Great Ormond St Hospital For Children Nhs Trust

London, United Kingdom

Great Ormond St Hospital For Children Nhs Trust

London, United Kingdom

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Alatzoglou K.S.,University College London | Azriyanti A.,University of Oxford | Rogers N.,University of Adelaide | Ryan F.,University of Oxford | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: SOX3 is an early developmental transcription factor involved in pituitary development. In humans, over- and underdosage of SOX3 is associated with X-linked hypopituitarism with variable phenotypes ranging from isolated GH deficiency (GHD) to panhypopituitarism, with or without mental retardation and, in most cases, with reported pituitary imaging, an ectopic/undescended posterior pituitary. Patient: We present a young patient with hemophilia B and developmental delay who had a 2.31-Mb deletion on Xq27 including SOX3, F9, and eight other contiguous genes. He developed GH and gonadotropin deficiency, whilst his thyroid function was in the low normal range. Magnetic resonance imaging revealed a eutopic posterior pituitary and the unusual finding of a persistent craniopharyngeal canal that has not previously been described in patients with congenital hypopituitarism. Objective and Methods: To establish whether loss of SOX3 can account for the human phenotype, we examined in detail the hypothalamo-pituitary region of neonatal Sox3 null mice. Results: Consistent with the patient's phenotype, Sox3 null mice exhibit a ventral extension of the anterior pituitary that penetrates, and generates a mass beneath, the sphenoid bone. This suggests that the defect results from abnormal induction of Rathke's pouch, leading to a persistent connection between Rathke's pouch and the oral ectoderm. Conclusions: Our observations expand the spectrum of phenotypes observed in association with altered SOX3 dosage and may affect the approach to genetic screening. Screening for SOX3 should be advised not only for hypopituitary patients with an ectopic posterior pituitary, but also for those with a structurally normal pituitary and additional findings, including clefts and a persistent craniopharyngeal canal, with or without mental retardation. Copyright © 2014 by the Endocrine Society.


Wenham M.,University of Cambridge | Wenham M.,University of Oxford | Grieve S.,University of Cambridge | Cummins M.,Bristol Royal Hospital for Children | And 8 more authors.
Haematologica | Year: 2010

Hermansky Pudlak syndrome type 2 (HPS2) is a rare disorder associated with mutations in the Adaptor Protein 3 (AP-3) complex, which is involved in sorting transmembrane proteins to lysosomes and related organelles. We now report 2 unrelated subjects with HPS2 who show a characteristic clinical phenotype of oculocutaneous albinism, platelet and T-lymphocyte dysfunction and neutropenia. The subjects were homozygous for different deletions within AP3B1 (g.del180242-180866, c.del153-156), which encodes the AP-3β3A subunit, resulting in frame shifts and introduction of nonsense substitutions (p.E693fsX13, p.E52fsX11). In the subject with p.E693fsX13, this resulted in expression of a truncated variant β3A protein. Cytotoxic T-lymphocyte (CTL) clones from both study subjects showed increased cell-surface expression of CD63 and reduced cytotoxicity. Platelets showed impaired aggregation and reduced uptake of 3H-serotonin. These findings are consistent with CTL granule and platelet dense granule defects, respectively. This report extends the clinical and laboratory description of HPS2. ©2010 Ferrata Storti Foundation.


PubMed | Anthony Nolan Cell Therapy Center, Queen Mary, University of London, Anthony Nolan Research Institute, University College London and Great Ormond St Hospital For Children Nhs Trust
Type: | Journal: Scientific reports | Year: 2016

Expression of major histocompatibility antigens class-2 (MHC-II) under non-inflammatory conditions is not usually associated with the nervous system. Comparative analysis of immunogenicity of human embryonic/fetal brain-derived neural stem cells (hNSCs) and human mesenchymal stem cells with neurogenic potential from umbilical cord (UC-MSCs) and paediatric adipose tissue (ADSCs), while highlighting differences in their immunogenicity, led us to discover subsets of neural cells co-expressing the neural marker SOX2 and MHC-II antigen in vivo during human CNS development. MHC-II proteins in hNSCs are functional, and differently regulated upon differentiation along different lineages. Mimicking an inflammatory response using the inflammatory cytokine IFN induced MHC-II up-regulation in both astrocytes and hNSCs, but not in UC-MSCs and ADSCs, either undifferentiated or differentiated, though IFN receptor expression was comparable. Together, hypoimmunogenicity of both UC-MSCs and ADSCs supports their suitability for allogeneic therapy, while significant immunogenicity of hNSCs and their progeny may at least in part underlie negative effects reported in some patients following embryonic neural cell grafts. Crucially, we show for the first time that MHC-II expression in developing human brains is not restricted to microglia as previously suggested, but is present in discrete subsets of neural progenitors and appears to be regulated independently of inflammatory stimuli.


