Neil W Bulstrode

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (23)61.17 Total impact

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    ABSTRACT: Human somatic stem cells with neural differentiation potential can be valuable for developing cell-based therapies, including treatment of birth-related defects, while avoiding issues associated with cell reprogramming. Precisely defining the "identity" and differentiation potential of somatic stem cells from different sources, has proven difficult, given differences in sets of specific markers, protocols used and lack of side-by-side characterization of these cells in different studies. Therefore, we set to compare expression of mesenchymal and neural markers in human umbilical cord-derived mesenchymal stem cells (UC-MSCs), paediatric adipose-derived stem cells (p-ADSCs) in parallel with human neural stem cells (NSCs). We show that UC-MSCs at a basal level express mesenchymal and so-called “neural” markers, similar to that we previously reported for the p-ADSCs. All somatic stem cell populations studied, independently from tissue and patient of origin, displayed a remarkably similar expression of surface markers, with the main difference being the restricted expression of CD133 and CD34 to NSCs. Expression of certain surface and neural markers was affected by the expansion medium used. As predicted, UC-MSCs and p-ADSCs demonstrated tri-mesenchymal lineage differentiation potential, though p-ADSCs display superior chondrogenic differentiation capability. UC-MSCs and p-ADSCs responded also to neurogenic induction by up-regulating neuronal markers, but crucially they appeared morphologically immature when compared with differentiated NSCs. This highlights the need for further investigation into the use of these cells for neural therapies. Crucially, this study demonstrates the lack of simple means to distinguish between different cell types and the effect of culture conditions on their phenotype, and indicates that a more extensive set of markers should be used for somatic stem cell characterization, especially when developing therapeutic approaches.
    Stem Cell Research 04/2015; 11(1). DOI:10.1016/j.scr.2015.04.003 · 3.91 Impact Factor
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    ABSTRACT: Extravasation is an iatrogenic injury that may produce soft tissue necrosis requiring surgical reconstruction (Rose et al., 2008) and (Goon et al., 2006).(1)(,2) Previous review of extravasation injuries within our hospital showed that early referral to plastic surgeons and washout of high-risk cases lead to favourable outcome in 86% of patients (Gault, 1993).(3) Hospital-wide guidelines were introduced in 2005. This paper closes the audit loop by evaluating extravasation injuries outcome following the introduction of these guidelines. All patients referred to the plastic surgery department for extravasation injuries between October 2008 and October 2009 were reviewed. A favourable outcome was defined as resolution without tissue loss requiring surgical reconstruction. Patients were excluded if they sustained the extravasation in other institution. A total of 82 extravasation injuries in 78 patients were reviewed during the audit period. Mean age was 3.2 years (Median 0.2 years, Minimum 0 day, and maximum 16.7 years). The injuries were more frequent on the left half of the body (52%) and involving the upper limbs (59%). Mean time to referral was 8 h, with 60% of patients referred within 6 h of the injury, 30% in 6-12 h, and 10% referred after more than 12 h 26% of the injuries required washout treatment - the rest was treated conservatively. Tissue necrosis occurred in 3 cases (4%) but required no surgical intervention due to the small area affected. Our audit showed an improved outcome of extravasation injury following introduction of hospital-wide guidelines of early referral to specialist team and washout of high-risk cases. Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
    Journal of Plastic Reconstructive & Aesthetic Surgery 01/2015; 68(4). DOI:10.1016/j.bjps.2014.12.029 · 1.47 Impact Factor
  • Whitney L. Quong, Neil W. Bulstrode
    European Journal of Plastic Surgery 01/2015; DOI:10.1007/s00238-015-1087-0
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    ABSTRACT: Terminal myelocystocele is a severe form of spinal dysraphism characterized by cystic expansion of the terminal spinal cord that herniates through a deficiency of the posterior sacral spinal elements to fuse with the subcutaneous fat. Postnatal enlargement of the subcutaneous fluid-filled sac may result in progressive neurological deficit and threaten the viability of the overlying skin. Surgical repair entails spinal cord untethering, resection of nonfunctional neural elements and watertight reconstruction of the terminal thecal sac. Young age at the time of surgery, large dural defect, attenuated tissues and locally altered CSF dynamics frequently mean that wound complications including CSF leakage and pseudomeningocele formation are common. With consideration of these requirements, we describe our surgical technique in terminal myelocystocele repair, which combines a novel surgical incision and for the first time in a neurosurgical setting, the use of a de-epithelialized skin flap to augment the closure. We report successful operative outcomes in three infant patients with terminal myelocystocele.
