A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses

Background: Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse. Results: Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb – 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p <0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042). Conclusions: Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses

Mechanisms underlying heterologous skin scaffold-mediated tissue remodeling

Biocompatibility of two newly developed porcine skin scaffolds was assessed after 3, 14, 21 and 90 days of implantation in rats. Both scaffolds showed absence of cells, preservation of ECM and mechanical properties comparable to non-decellularised skin before implantation. Host cell infiltration was much prominent on both scaffolds when compared to Permacol (surgical control). At day 3, the grafts were surrounded by polymorphonuclear cells, which were replaced by a notable number of IL-6-positive cells at day 14. Simultaneously, the number of pro-inflammatory M1-macrophage was enhanced. Interestingly, a predominant pro-remodeling M2 response, with newly formed vessels, myofibroblasts activation and a shift on the type of collagen expression was sequentially delayed (around 21 days). The gene expression of some trophic factors involved in tissue remodeling was congruent with the cellular events. Our findings suggested that the responsiveness of macrophages after non-crosslinked skin scaffolds implantation seemed to intimately affect various cell responses and molecular eventsand this range of mutually reinforcing actions was predictive of a positive tissue remodeling that was essential for the long-standing success of the implants. Furthermore, our study indicates that non-crosslinked biologic scaffold implantation is biocompatible to the host tissue and somehow underlying molecular events involved in tissue repair.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fed Univ Sao Paulo UNIFESP, Postgrad Struct & Funct Biol, BR-04023900 Sao Paulo, SP, BrazilSao Paulo State Univ UNESP, Dept Biol, BR-15054000 Sao Jose Do Rio Preto, SP, BrazilSao Paulo State Univ UNESP, Inst Biociencias Letras & Ciencias Exatas, BR-15054000 Sao Jose Do Rio Preto, SP, BrazilUCL, Northwick Pk Inst Med Res, Dept Surg Res, London HA1 3UJ, Middx, EnglandPost-Graduation in Structural and Functional Biology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, 04023-900, BrazilFAPESP: 2012/21603-2FAPESP: 2012/13041-4FAPESP: 2014/18557-4CNPq: 308144/2014-7CNPq: 245859/2012-8Web of Scienc

Arachidonic acid and DHA status in pregnant women is not associated with cognitive performance of their children at 4 or 6–7 years

Arachidonic acid (ARA) and DHA, supplied primarily from the mother, are required for early development of the central nervous system. Thus, variations in maternal ARA or DHA status may modify neurocognitive development. We investigated the relationship between maternal ARA and DHA status in early (11·7 weeks) or late (34·5 weeks) pregnancy on neurocognitive function at the age of 4 years or 6–7 years in 724 mother–child pairs from the Southampton Women’s Survey cohort. Plasma phosphatidylcholine fatty acid composition was measured in early and late pregnancy. ARA concentration in early pregnancy predicted 13 % of the variation in ARA concentration in late pregnancy (β=0·36, P&lt;0·001). DHA concentration in early pregnancy predicted 21 % of the variation in DHA concentration in late pregnancy (β=0·46, P&lt;0·001). Children’s cognitive function at the age of 4 years was assessed by the Wechsler Preschool and Primary Scale of Intelligence and at the age of 6–7 years by the Wechsler Abbreviated Scale of Intelligence. Executive function at the age of 6–7 years was assessed using elements of the Cambridge Neuropsychological Test Automated Battery. Neither DHA nor ARA concentrations in early or late pregnancy were associated significantly with neurocognitive function in children at the age of 4 years or the age of 6–7 years. These findings suggest that ARA and DHA status during pregnancy in the range found in this cohort are unlikely to have major influences on neurocognitive function in healthy children.</p

Tracheal Replacement Therapy with a Stem Cell-Seeded Graft: Lessons from Compassionate Use Application of a GMP-Compliant Tissue-Engineered Medicine