Mengel E.,Charité - Medical University of Berlin | Tylki-Szymanska A.,Childrens Memorial Health Institute | Kleinotiene G.,Vilnius University | Reinke J.,Charité - Medical University of Berlin | Vellodi A.,Great Ormond St Hospital for Children NHS Trust
Journal of Inherited Metabolic Disease | Year: 2011

In 2007, the European Task Force for neuronopathic Gaucher disease (NGD) published a review of 55 patients across four countries. Although some observations were possible, analysis was difficult due to the absence of a systematic way of assessing patients. In response to this, a Severity Scoring Tool (SST) was devised to offer a systematic means of assessing the neurological presentation seen. The SST has been modified (mSST) and is a valid tool for monitoring neurological progression. This review describes disease status and progression of neurological manifestations in a cohort of 39 chronic NGD patients across three European countries over a period of 4 years, using the mSST. © SSIEM and Springer 2011.


Mekahli D.,Great Ormond St Hospital For Children Nhs Trust | Mekahli D.,University Hospitals Leuven | Ledermann S.,Great Ormond St Hospital For Children Nhs Trust | Gullett A.,Great Ormond St Hospital For Children Nhs Trust | And 2 more authors.
Pediatric Nephrology | Year: 2014

Background: The health related quality of life (HRQoL) of young adults treated for chronic kidney disease (CKD) stage 4/5 from infancy is unknown. Methods: A HRQoL questionnaire was sent to all 41 patients aged >16 years from a previously characterised cohort of infants with CKD stage 4/5 born between 1986 and 1997. Patient scores were compared with a previously reported cohort of patients who needed renal replacement therapy (RRT) in mid childhood and in the normal population. Results: All patients (11 women) completed the questionnaire at a median (range) age of 19.2 (16.3-23.4) years. At the time of the survey, 5 (12.5 %) were on dialysis, 35 (85.5 %) had a functioning kidney transplant, one (2 %) was still conservatively treated and 22 (54 %) had comorbidities; 68 % were either studying or in paid employment, with 17 % actively seeking employment. Although patients described a lower HRQoL than a healthy, age-matched UK group, in some aspects, scores were comparable with patients needing RRT in later childhood. Lower scores were associated with comorbidities, dialysis at last follow-up, more than one treatment modality change and short stature. Conclusions: Our survey demonstrates very encouraging results for long-term HRQoL of infants with severe CKD and highlights the negative impact of comorbidities. These data will help clinicians to counsel and inform families. © 2014 IPNA.


Guasti L.,University College London | Guasti L.,Center for Endocrinology | Vagaska B.,University College London | Bulstrode N.W.,Great Ormond St Hospital For Children Nhs Trust | And 2 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2014

Scaffold cellularization for cartilage engineering can aid implant properties, their retention and minimize repeated intervention, particularly in paediatric reconstructive craniofacial surgery. We developed novel bionanoscaffolds using paediatric adipose tissue-derived stem cells (hADSCs), an accessible autologous cell source, and POSS-PCU. Little is known about cellular responses to this nanomaterial, though it was used in human. We assessed: 1) POSS-PCU cellularization and bioaffinity to hADSCs; 2) hADSC chondrogenic differentiation ability in POSS-PCU; 3) whether bionanoscaffolds became encased within a vascular network and/or vascularised. POSS-PCU supported ADSC survival and proliferation and their migration and differentiation into cartilage within the nanoscaffold. Furthermore, after CAM-grafting, bionanoscaffolds were rapidly surrounded by blood vessels without any apparent negative reaction and erythrocytes of host origin were detected inside the scaffold, suggesting invasion from some capillaries. Altogether, this study demonstrates that POSS-PCU displays excellent bioactivity and hADSC/POSS-PCU bionanoscaffolds offer much promise for autologous cell-based tissue engineering for clinical applications. From the Clinical Editor: In this study, human adipose tissue derived stem cells were used in combination with POSS-PCU nanoscaffolds to generate cartilage tissue demonstrating excellent bioactivity for autologous cell-based tissue engineering for clinical applications. © 2014 Elsevier Inc.


PubMed | Great Ormond St Hospital For Children Nhs Trust and University College London
Type: Journal Article | Journal: Nanomedicine : nanotechnology, biology, and medicine | Year: 2014

Scaffold cellularization for cartilage engineering can aid implant properties, their retention and minimize repeated intervention, particularly in paediatric reconstructive craniofacial surgery. We developed novel bionanoscaffolds using paediatric adipose tissue-derived stem cells (hADSCs), an accessible autologous cell source, and POSS-PCU. Little is known about cellular responses to this nanomaterial, though it was used in human. We assessed: 1) POSS-PCU cellularization and bioaffinity to hADSCs; 2) hADSC chondrogenic differentiation ability in POSS-PCU; 3) whether bionanoscaffolds became encased within a vascular network and/or vascularised. POSS-PCU supported ADSC survival and proliferation and their migration and differentiation into cartilage within the nanoscaffold. Furthermore, after CAM-grafting, bionanoscaffolds were rapidly surrounded by blood vessels without any apparent negative reaction and erythrocytes of host origin were detected inside the scaffold, suggesting invasion from some capillaries. Altogether, this study demonstrates that POSS-PCU displays excellent bioactivity and hADSC/POSS-PCU bionanoscaffolds offer much promise for autologous cell-based tissue engineering for clinical applications.In this study, human adipose tissue derived stem cells were used in combination with POSS-PCU nanoscaffolds to generate cartilage tissue demonstrating excellent bioactivity for autologous cell-based tissue engineering for clinical applications.


