Grigoriadou S.,Royal London Hospital |
Gilmour K.C.,Great Ormond Street Hospital NHS Trust |
Gilmour K.C.,University College London |
Gaspar H.B.,Great Ormond Street Hospital NHS Trust |
Gaspar H.B.,University College London
Clinical and Experimental Immunology | Year: 2011
Familial haemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled T cell and macrophage activation and hypercytokinaemia. The incidence of FHL is 0·12/100·000 children born per year, with a male to female ratio of 1:1. The disease is classified into six different types based on genetic linkage analysis and chromosomal localization; five specific genetic defects have been identified, which account for approximately 90% of all patients. Type 1 is due to an as yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene, type 3 by mutations in the Munc-13-4 (UNC13D) gene, type 4 by mutations in the syntaxin 11 (STX11) gene and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies in different ethnic groups. The most common presenting features are pyrexia of unknown origin, pronounced hepatosplenomegaly and cytopenias. Neurological features tend to present later and are associated with poor prognosis. Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHL. Biochemical features such as hyperferritinaemia, hypertriglyceridaemia and hypofibrinogenaemia are usually present, along with high levels of soluble interleukin 2 receptor in the blood and cerebrospinal fluid. Bone marrow aspirate may demonstrate the characteristic haemophagocytes, but initially is non-diagnostic in two-thirds of patients. Established international clinical, haematological and biochemical criteria now facilitate accurate clinical diagnosis. The disease is fatal unless a haematopoietic stem cell transplant (HSCT) is performed. The introduction of HSCT has dramatically improved the prognosis of the disease. However, the mortality of the disease is still significantly high and a number of challenges remain to be addressed. Active disease at the time of the transplant is the major significant poor prognostic factor. Delayed diagnosis, after irreversible organ damage has occurred, especially neurological damage, disease reoccurrence and pre-transplant mortality, remain a concern. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.
Walker I.A.,Great Ormond Street Hospital NHS Trust |
Newton M.,Vanderbilt University |
Bosenberg A.T.,University of Washington
Paediatric Anaesthesia | Year: 2011
Access to safe surgery should be considered as part of the basic human right for health, but unfortunately, this ideal is far from being reached in many low-income countries. Pulse oximetry is recommended as a minimum standard of monitoring by all anesthesia organizations that have set standards, yet around 78 000 operating theaters worldwide lack this essential monitor. The WHO Safe Surgery Saves Lives Program has identified evidence-based guidelines for safe surgery that are applicable in any setting, and the Global Pulse Oximetry Program will help improve access to pulse oximetry in countries where it is not available. However, these initiatives are just a start; capacity, infrastructure, trained healthcare providers and access to essential drugs, and equipment for anesthesia and surgery need to become a public health priority in many low-income countries. © 2011 Blackwell Publishing Ltd.
Shipway L.,Great Ormond Street Hospital NHS Trust
Paediatric nursing | Year: 2010
Children and young people with cancer often experience a diminished oral intake and exhibit subsequent weight loss and poor nutrition as a result of the side effects of treatments. This article studies the case of a five-year-old boy who developed nutritional problems to demonstrate the need for clear and systematic guidelines and protocols for nurses and health professionals to make uniform decisions in the management of such situations.
Pichler J.,Great Ormond Street Hospital NHS Trust |
Pichler J.,Medical University of Vienna |
Soothill J.,Great Ormond Street Hospital NHS Trust |
Hill S.,Great Ormond Street Hospital NHS Trust
Clinical Nutrition | Year: 2014
Background & aims: Catheter-related-blood-stream-infection (CRBSI) might be prevented by optimal catheter connector antisepsis in children with intestinal failure on parenteral nutrition (PN). We changed the disinfectant used from isopropanol 70% to chlorhexidine 2% in 70% isopropanol, which leaves a residue of chlorhexidine on the connector. Methods: We conducted this before/after study in children treated with PN for >28 days. Episodes of CRBSI were recorded for all 42 children treated for >28 days during May-November 2006 before introducing chlorhexidine and for all 50 children treated in May-November 2007 after chlorhexidine was introduced. The number of hospital-acquired CRBSI and number of PN days was counted for each period. The rate of CRBSI/1000 catheter days and the proportion of patients that experienced at least one CRBSI during the two periods were compared. Results: There were 3.1 CRBSI/1000 catheter days prior to using chlorhexidine and 0.4 CRBSI/1000 catheter days after it was introduced, p=0.03.Prior to chlorhexidine 10/42 (24%) patients experienced at least one episode of CRBSI, compared to 3/50, (6%) after introducing it (p=0.02). The survival rate in both periods was similar, but after chlorhexidine significantly more children made a full recovery and a lower proportion of children had irreversible intestinal failure (p=0.01). Conclusions: Our results support the use of 2% chlorhexidine not only to reduce risk of sepsis for central venous catheter connector antisepsis in catheters used for intravenous nutrition, but also to improve the patients' chances of recovering intestinal function. © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.