    Child s Nervous System 12/2014; 31(3). DOI:10.1007/s00381-014-2598-x · 1.16 Impact Factor
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    ABSTRACT: Background: The incidence of midline frontonasal dermoid cysts is one in 20,000 to one in 40,000. These lesions may have intracranial extension. This is explained by the anatomy and embryology of nasofrontal development. Skin involvement may also be extensive. Incomplete excision frequently leads to recurrence. The authors report their experience and pathway for management of midline dermoids. Methods: Databases were searched to identify patients who had undergone surgery for removal of a dermoid cyst. Preoperative imaging and indications for surgery were reviewed. Cases were grouped according to surgical approach, and outcomes and complications were identified. Results: Fifty-five patients were treated. Magnetic resonance imaging or computed tomography was used to delineate the anatomy, and surgical excision was expedited if there was a history of infection, especially if imaging suggested intracranial extension. Twelve patients were treated endoscopically (one was converted to open). Eleven required transcranial approaches for intracranial extension (20 percent). Of these, one lesion breached the dura. The remaining 32 patients had dermoids excised with an open approach (direct, bicoronal, or rhinoplasty). There were no recurrences in the open group and there was one recurrence in the transcranial group. This was treated by reexcision. Conclusion: Midline dermoid cysts are relatively uncommon. However, knowledge of the pathogenesis of these lesions together with the authors' experience over 15 years has allowed them to develop a protocol-driven approach, with a low incidence of complications.
    Plastic &amp Reconstructive Surgery 10/2014; 135(1). DOI:10.1097/PRS.0000000000000833 · 3.33 Impact Factor
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    ABSTRACT: Treacher Collins syndrome (TCS), mandibulofacial dysostosis, or Franceschetti–Zwahlen–Klein syndrome, is a rare genetic disorder characterised by dysgenesis of the hard and soft tissues of the first and second branchial arches. Early operations focus on maintaining the airway, protecting the eyes, and supporting auditory neurological development. Later operations include staged reconstruction of the mouth, face, and external ear. Bimaxillary surgery can improve the maxillomandibular facial projection, but correction of malar, orbital rim, and temporal defects may be more difficult. We present a clinical review of the syndrome with a chronological approach to the operations.
    British Journal of Oral and Maxillofacial Surgery 09/2014; 52(7). DOI:10.1016/j.bjoms.2014.02.007 · 1.13 Impact Factor
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    ABSTRACT: Context: The hormone fibroblast growth factor 21 (FGF21) is a key metabolic regulator in the adaptation to fasting. In food-restricted mice, inhibition of skeletal growth is mediated by the antagonistic effect of FGF21 on GH action in the liver and growth plate. Objective: The objective of the study was to assess the role of FGF21 in growth regulation in humans using postnatal growth failure of very preterm infants as a model. Design: FGF21 levels were measured serially in very preterm infants, and their linear growth evaluated from birth to term-equivalent age. Primary chondrocytes obtained from pediatric donors were used to test whether FGF21 can directly interfere with GH signaling. Results: A negative association (β -.415, P < .005, linear regression model) of FGF21 levels with the change in SD score for length was found. In primary chondrocytes, FGF21 upregulated basal and GH-induced SOCS2 expression and inhibited GH-induced STAT5 phosphorylation as well as GH-induced COLII and ALP expression. Finally, FGF21 inhibited GH-induced IGF-1 expression and cell proliferation, indicating GH resistance. However, FGF21 did not affect IGF-1-induced cell proliferation. Conclusions: Elevated FGF21 serum levels during the first weeks of life are independently associated with postnatal growth failure in preterm infants. Furthermore, our data provide mechanistic insights into GH resistance secondary to prematurity and may offer an explanation for the growth failure commonly seen in chronic conditions of childhood.