Fattah A.,Great Ormond St Hospital For Children Nhs Trust | Sebire N.J.,Great Ormond St Hospital For Children Nhs Trust | Bulstrode N.W.,Great Ormond St Hospital For Children Nhs Trust
Journal of Plastic, Reconstructive and Aesthetic Surgery | Year: 2010

Background: Current techniques of autologous ear reconstruction involve the soft tissue coverage of a carved costal cartilage framework. However, assessment of the morbidity associated with this donor site has been little documented. This study describes a method to reconstruct the defect and analyses the outcomes with or without donor site reconstitution. Methods: The donor site was reconstituted by wrapping morcelised cartilage in a vicryl mesh. Twenty-one patients with reconstitution and nine without were recruited to the study. Scar quality and length, dimensions of donor defect and visible deformity were recorded according to a modified Vancouver scar scale. Patients were also assessed by the SF36 questionnaire, a well-validated health survey. In a subset of our study group, we assessed the fate of the donor site reconstitution by direct visualisation in situ and histological analysis. Results: Fifteen donor sites of patients without donor site reconstitution were compared to 23 reconstructed donor sites. In those without, all had a palpable defect with nearly half exhibiting visible chest deformity. In contrast, those that had rib reconstitution did not demonstrate significant chest wall deformity. Intraoperative examination demonstrated formation of a neo-rib, histologically proven to comprise hyaline cartilage admixed with fibrous tissue. Analysis of SF36 results showed a higher satisfaction in the reconstituted group, but in both groups, the donor site was of little overall morbidity. Conclusions: Although there is little difference between the groups in terms of subjectively perceived benefit, rib reconstitution is objectively associated with better costal margin contour and less chest wall deformity. © 2009 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.


Hoskote A.,Great Ormond St Hospital For Children Nhs Trust | Carter C.,Great Ormond St Hospital For Children Nhs Trust | Rees P.,Great Ormond St Hospital For Children Nhs Trust | Elliott M.,Great Ormond St Hospital For Children Nhs Trust | And 2 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2010

Objectives: To identify pretransplant factors associated with postprocedural right ventricular failure and the relationship between right ventricular failure and long-term survival in children. Methods: Records were reviewed for children having heart transplantation from 2000 to 2006. Results: Right ventricular failure was identified by clinical and echocardiographic parameters in 33/129 (25%) recipients: dilated cardiomyopathy in 14/90 (15%), congenital heart disease in 11/27 (41%), and restrictive cardiomyopathy in 8/12 (66%). In 9 of 12 (75%), known elevated (reactive) pulmonary vascular resistance progressed to right ventricular failure. In a further 23/117 (20%) recipients, pulmonary vascular resistance within predefined acceptable range progressed to right ventricular failure. Multiple logistic regression analyses indicated elevated pulmonary vascular resistance (odds ratio 12.30; 95% confidence interval 2.73, 55.32; P = .001) and primary diagnosis, restrictive cardiomyopathy (odds ratio 9.21; 95% confidence interval 2.07, 41.12; P = .004), and congenital heart disease (odds ratio 4.07; 95% confidence interval 1.36, 12.19; P = .012) were strongly associated with right ventricular failure, but duration of heart failure, pretransplant mechanical support, donor status, and ischemic times were not. Treatment included inhaled nitric oxide in 28 (84%), mechanical support in 10 (31%), hemofiltration in 13 (40%), and retransplantation in 2. A Cox multiple regression model including: primary diagnosis, right ventricular failure, and elevated pulmonary vascular resistance indicated that only the latter was independently linked with eventual mortality (hazards ratio 5.45; 95% confidence interval 1.36, 21.96; P = .017). Conclusions: Primary diagnosis and pretransplant elevated reactive pulmonary vascular resistance are both linked to the evolution of right ventricular failure. Pulmonary vascular resistance assessment in end-stage heart failure is challenging; therefore, avoidance of right ventricular failure may not always be possible. Aggressive early treatment may mitigate the effects of right ventricular failure: pretransplant elevated pulmonary vascular resistance was independently associated with long-term survival, but right ventricular failure was not. © 2010 The American Association for Thoracic Surgery.

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