Walker I.A.,Great Ormond Street Hospital NHS Trust |
Obua A.D.,University of Mbarara |
Mouton F.,University of Rochester |
Ttendo S.,Mbarara University Teaching Hospital |
Wilson I.H.,Royal Devon and Exeter NHS Foundation Trust
Bulletin of the World Health Organization | Year: 2010
Objective To study paediatric surgery rates in south-western Uganda, compare them to rates in England, and determine if existing surgical facilities and workforce meet World Health Organization (WHO) standards. Methods To obtain information on surgical facilities and workforce, we conducted a cross-sectional survey of all hospitals performing major surgery in 14 districts of south-western Uganda in 2007-2008. Using theatre logbook data, we determined the surgical rates, types of surgery performed and in-theatre surgical outcomes. Findings Of 72 hospitals surveyed, 29 were performing major surgery. None met WHO standards for essential surgery. There were 0.7 accredited surgeons per 100 000 population and no paediatric surgeons. Most anaesthetists were not physicians (accredited anaesthetist per 100 000 population: 1.1). The annual surgical rate for children aged ≤ 14 years was 180 operations per 100 000 population; most were emergency procedures. The annual surgical rate for patients of all ages was 652 operations per 100 000 population, with a median of 422 per operating theatre (range: 60-3497) and of 226 per surgeon (range: 60-1748). Mission or nongovernmental organization (NGO) hospitals, which had 44% of the hospital beds in the region, performed 3039 (55%) of the paediatric operations. Externally funded surgeons performed 80% of the 140 cleft lip and palate operations. Four in-theatre deaths occurred in children ≤ 14 years old (in-theatre mortality: 7.7 deaths per 10 000 operations). Conclusion Access to all surgery, including paediatric surgery, is poor in south-western Uganda and investment in basic health-care facilities and surgical workforce and training is urgently needed. Mission and NGO hospitals make a valuable contribution to elective surgery, and externally funded surgeons make an important contribution to specialist surgery. In-theatre mortality was lower than reported for similar settings.
Turner H.,University of Southampton |
Bryant-Waugh R.,Great Ormond Street Hospital NHS Trust |
Peveler R.,University of Southampton
Eating Behaviors | Year: 2010
Study purpose: Eating disorder not otherwise specified (EDNOS) remains poorly evaluated in terms of eating disorder features and relationship to mood, health status and general functioning. This study investigated the clinical profiles of a sample of EDNOS patients, and how they compared to patients with anorexia nervosa (AN) and bulimia nervosa (BN). Method: The sample consisted of 178 patients. All completed the Eating Disorder Examination, Beck Depression Inventory, Work and Social Adjustment Scale and Sf-36. ANOVAs were conducted to explore group differences. Results: No differences were found for depression. No differences were found between BN and EDNOS on measures of health status and general functioning. AN patients reported greater role limitations due to physical health and experienced greater physical pain compared with BN or EDNOS patients, and reported poorer social functioning, lower vitality and higher functional impairment compared with EDNOS patients. Conclusion: EDNOS patients are generally no less clinically impaired than those with BN. However AN patients may be more impaired in some aspects of general functioning compared with BN or EDNOS patients. © 2009 Elsevier Ltd. All rights reserved.
Zhang F.,University College London |
Frost A.R.,University College London |
Blundell M.P.,University College London |
Bales O.,Guys Hospital |
And 3 more authors.