    Journal of Clinical Endocrinology &amp Metabolism 08/2014; DOI:10.1210/jc.2014-1566 · 6.31 Impact Factor
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    ABSTRACT: Jeune syndrome (asphyxiating thoracic dystrophy) is a rare disorder characterized by skeletal dysplasia, reduced diameter of the thoracic cage and extrathoracic organ involvement. Fatal, early respiratory insufficiency may occur. Two-stage lateral thoracic expansion has been reported, addressing each side sequentially over 3-12 months. While staged repair theoretically provides less invasive surgery in a small child with respiratory distress, we utilized a single stage, bilateral procedure aiming to rapidly maximize lung development. Combined bilateral surgery also offered the chance of rapid recovery, and reduced hospital stay. We present our early experience of this modification of existing surgical treatment for an extremely rare condition, thought to be generally fatal in early childhood. Nine children (6 males, 3 females; median age 30 months [3.5-75]) underwent thoracic expansion for Jeune syndrome in our centre. All patients required preoperative respiratory support (5 with tracheostomy, 8 requiring positive pressure ventilation regularly within each day/night cycle). Two children underwent sequential unilateral (2-month interval between stages) and 7 children bilateral thoracic expansion by means of staggered osteotomies of third to eighth ribs and plate fixation of fourth to fifth rib and sixth to seventh rib, leaving the remaining ribs floating. There was no operative mortality. There were 2 deaths within 3 months of surgery, due to pulmonary hypertension (1 following two-stage and 1 following single-stage thoracic expansion). At the median follow-up of 11 months (1-15), 3 children have been discharged home from their referring unit and 2 have significantly reduced respiratory support. One child remains on non-invasive ventilation and another is still ventilated with a high oxygen requirement. Jeune syndrome is a difficult condition to manage, but bilateral thoracic expansion offers an effective reduction in ventilator requirements in these children. While two-stage repair has been described previously, this is the first report of single-stage bilateral thoracic expansion. Single-stage repair is feasible and may offer better resource management and significant cost savings by potentially reducing theatre usage and overall length of stay (intensive care and hospital) without compromising clinical outcomes.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 03/2014; 46(4). DOI:10.1093/ejcts/ezu074 · 2.81 Impact Factor
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    ABSTRACT: Postpneumonectomy syndrome is a rare complication following pneumonectomy with its related change in mediastinal configuration. Symptoms range from airway obstruction to esophageal symptoms, leading at times to a persistent requirement for respiratory support. Surgery is often beneficial, which is in the form of placement of a prosthesis, with variable results. We report 2 cases of postpneumonectomy syndrome: one with successful relief, and the other in which the saline-filled prosthesis failed to achieve the desired result.
    Asian cardiovascular & thoracic annals 12/2013; DOI:10.1177/0218492313516115
  • M S Lloyd, C Wallis, N Muthialu, M Elliott, N. W. Bulstrode
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    ABSTRACT: Postpneumonectomy syndrome (PPS) is a rare syndrome whereby the airway and oesophagus become obstructed due to extreme rotation of the mediastinum after pneumonectomy. Our treatment of this condition involved mediastinal repositioning and placement of a saline filled tissue expander into the pleural space. This has not been reported in the plastic surgical literature and we describe technical difficulties and how they were overcome.
    Journal of Plastic Reconstructive & Aesthetic Surgery 12/2013; 67(5). DOI:10.1016/j.bjps.2013.11.002 · 1.47 Impact Factor
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    ABSTRACT: 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.
