Successful Transplantation of Human Kidneys Deemed Untransplantable but Resuscitated by Ex Vivo Normothermic Machine Perfusion

We report the successful transplantation of a pair of human kidneys that were declined for transplantation due to inadequate in situ perfusion but subsequently transplanted after perfusion and assessment using ex vivo normothermic perfusion (EVNP). The kidneys were from a 35-year-old man, a donation after circulatory death donor. Both kidneys were declined by all UK transplant centers. On arrival, the kidneys had significant areas of incomplete clearance of blood from the microcirculation that did not clear after a further attempt to flush them. Kidneys underwent 60 min of EVNP with an oxygenated packed red blood cell–based solution warmed to 35.2°C. During EVNP, the patchy areas cleared in both kidneys. The mean renal blood flow and total urine output were 68.0 mL/min/100 g and 560 mL in the left kidney and 59.9 mL/min/100 g, 430 mL in the right, respectively. Based on the EVNP perfusion parameters, both kidneys were deemed suitable for transplantation. They were transplanted without any complications, and both recipients had initial graft function. The serum creatinine levels at 3 months were 1.2 mg/dl in the recipient of the left kidney and 1.62 mg/dl in the recipient of the right kidney. EVNP technology can be used to assess and rescue kidneys previously deemed unsuitable for transplantation.This study was supported by Kidney Research UK. The research was also funded by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health, or NHSBT

Relativistic effects and primordial non-Gaussianity in the galaxy bias

When dealing with observables, one needs to generalize the bias relation between the observed galaxy fluctuation field to the underlying matter distribution in a gauge-invariant way. We provide such relation at second-order in perturbation theory adopting the local Eulerian bias model and starting from the observationally motivated uniform-redshift gauge. Our computation includes the presence of primordial non-Gaussianity. We show that large scale-dependent relativistic effects in the Eulerian bias arise independently from the presence of some primordial non-Gaussianity. Furthermore, the Eulerian bias inherits from the primordial non-Gaussianity not only a scale-dependence, but also a modulation with the angle of observation when sources with different biases are correlated.Comment: 12 pages, LaTeX file; version accepted for publication in JCA

Ex vivo normothermic perfusion of isolated segmental porcine bowel: a novel functional model of the small intestine.

BACKGROUND: There is an unmet need for suitable ex vivo large animal models in experimental gastroenterology and intestinal transplantation. This study details a reliable and effective technique for ex vivo normothermic perfusion (EVNP) of segmental porcine small intestine. METHODS: Segments of small intestine, 1.5-3.0 m in length, were retrieved from terminally anaesthetized pigs. After a period of cold ischaemia, EVNP was performed for 2 h at 37°C with a mean pressure of 80 mmHg using oxygenated autologous blood diluted with Ringer's solution. The duration of EVNP was extended to 4 h for a second set of experiments in which two segments of proximal to mid-ileum (1.5-3.0 m) were retrieved from each animal and reperfused with whole blood (control) or leucocyte-depleted blood to examine the impact of leucocyte depletion on reperfusion injury. RESULTS: After a mean cold ischaemia time of 5 h and 20 min, EVNP was performed in an initial group of four pigs. In the second set of experiments, five pigs were used in each group. In all experiments bowel segments were well perfused and exhibited peristalsis during EVNP. Venous glucose levels significantly increased following luminal glucose stimulation (mean(s.e.m.) basal level 1.8(0.6) mmol/l versus peak 15.5(5.8) mmol/l; P < 0.001) and glucagon-like peptide 1 (GLP-1) levels increased in all experiments, demonstrating intact absorptive and secretory intestinal functions. There were no significant differences between control and leucocyte-depleted animals regarding blood flow, venous glucose, GLP-1 levels or histopathology at the end of 4 h of EVNP. CONCLUSIONS: This novel model is suitable for the investigation of gastrointestinal physiology, pathology and ischaemia reperfusion injury, along with evaluation of potential therapeutic interventions

