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  • Journal of Reproductive Immunology. 01/2014; s 101–102:12.
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    ABSTRACT: Advanced therapy medicinal products (ATMP) are gene therapy, somatic cell therapy or tissue-engineered products regulated under (EC) No. 1394/2007 to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients. Academic good manufacturing practice (GMP) centers are major contributors in the development of ATMPs and this study assessed the impact of regulations on them. European academic and non-industrial facilities (n = 747) were contacted, and a representative sample of 50 replied to a detailed questionnaire. Experienced centres were further selected in every Member State (MS) for semi-structured interviews. Indicators of ATMP production and development success were statistically assessed, and opinions about directive implementation were documented. Facilities experienced in manufacturing cell therapy transplant products are the most successful in developing ATMPs. New centres lacking this background struggle to enter the field, and there remains a shortage of facilities in academia participating in translational research. This is compounded by heterogeneous implementation of the regulations across MS. GMP facilities successfully developing ATMPs are present in all MS. However, the implementation of regulations is heterogeneous between MS, with substantial differences in the definition of ATMPs and in the approved manufacturing environment. The cost of GMP compliance is underestimated by research funding bodies. This is detrimental to development of new ATMPs and commercialization of any that are successful in early clinical trials. Academic GMP practitioners should strengthen their political visibility and contribute to the development of functional and effective European Union legislation in this field.
    Cytotherapy 01/2014; 16(3):289.
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    ABSTRACT: Biomarkers of ischemia-reperfusion injury allow risk stratification and early identification of delayed graft function after kidney transplantation. Welberry Smith et al. describe a novel serum biomarker, aminoacylase-1, that not only is associated with delayed graft function but can predict the long-term outcome years after transplantation.
    Kidney International 12/2013; 84(6):1072-4.
  • Bone marrow transplantation 11/2013;
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    ABSTRACT: AR42J B-13 (B-13) cells form hepatocyte-like (B-13/H) cells in response to glucocorticoid treatment. To establish its utility in toxicity and genotoxicity screening, CYP induction; susceptibility to toxins and transporter gene expression were examined. Conversion to B-13/H cells resulted in expression of male-specific CYP2C11 and sensitivity to methapyrilene. B-13/H cells constitutively expressed CYP1A, induced expression in response to an AhR agonist and activated benzo[α]yrene to a DNA damaging species. Functional CYP1A2 was not expressed due to deletions in the CYP1A2 gene. A B-13 cell line stably expressing the human CYP1A2 was therefore engineered (B-13(-TR/h1A2)) and thederived B-13/H cells expressed metabolically functional CYP1A2. Treatment with the cooked food mutagen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine resulted in a dose-dependent increase in DNA damage. B-13/H cells expressed CAR and induced CYP2B1 mRNA levels in response to classical CAR activators. However, translation to functional CYP2B1 protein was low and increased minimally by CAR activator treatment. B-13/H cells expressed high levels of PXR and induced CYP3A1 in response to classical PXR activators. CYP3A genes were inducible, functional and activated aflatoxin B1 to a DNA damaging species. All 23 major hepatic transporters were induced when B-13 cells were converted to B-13/H cells, although in many cases, levels remained below those present in adult rat liver. However, BSEP, Abcb1b, MRP and BCRP transporters were functional in B-13/H cells. These data demonstrate that the B-13 cell generates hepatocyte-like cells with functional drug metabolism and transporter activities which can alone - or in a humanised form - be used to screen for hepatotoxic and genotoxic endpoints in vitro.
    Toxicological Sciences 11/2013;
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    ABSTRACT: 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. Since 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 97 days for high and low dose serotherapy respectively. The low dose serotherapy group had higher CD3+, CD4+ and early thymic emigrant counts at 4 months compared to the high dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplant 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.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2013;
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    ABSTRACT: The purpose of this study is to evaluate the effects of targeting both the motivation and action phases of behaviour change in a 5-week intervention to increase physical activity (PA) among patients with rheumatoid arthritis (RA) not meeting current PA recommendations. In a randomised controlled trial, a control group-which received a group-based patient education session led by a physical therapist-was compared to a treatment group which received the education session plus a motivational interview from a physical therapist and two self-regulation coaching sessions from a rheumatology nurse. Outcomes included leisure-time PA, days per week with at least 30 min of moderate-intensity PA, self-efficacy and autonomous motivation (cognitions which predict PA initiation and maintenance), disease activity, functional status, depressive symptoms and fatigue. Effects were assessed using mixed models repeated measures. Of the 78 patients randomised, 76 and 67 completed the post-treatment and follow-up assessments, respectively. Significant treatment effects were found for leisure-time PA (p = 0.022), active days/week (p = 0.016), self-efficacy (p = 0.008) and autonomous motivation (p = 0.001). At post-treatment and 6-months follow-up, significantly more treated patients than controls met current PA recommendations. No significant effects were found for disease activity, functional status, depressive symptoms or fatigue. Combining motivation- and action-focused intervention approaches improved PA-related cognitions and led to improved uptake and maintenance of leisure-time PA. However, further research is necessary to identify ways of helping patients with RA transition to-and maintain-more intensive forms of PA which are more likely to improve disease activity and functional status.
    Clinical Rheumatology 11/2013;
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    ABSTRACT: Hypoglycaemia remains an over-riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long duration diabetes and is one of the most feared diabetes-related complications. In this review we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter-regulation, hypoglycaemia associated autonomic failure, psychosocial and behavioural factors, and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta-cell replacement therapies have been employed yet there is little RCT evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, frequency and severity of all hypoglycaemic episodes. This article is protected by copyright. All rights reserved.
    Diabetes/Metabolism Research and Reviews 11/2013;
  • The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 11/2013; 32(11):1054-5.
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    ABSTRACT: Background and objectiveNeutrophils are consistently found in inflamed and infected airways in idiopathic bronchiectasis, but relatively little is known about the function of blood neutrophils in this condition. We hypothesized that peripheral blood neutrophil (PBN) phagocytosis and superoxide generation are impaired in bronchiectasis, and that granulocyte-macrophage colony-stimulating factor (GM-CSF) is capable of improving neutrophil function. Methods Neutrophils were isolated from the peripheral blood of patients with idiopathic bronchiectasis who were free of exacerbation, and from healthy controls of similar age (n = 21 in both groups). Ingestion of serum-opsonized zymosan by neutrophils was used to quantify phagocytic capacity. Superoxide generation in neutrophils was measured in response to addition of platelet activating factor and formyl-methionyl-leucyl-phenylalanine. Experiments were performed in the presence or absence of GM-CSF. ResultsNo differences were observed in either phagocytic capacity (P = 0.99) or superoxide generation (P = 0.81) when comparing patients and controls. However, a significant increase in phagocytic capacity above baseline levels in both patients (P < 0.005) and controls (P < 0.005) was induced by GM-CSF. Similarly, the superoxide generation in patients (P < 0.005) and controls (P = 0.001) was significantly increased by GM-CSF. ConclusionsPBN function was preserved in idiopathic bronchiectasis. Enhancement of neutrophil phagocytosis and superoxide generation by GM-CSF requires further study.
    Respirology 11/2013; 18(8).
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