Should such a faith offend? Bishop Barnes and the British eugenics movement, c.1924-1953

This dissertation explores the eugenic ideology of E.W. Barnes in its conceptual evolution and practical application from 1924 to 1953. As the Bishop of Birmingham and one of the prominent members of the Eugenics Society, Barnes used the pulpit as a platform to promote eugenic reform both before and after 1945. Above all, he believed it essential for Britain’s biological and spiritual progress to address the alleged widespread mental deficiency in the population through eugenic measures, namely: birth control, sterilization and euthanasia. Barnes’ unique blend of Modernist Christianity and biological determinism received national media attention. Responses to his creed were highly polarized, oscillating between praise and moral reprehension. It is surprising that historians of religion and eugenics have largely overlooked Barnes and his considerable contribution. Towards rectifying this neglect, this dissertation represents a new insight in the growing literature on both the British eugenics movement in general and the attitudes of the Anglican Church towards eugenics in particular. By engaging with these two broad spheres of thought, Barnes’ ideas offer a lens through which one can view the somewhat blurred lines between ‘traditional’ religion and ‘secular’ eugenics in the 20th century. Rather than constituting mutually antagonistic approaches, eugenic and Christian interpretations of social improvement were seen by a number of eugenicists at the time as complementary. If the path towards human biological improvement was charted by eugenicists, then according to Barnes, Christianity held their moral compass. After the fall of Nazism, the British eugenics movement found itself discredited and marginalized. In the eyes of many, eugenics was complicit – or at least guilty by conceptual association – in the National Socialist humanitarian atrocities, which were becoming widely known. Remarkably, while many eugenicists chose to distance themselves from negative eugenics after the Second World War, Barnes endorsed sterilization and euthanasia all the more fervently. While many responded with vehement criticism, opposition to his suggestions was not universal, and many continued to agree that, among other things, it was a national responsibility to prevent the ‘mentally deficient’ from reproducing. In analysing the development of Barnes’ eugenic ideas between c. 1924 and 1953, this dissertation has also opened new avenues of research, in particular the examination of ideas relating to eugenics and religion in Britain and the extent to which eugenic concerns continue to permeate biomedical debates today

Global measurement of coagulation in plasma from normal and haemophilia dogs using a novel modified thrombin generation test – Demonstrated in vitro and ex vivo

Canine models of severe haemophilia resemble their human equivalents both regarding clinical bleeding phenotype and response to treatment. Therefore pre-clinical studies in haemophilia dogs have allowed researchers to make valuable translational predictions regarding the potency and efficacy of new anti-haemophilia drugs (AHDs) in humans. To refine in vivo experiments and reduce number of animals, such translational studies are ideally preceded by in vitro prediction of compound efficacy using a plasma based global coagulation method. One such widely used method is the thrombin generation test (TGT). Unfortunately, commercially available TGTs are incapable of distinguishing between normal and haemophilia canine plasma, and therefore in vitro prediction using TGT has so far not been possible in canine plasma material

Soy Phosphatidylinositol–Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain–Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs

Soy phosphatidylinositol (PI) containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain deleted Factor VIII (BDD FVIII) in Hemophilia A (HA) mice. We hypothesize that PI associated BDD FVIII is more potent than the free protein, and using mathematical modeling, have projected that PI associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. 2 HA dogs were administered a 50 U/kg iv dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses like whole blood clotting time (WBCT) and thromboelastography (TEG) were conducted on recovered plasma and whole blood samples. PI association decreased clearance (~25%) and increased plasma exposure (~1.4 fold) of rcFVIII. PI-rcFVIII treated animals had prolonged improvements in WBCTs and TEG parameters compared to free rcFVIII treated animals. Since rcFVIII is a BDD form of FVIII, these studies provide proof-of-principle that observations with human BDD FVIII in mice translate to higher animal species. Additionally, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients

Imperfect identity

Questions of identity over time are often hard to answer. A long tradition has it that such questions are somehow soft: they have no unique, determinate answer, and disagreements about them are merely verbal. I argue that this claim is not the truism it is taken to be. Depending on how it is understood, it turns out either to be false or to presuppose a highly contentious metaphysical claim

