglacial bedload export is strongly filtered over short distances, unlike suspended load whose signal is less impacted. The reason is related to the interplay of short particle advection lengths with strong morphodynamic forcing. The subglacial sediment export signal is thus rapidly replaced by one combining (a) the local forcing by stream hydraulics and (b) the reworking of the proglacial braid plain itself. These findings have implications for estimating subglacial erosion rates, natural hazard mitigation, sediment management for hydropower plants and ecological succession related to rapid glacier retreat.Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschun

Application of Photogrammetry in Biomedical Science

Peer reviewedPostprin

Spontaneous Eosinophilic Nasal Inflammation in a Genetically-Mutant Mouse: Comparative Study with an Allergic Inflammation Model

Background: Eosinophilic inflammation is a hallmark of chronic rhinosinusitis with nasal polyps. To model this disease process experimentally, nasal sensitization of mice with ovalbumin or aspergillus has been described. Here, we describe a genetically mutant mouse that develops robust spontaneous nasal eosinophilic inflammation. These mice lack the enzyme SHP-1 that down-regulates the IL-4Ra/stat6 signaling pathway. We compared nasal inflammation and inflammatory mediators in SHP-1 deficient mice (mev) and an ovalbumin-induced nasal allergy model. Methods: A novel technique of trans-pharyngeal nasal lavage was developed to obtain samples of inflammatory cells from the nasal passages of allergic and mev mice. Total and differential cell counts were performed on cytospin preparations. Expression of tissue mRNA for IL-4, IL-13, and mouse beta-defensin-1 (MBD-1) was determined by quantitative PCR. Eotaxin in the lavage fluid was assessed by ELISA. Results: Allergic and mev mice had increased total cells and eosinophils compared with controls. Expression of IL-4 was similarly increased in both allergic and mev mice, but expression of IL-13 and eotaxin was significantly greater in the allergic mice than mev mice. Eotaxin was significantly up-regulated in both allergic rhinitis and mev mice. In both models of eosinophilic inflammation, down-regulation of the innate immune marker MBD-1 was observed. Conclusions: The mev mice display spontaneous chronic nasal eosinophilic inflammation with potential utility for chroni