Tracheal replacement for the treatment of end-stage airway disease remains an elusive goal. The use of tissue-engineered tracheae in compassionate use cases suggests that such an approach is a viable option. Here, a stem cell-seeded, decellularized tissue-engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. The graft represents the first cell-seeded tracheal graft manufactured to full good manufacturing practice (GMP) standards. We report important preclinical and clinical data from the case, which ended in the death of the recipient. Early results were encouraging, but an acute event, hypothesized to be an intrathoracic bleed, caused sudden airway obstruction 3 weeks post-transplantation, resulting in her death. We detail the clinical events and identify areas of priority to improve future grafts. In particular, we advocate the use of stents during the first few months post-implantation. The negative outcome of this case highlights the inherent difficulties in clinical translation where preclinical in vivo models cannot replicate complex clinical scenarios that are encountered. The practical difficulties in delivering GMP grafts underscore the need to refine protocols for phase I clinical trials

ASKAP and MeerKAT surveys of the magellanic clouds

The Magellanic Clouds are a stepping stone from the overwhelming detail of the Milky Way in which we are immersed, to the global characteristics of galaxies both in the nearby and distant universe. They are interacting, gas-rich dwarf galaxies of sub-solar metallicity, not unlike the building blocks that assembled the large galaxies that dominate groups and clusters, and representative of the conditions at the height of cosmic star formation. The Square Kilometre Array (SKA) can make huge strides in understanding galactic metabolism and the ecological processes that govern star formation, by observations of the Magellanic Clouds and other, nearby Magellanic-type irregular galaxies. Two programmes with SKA Pathfinders attempt to pave the way: the approved Galactic ASKAP Spectral Line Survey (GASKAP) includes a deep survey in H I and OH of the Magellanic Clouds, whilst MagiKAT is proposed to perform more detailed studies of selected regions within the Magellanic Clouds - also including Faraday rotation measurements and observations at higher frequencies. These surveys also close the gap with the revolutionizing surveys at far-IR wavelengths with the Spitzer Space Telescope and Herschel Space Observatory

Impact of periconceptional undernutrition on adrenal growth and adrenal insulin-like growth factor and steroidogenic enzyme expression in the sheep fetus during early pregnancy

Copyright © 2007 by The Endocrine SocietyPericonceptional undernutrition (PCUN) results in an earlier prepartum activation of the pituitary-adrenal axis in twin compared with singleton fetuses. We have tested the hypotheses that the functional development of the fetal sheep adrenal is delayed in twins compared with singletons in early gestation and that PCUN accelerates adrenal growth and increases the expression of intraadrenal IGF-I and -II and cytochrome P450 17-hydroxylase (CYP17) as early as 55 d gestation. We have investigated the effect of PCUN in the ewe (restricted at 70% of control allowance, n = 21; control, n = 24) from at least 45 d before mating until d 7 after mating on maternal cortisol and progesterone concentrations, fetal adrenal weight, adrenal IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF-IIR, and CYP17 mRNA expression and placental 11ß-hydroxysteroid dehydrogenase-1 and -2 mRNA and protein expression at d 53–56 pregnancy. The relative weight of the fetal adrenal and adrenal IGF-I, IGF-IR, IGF-II, IGF-IIR, and CYP17 mRNA expression were lower in twin compared with singleton fetuses. In singleton fetuses of PCUN ewes, there was a loss of the relationship between adrenal IGF-II/IGF-IIR expression and either adrenal weight or CYP17 mRNA, which was present in controls. Similarly in twin fetuses, PCUN resulted in the loss of the relationships between adrenal weight and IGF-I expression and between adrenal CYP17 and IGF-II expression, which were present in controls. Our findings suggest that differences in the timing of the prepartum activation of the fetal adrenal in twins and singletons have their origins in early gestation and highlight the importance of the interaction between the periconceptional environment and embryo number in setting the growth trajectory of the fetal adrenal.Severence M. MacLaughlin, Simon K. Walker, David O. Kleemann, Jane P. Sibbons, Darran N. Tosh, Sheridan Gentili, Catherine L. Coulter and I. Caroline McMille