Experimental Validation of ARFI Surveillance of Subcutaneous Hemorrhage (ASSH) Using Calibrated Infusions in a Tissue-Mimicking Model and Dogs

Acoustic radiation force impulse (ARFI) Surveillance of Subcutaneous Hemorrhage (ASSH) has been previously demonstrated to differentiate bleeding phenotype and responses to therapy in dogs and humans, but to date, the method has lacked experimental validation. This work explores experimental validation of ASSH in a poroelastic tissue-mimic and in vivo in dogs. The experimental design exploits calibrated flow rates and infusion durations of evaporated milk in tofu or heparinized autologous blood in dogs. The validation approach enables controlled comparisons of ASSH-derived bleeding rate (BR) and time to hemostasis (TTH) metrics. In tissue-mimicking experiments, halving the calibrated flow rate yielded ASSH-derived BRs that decreased by 44% to 48%. Furthermore, for calibrated flow durations of 5.0 minutes and 7.0 minutes, average ASSH-derived TTH was 5.2 minutes and 7.0 minutes, respectively, with ASSH predicting the correct TTH in 78% of trials. In dogs undergoing calibrated autologous blood infusion, ASSH measured a 3-minute increase in TTH, corresponding to the same increase in the calibrated flow duration. For a measured 5% decrease in autologous infusion flow rate, ASSH detected a 7% decrease in BR. These tissue-mimicking and in vivo preclinical experimental validation studies suggest the ASSH BR and TTH measures reflect bleeding dynamics

Porcine and Canine von Willebrand Factor and von Willebrand Disease: Hemostasis, Thrombosis, and Atherosclerosis Studies

Use of animal models of inherited and induced von Willebrand factor (VWF) deficiency continues to advance the knowledge of VWF-related diseases: von Willebrand disease (VWD), thrombotic thrombocytopenic purpura (TTP), and coronary artery thrombosis. First, in humans, pigs, and dogs, VWF is essential for normal hemostasis; without VWF bleeding events are severe and can be fatal. Second, the ADAMTS13 cleavage site is preserved in all three species suggesting all use this mechanism for normal VWF multimer processing and that all are susceptible to TTP when ADAMTS13 function is reduced. Third, while the role of VWF in atherogenesis is debated, arterial thrombosis complicating atherosclerosis appears to be VWF-dependent. The differences in the VWF gene and protein between humans, pigs, and dogs are relatively few but important to consider in the design of VWF-focused experiments. These homologies and differences are reviewed in detail and their implications for research projects are discussed. The current status of porcine and canine VWD are also reviewed as well as their potential role in future studies of VWF-related disorders of hemostasis and thrombosis

Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce

Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals

Acoustic radiation force beam sequence performance for detection and material characterization of atherosclerotic plaques: preclinical, ex vivo results

This work presents preclinical data demonstrating performance of acoustic radiation force (ARF) based elasticity imaging with five different beam sequences for atherosclerotic plaque detection and material characterization. Twelve trained, blinded readers evaluated parametric images taken ex vivo under simulated in vivo conditions of 22 porcine femoral arterial segments. Receiver operating characteristic (ROC) curve analysis was carried out to quantify reader performance using spatially-matched immunohistochemistry for validation. The beam sequences employed had high sensitivity and specificity for detecting Type III+ plaques (Sens: 85%, Spec: 79%), lipid pools (Sens: 80%, Spec: 86%), fibrous caps (Sens: 86%, spec: 82%), calcium (Sens: 96%, Spec: 85%), collagen (Sens: 78%, Spec: 77%), and disrupted internal elastic lamina (Sens: 92%, Spec: 75%). 1:1 single-receive tracking yielded the highest median areas under the ROC curve (AUC), but was not statistically significantly higher than 4:1 parallel-receive tracking. Excitation focal configuration did not result in statistically different AUCs. Overall, these results suggest ARF-based imaging is relevant to detecting and characterizing plaques and support its use for diagnosing and monitoring atherosclerosis

Academic Senate - Meeting Minutes, 4/18/2017

<p>All values are presented with SD. Differences between <i>LDLR−/−</i> and the other two genotypes are significant where indicated, ANOVA: *p<0.05, **p<0.01.</p