Guidelines for developing a risk-based plan to mitigate virus transmission from imported feed ingredients

There is increasing concern regarding the risk of swine disease transmission via feed ingredients, whether imported or domestically produced. This risk may be reduced in the feed ingredient supply chain by identifying and implementing preventive controls (supply chain, sanitation, transportation, and process) at different steps of the chain. The objective of this study was to develop a practical guide to help feed ingredient suppliers and buyers to safely manufacture, package, transport, and use feed ingredients in swine feeding programs. The Food Safety Modernization Act (FSMA) provides the basis of this study because these regulations require proactive risk-based preventive control processes that are applied in the food supply chain to prevent or reduce the risk of hazards from being present in the final product. Using this conceptual framework, implementation of preventive controls in the feed production chain can control or decrease the potential introduction of foreign animal viruses through feed ingredients into the U.S. A decision tree was developed as a first step in identifying preventive controls and potential high-risk feed ingredient sourcing scenarios. A case-study using Porcine Epidemic Diarrhea virus (PEDV) and the corresponding decision tree was developed as an illustration on how to use this new approach. Although this approach is based on swine viral diseases, it can serve as a template for other pathogenic viruses and species.Swine Health Information Center, Ames, I

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks

Background For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). Objective To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). Methods Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). Results A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. Conclusions In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms

Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis

<div><p>Background</p><p>Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 μM BPA decreases basal, but not LH-stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models.</p><p>Methods</p><p>Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 μM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 μM BPA (~ 500 μg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 μM and 0.038 μM respectively. Mice grafted with second trimester testes received 0.5 and 50 μg/kg/day BPA by oral gavage for 5 weeks.</p><p>Results</p><p>With first trimester human testes, using the hFeTA model, 10 μM BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2γ, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice.</p><p>Conclusions</p><p>Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures.</p></div

Role of NO in arterial vascular function of intertidal fish (Girella laevifrons) and marine fish (Isacia conceptionis)

Abstract Previous studies performed in intertidal fish (Girella laevifrons),as well as marine fish (Isacia conceptionis), showed that acetylcholine (ACh) produced contractions mediated by cyclooxygenases that were dependent on the area and potency of contraction in several arterial vessels. Given that the role of nitric oxide is poorly understood in fish, the objective of our study was to evaluate the role of nitric oxide in branchial afferent (ABA), branchial efferent (ABE), dorsal (DA) and mesenteric (MA) arterial vessels from both Girella laevifrons and Isacia conceptionis. We studied afferent and efferent branchial, dorsal and mesenteric arteries that were dissected from 6 juvenile specimens. Isometric tension studies were done using dose response curves (DRC) for Ach (10&#8211;13 to 10&#8211;3 M) and blockade with L-NAME (10&#8211;5 M), and DRC for sodium nitroprusside (SNP, a donor of NO). L-NAME produced an attenuation of the contractile response in the dorsal, afferent and efferent branchial arteries and a potentiation of the contraction in the MA. SNP caused 70% dilation in the mesenteric artery and 40% in the dorsal artery. Our results suggest that Ach promotes precarious dilatation in MA mediated by NO; data that is supported by the use of sodium nitroprusside. In contrast, in the vessels DA, ABA and EBA our results support that the pathway Ach-NO-relaxation is absent in both species

Acetylcholine produces contraction mediated by cyclooxigenase pathway in arterial vessels in the marine fish (Isacia conceptionis)

Preliminary studies showed that dorsal artery contraction mediated by acetylcholine (ACh) is blocked with indomethacin in intertidal fish (G. laevifrons). Our objective was to characterize the cholinergic pathway in several artery vessels of the I. conceptionis. Afferent and efferent branchial, dorsal and mesenteric arteries were dissected of 6 juvenile specimens, isometric tension studies were done using doses response curves (DRC) for Ach (10–13 to 10–3 M), and cholinergic pathways were obtained by blocking with atropine or indomethacin. CRC to ACh showed a pattern of high sensitivity only in efferente branchial artery and low sensibility in all vessels. Furthermore, these contractions were blocked in the presence of atropine and indomethacin in all vessels. Our results corroborate previous results observed in intertidal species that contraction induced by acetylcholine is mediated by receptors that activate a cyclooxygenase contraction pathway

Vascular function in arteries of intertidal fish Girella laevifrons(Kyphosidae)

Preliminary studies showed that dorsal artery contraction mediated by acetylcholine (ACh) is blocked with indomethacin in intertidal fish (Girella laevifrons). Our objective was to characterise the cholinergic pathway in several artery vessels of the G. laevifrons. Afferent and efferent branchial, dorsal and mesenteric arteries were dissected of 6 juvenile specimens, isometric tension studies were done using dose response curves (DRC) for Ach (10–13 to 10–3 M), and cholinergic pathways were obtained by blocking with atropine or indomethacin. CRC to ACh showed a pattern of high and low sensitivity. Furthermore, these contractions were blocked in the presence of atropine and indomethacin in all vessels. Our results suggest that contraction observed with acetylcholine is mediated by receptors that activate a cyclooxygenase contraction pathway

Acetylcholine produces contractions mediated by the cyclooxygenase pathway in arterial vessels in the Chilean frog (Calyptocephalella gayi)

Abstract Previous studies performed in marine fish (I. conceptionis and G. laevifrons) showed that indomethacin blocked arterial contraction mediated by acetylcholine (ACh). The objective of this study was to determine if contraction induced by acetylcholine is mediated by the cyclooxygenase pathway in several arterial vessels in the Chilean frog Calyptocephalella gayi. Arteries from the pulmonary (PA), dorsal (DA), mesenteric (MA) and iliac (IA) regions were dissected from 6 adult specimens, and isometric tension studies were done using dose response curves (DRC) for ACh (10-13 to 10-3 M) in presence of a muscarinic antagonist (Atropine 10-5 M) and an unspecific inhibitor of cyclooxygenases (Indomethacin, 10-5M). All the studied arteries exhibited vasoconstriction mediated by ACh. This vasoconstriction was abolished in the presence of atropine in DA, MA and IA and attenuated in PA. Indomethacin abolished the vasoconstriction in MA and attenuated the response in PA, DA and IA. Similar to marine fish, C. gayi have an ACh-mediated vasoconstrictor pattern regulated by muscarinic receptors that activate a cyclooxygenase contraction pathway. These results suggest that the maintenance in vasoconstrictor mechanisms mediated by ACh→COX →vasoconstriction is conserved from fish to frogs