Molecular Therapy | Year: 2010
DNA methylation may restrict the activity of gene transfer vectors due to inadvertent silencing. In P19 embryonic carcinoma cells in vitro, we found that transgene expression regulated by the SFFV LTR and EF1α promoter declined rapidly within 16 days, but for A2UCOE derived from the human HNRPA2B1-CBX3 housekeeping gene locus, remained completely stable. Silencing correlated with extensive epigenetic methylation of CpG sites, whereas the A2UCOE was almost completely resistant. Linking of the A2UCOE upstream of the SFFV LTR protected this element from both DNA methylation and silencing. Analysis of engrafted hematopoietic cells in vivo transduced with the same vectors revealed a similar pattern. The A2UCOE displayed little or no methylation in either primary or secondary graft recipients, and gene expression profiles were highly conserved between the two groups. These studies provide convincing evidence that DNA methylation plays a direct role in regulating self-inactivating (SIN) lentiviral transgene expression, and that the stability of expression from the A2UCOE is, at least in part, due to methylation resistance. The A2UCOE therefore has considerable utility for gene therapy applications where reliable and sustained gene expression is desirable. © The American Society of Gene & Cell Therapy.
Cooray S.,University College London |
Cooray S.,Great Ormond Street Hospital NHS Trust |
Howe S.J.,University College London |
Thrasher A.J.,University College London
Methods in Enzymology | Year: 2012
Retroviruses are useful tools for the efficient delivery of genes to mammalian cells, owing to their ability to stably integrate into the host cell genome. Over the past few decades, retroviral vectors have been used in gene therapy clinical trials for the treatment of a number of inherited diseases and cancers. The earliest retrovirus vectors were based on simple oncogenic gammaretroviruses such as Moloney murine leukemia virus (MMLV) which, when pseudotyped with envelope proteins from other viruses such as the gibbon ape leukemia virus envelope protein (GALV) or vesicular stomatitis virus G protein (VSV-G), can efficiently introduce genes to a wide range of host cells. However, gammaretroviral vectors have the disadvantage that they are unable to efficiently transduce nondividing or slowly dividing cells. As a result, specific protocols have been developed to activate cells through the use of growth factors and cytokines. In the case of hematopoietic stem cells, activation has to be carefully controlled so that pluripotency is maintained. For many applications, gammaretroviral vectors are being superseded by lentiviral vectors based on human immunodeficiency virus type-1 (HIV-1) which has additional accessory proteins that enable integration in the absence of cell division. In addition, retroviral and lentiviral vector design has evolved to address a number of safety concerns. These include separate expression of the viral genes in trans to prevent recombination events leading to the generation of replication-competent viruses. Further, the development of self-inactivating (SIN) vectors reduces the potential for transactivation of neighboring genes and allows the incorporation of regulatory elements that may target gene expression more physiologically to particular cell types. © 2012 Elsevier Inc. All rights reserved.
Larcher V.,Great Ormond Street Hospital NHS Trust |
Hutchinson A.,Great Ormond Street Hospital NHS Trust
Archives of Disease in Childhood | Year: 2010
Competence is an essential legal requirement for valid consent to medical treatment. Children under 16 may be considered 'Gillick competent' to make treatment decisions, but may need to demonstrate this. Applied tests for competence are wide-ranging and context dependent. Competence is related to cognitive ability and experience and may be enhanced by education, encouragement etc.; there is a general duty for professionals to enhance the competence of children in their care. The need to assess a child's competence may occur when s/he wishes to make a controversial decision whose wisdom others dispute. Potential assessors should have the necessary practical skills and an understanding of the child in their social and medical context. Assessments should be developmentally appropriate, explore systemic influences, and consider the child's emotional state, cognitive development and ability to balance risks and benefits. The involvement of a psychologist or other independent third party should be considered in cases that raise serious concerns about competency, or that involve complex decisions or conflict between the various parties. In rare cases courts may be involved.
Cleary M.A.,Great Ormond Street Hospital NHS Trust
Paediatrics and Child Health (United Kingdom) | Year: 2015
Phenylketonuria remains one of the most common inborn errors in the United Kingdom. It is detected on the newborn heel-prick screening sample allowing early treatment with a strict low phenylalanine diet supplemented with artificial amino acids, and appropriate vitamin and minerals. Although the long-term prognosis is good, there is an increasing body of evidence highlighting subtle problems in neuropsychological function with slower reaction times and poorer executive function than peers. White matter changes clearly seen on brain magnetic resonance imaging may have some relationship to these neuropsychological difficulties but their significance is not clearly understood. The diet, although successful, is difficult to follow lifelong and with its attendant risks of nutritional deficiencies needs careful specialist management. In view of these challenges new treatments such as sapropterin (a tetrahydrobiopterin analogue) and large neutral amino acids are currently being used in phenylketonuria and a human trial has started using ammonia lyase as enzyme replacement therapy. Maternal phenylketonuria syndrome remains a risk for those who conceive whilst blood phenylalanine is elevated and females must be counselled early in childhood to avoid this risk. © 2014.