Searching for the light dark gauge boson in GeV-scale experiments

We study current constraints and search prospects for a GeV scale vector boson at a range of low energy experiments. It couples to the Standard Model charged particles with a strength <= 10^-3 to 10^-4 of that of the photon. The possibility of such a particle mediating dark matter self-interactions has received much attention recently. We consider searches at low energy high luminosity colliders, meson decays, and fixed target experiments. Based on available data, searches both at colliders and in meson decays can discover or exclude such a scenario if the coupling strength is on the larger side. We emphasize that a dedicated fixed target experiment has a much better potential in searching for such a gauge boson, and outline the desired properties of such an experiment. Two different optimal designs should be implemented to cover the range of coupling strength 10^-3 to 10^-5, and < 10^-5 of the photon, respectively. We also briefly comment on other possible ways of searching for such a gauge boson.Comment: 33 pages, 5 figures; v2: corrected discussion of Upsilon decays, updates to discussion of fixed-target experiments and QED constraints, numerous minor changes, references added; v3: typo corrected relative to the JHEP published versio

Use of Ex Vivo Normothermic Perfusion for Quality Assessment of Discarded Human Donor Pancreases.

A significant number of pancreases procured for transplantation are deemed unsuitable due to concerns about graft quality and the associated risk of complications. However, this decision is subjective and some declined grafts may be suitable for transplantation. Ex vivo normothermic perfusion (EVNP) prior to transplantation may allow a more objective assessment of graft quality and reduce discard rates. We report ex vivo normothermic perfusion of human pancreases procured but declined for transplantation, with ABO-compatible warm oxygenated packed red blood cells for 1-2 h. Five declined human pancreases were assessed using this technique after a median cold ischemia time of 13 h 19 min. One pancreas, with cold ischemia over 30 h, did not appear viable and was excluded. In the remaining pancreases, blood flow and pH were maintained throughout perfusion. Insulin secretion was observed in all four pancreases, but was lowest in an older donation after cardiac death pancreas. Amylase levels were highest in a gland with significant fat infiltration. This is the first study to assess the perfusion, injury, as measured by amylase, and exocrine function of human pancreases using EVNP and demonstrates the feasibility of the approach, although further refinements are required.This study was financially supported by a grant from the Mason Medical Research Foundation.This is the author accepted manuscript. The final version is available via Wiley at http://onlinelibrary.wiley.com/doi/10.1111/ajt.13303/abstract

Modelling non-dust fluids in cosmology

Currently, most of the numerical simulations of structure formation use Newtonian gravity. When modelling pressureless dark matter, or `dust', this approach gives the correct results for scales much smaller than the cosmological horizon, but for scenarios in which the fluid has pressure this is no longer the case. In this article, we present the correspondence of perturbations in Newtonian and cosmological perturbation theory, showing exact mathematical equivalence for pressureless matter, and giving the relativistic corrections for matter with pressure. As an example, we study the case of scalar field dark matter which features non-zero pressure perturbations. We discuss some problems which may arise when evolving the perturbations in this model with Newtonian numerical simulations and with CMB Boltzmann codes.Comment: 5 pages; v2: typos corrected and refs added, submitted version; v3: version to appear in JCA

Distribution, Elimination, and Biopersistence to 90 Days of a Systemically Introduced 30 nm Ceria-Engineered Nanomaterial in Rats

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were quantified for 2 weeks. Nine organs were weighed and samples collected from 14 tissues/organs/systems, blood and cerebrospinal fluid for cerium determination. Histology and oxidative stress were assessed. Less than 1% of the nanoceria was excreted in the first 2 weeks, 98% in feces. Body weight gain was initially impaired. Spleen weight was significantly increased in some ceria-treated groups, associated with abnormalities. Ceria was primarily retained in the spleen, liver, and bone marrow. There was little decrease of ceria in any tissue over the 90 days. Granulomas were observed in the liver. Time-dependent oxidative stress changes were seen in the liver and spleen. Nanoscale ceria was persistently retained by organs of the mononuclear phagocyte system, associated with adverse changes. The results support concern about the long-term fate and adverse effects of inert nanoscale metal oxides that distribute throughout the body, are persistently retained, and produce adverse changes