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Moradpourhafshejani S.,Northumbria University | Hedley J.H.,Northumbria University | Hedley J.H.,International Center for Life | Haigh A.O.,Northumbria University | And 3 more authors.
RSC Advances | Year: 2013

Proflavine diazide (PD) with amido-azide substituents on the amine groups and its N-methylated analogue (MePD) bind strongly to DNA by nearest-neighbour intercalation with little sequence selectivity, presenting reactive azide groups in the major groove. PD is neutral in aqueous solution but experiences binding-coupled protonation on interaction with DNA with an apparent pK a shift of 2.5 units. MePD can be click modified in situ on DNA with alkyne-functionalised thienyl-pyrrole as a precursor for conducting polymer synthesis, and remains intercalated after reaction with the substituents aligned in the groove. This journal is © The Royal Society of Chemistry. Source

Gibson B.G.,Northumbria University | Briggs M.D.,Northumbria University | Briggs M.D.,International Center for Life
Orphanet Journal of Rare Diseases | Year: 2016

The large chondroitin sulphated proteoglycan aggrecan (ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms. This review discusses the known human and animal aggrecanopathies in the context of clinical presentation and potential disease mechanisms. © 2016 The Author(s). Source

Lane J.P.,Northumbria University | Evans P.T.G.,Northumbria University | Nademi Z.,Newcastle Upon Tyne Hospitals NHS Trust | Barge D.,Newcastle Upon Tyne Hospitals NHS Trust | And 7 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Cord blood transplantation (CBT) is curative for many primary immunodeficiencies (PIDs) but is associated with risks of viral infection and graft-versus-host disease (GvHD). Serotherapy reduces GvHD but potentially increases the risk of viral infection by delaying immune reconstitution. Because many PID patients have pre-existing viral infections, the optimal dose of serotherapy is unclear. We performed a retrospective analysis in 34 consecutive PID patients undergoing CBT and compared immune reconstitution, viral infection, GvHD, mortality, and long-term immune function between high-dose (n=11) and low-dose (n=9) serotherapy. Serotherapy dose had no effect on neutrophil engraftment. Median CD3+ engraftment occurred at 92.5 and 97days for high- and low-dose serotherapy, respectively. The low-dose serotherapy group had higher CD3+, CD4+, and early thymic emigrant counts at 4months compared with the high-dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplantation process was 90.9% for high-dose and 100% for low-dose groups. In conclusion, low-dose serotherapy enhanced T cell reconstitution and thymopoiesis during the first year after CBT with no increase in GvHD. © 2014 American Society for Blood and Marrow Transplantation. Source

Gilbert R.D.,University of Southampton | Stanley L.K.,International Center for Life | Fowler D.J.,University of Southampton | Angus E.M.,University of Southampton | And 2 more authors.
Clinical Kidney Journal | Year: 2013

A 2-year-old patient with a neuroblastoma developed haemolytic uraemic syndrome (HUS) following treatment with cisplatin and carboplatin. Following treatment with eculizumab, there was a substantial improvement in renal function with the recovery of the platelet count and the cessation of haemolysis. Subsequent investigations showed a novel, heterozygous CD46 splice site mutation with reduced peripheral blood neutrophil CD46 expression. Withdrawal of eculizumab was followed by the recurrence of disease activity, which resolved with re-introduction of therapy. Abnormal regulation of complement may be associated with other cases of cisplatin-induced HUS and treatment with eculizumab may be appropriate for other affected individuals. © 2013 The Author. Source

Wilson B.T.,Northumbria University | Wilson B.T.,International Center for Life | Jensen S.A.,University of Oxford | Mcanulty C.P.,International Center for Life | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Mutations in Fibrillin 1 (FBN1) are associated with Marfan syndrome and in some instances with the MASS phenotype (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal features, and striae). Potential confusion over diagnosis and management in patients with borderline features has been addressed through the revised Ghent nosology, which emphasizes the importance of aortic root dilatation and ectopia lentis as features of Marfan syndrome. The overlapping and more common mitral valve prolapse syndrome is precluded by ectopia lentis or aortic dilatation. Among these clinically related conditions, there is no compelling evidence that genotype predicts phenotype, with the exception of neonatal Marfan syndrome, mutations in which cluster within FBN1 exons 24-32. Recent reports also link two very different phenotypes to changes in FBN1. Heterozygous mutations in transforming growth factor β-binding protein-like domain 5 (TB5) can cause acromicric or geleophysic dysplasias-and mutations in the TB4 domain, which contains an integrin binding RGD loop, have been found in congenital scleroderma/stiff skin syndrome. We report on a variant in an evolutionarily conserved residue that stabilizes the integrin binding fragment of FBN1, associated with juvenile idiopathic arthritis, mitral valve prolapse or apparently normal phenotype in different family members. © 2013 Wiley Periodicals, Inc. Source

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