    Nanomedicine: nanotechnology, biology, and medicine 09/2013; 10(2). DOI:10.1016/j.nano.2013.08.006 · 5.98 Impact Factor
  • S Cugno, R D Farhadieh, N W Bulstrode
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    ABSTRACT: Autologous microtia reconstruction is generally performed in two stages. The second stage presents a unique opportunity to carry out other complementary procedures. The present study describes our approach to microtia reconstruction, wherein the second stage of reconstruction is combined with final refinements to the ear construct and/or additional procedures to enhance facial contour and symmetry. Retrospective analysis of patients who underwent two-stage microtia reconstruction by a single surgeon (NWB) was conducted in order to ascertain those that had ancillary procedures at the time of the second stage. Patient and operative details were collected. Thirty-four patients (male, 15, median age and age range at second stage, 11 and 10-18 years, respectively) who had complementary procedures executed during the second stage of auricular reconstruction were identified. Collectively, these included centralizing genioplasty (n = 1), fat transfer (n = 22), ear piercing (n = 7), and contralateral prominauris correction (n = 7). Six patients had correction for unilateral isolated microtia and in the remaining 28 patients, auricular reconstruction for microtia associated with a named syndrome. All patients reported a high rate of satisfaction with the result achieved and the majority (85%) reported no perceived need for additional surgical refinements to the ear or procedure(s) to achieve further facial symmetry. No peri- or post-operative complications were noted. Combining the final stage of autologous microtia reconstruction with other ancillary procedures affords a superior aesthetic outcome and decreased patient morbidity.
    Journal of Plastic Reconstructive & Aesthetic Surgery 08/2013; 66(11). DOI:10.1016/j.bjps.2013.06.042 · 1.47 Impact Factor
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    ABSTRACT: Congenital melanocytic naevi (CMN) can be associated with neurological abnormalities and increased risk of melanoma. Mutations in NRAS, BRAF and Tp53 have been described in individual CMN samples, however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesised that a single post-zygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and non-melanocytic central nervous system (CNS) lesions. Fifty-five samples from 15 patients with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12/15 patients, but absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In ten patients the mutation was consistently c.181C>A, p.Q61K, and in two c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from five patients were mutation positive, despite NRAS rarely reported as mutated in CNS tumours. Loss of heterozygosity was associated with onset of melanoma in two cases, implying a multi-step progression to malignancy. These results suggest that single post-zygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.Journal of Investigative Dermatology ccepted article preview online, 7 February 2013; doi:10.1038/jid.2013.70.
    Journal of Investigative Dermatology 02/2013; 133(9). DOI:10.1038/jid.2013.70 · 6.37 Impact Factor
  • Journal of Plastic Reconstructive & Aesthetic Surgery 01/2013; 66(4). DOI:10.1016/j.bjps.2012.11.037 · 1.47 Impact Factor
  • Journal of Plastic Reconstructive & Aesthetic Surgery 12/2012; 66(3). DOI:10.1016/j.bjps.2012.11.011 · 1.47 Impact Factor
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    ABSTRACT: Use of the free groin flap, one of the first microvascular free flaps described, has been neglected recently because it has a short pedicle and varies anatomically. However, we have found its anatomical features and type of tissue ideal for volumetric enhancement in severe hemifacial asymmetry. We present a retrospective review of a consecutive series of 14 patients who had hemifacial augmentation with a free groin flap (mean age at operation 17 years, range 10-42) since 2001, and discuss the surgical technique. The most common cause of asymmetry was hemifacial microsomia (n=6). Anatomical variation of the vessels in the groin did not cause problems. Arterial anastomosis was to the facial artery in 13 patients; 12 patients had simultaneous hard tissue procedures. No flaps failed. The free groin flap is a useful adjunct in the management of hemifacial deficits in volume when free fat grafts will not provide enough bulk. Although the operation can take longer than non-vascularised grafts, little tissue is lost so long-term results may be more predictable. We have found the anatomy fairly consistent and the short pedicle caused no problems.
    British Journal of Oral and Maxillofacial Surgery 10/2012; 51(4). DOI:10.1016/j.bjoms.2012.09.004 · 1.13 Impact Factor
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    ABSTRACT: Poikiloderma with neutropenia (PN) is a rare disorder attributed to mutations in the C16orf57 gene(1,2) , with many similarities to other hereditary poikilodermas (HP)(3) . The risks ascribed to this condition are yet to be fully elucidated.x1We report the case of a patient with PN who developed a Squamous Cell Carcinoma (SCC) of the toe at an early age including studies demonstrating abnormal neutrophil function.
    British Journal of Dermatology 08/2012; 168(3). DOI:10.1111/bjd.12016 · 4.10 Impact Factor
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    ABSTRACT: Congenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80% of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. We noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.
    Journal of Investigative Dermatology 05/2012; 132(8):2026-32. DOI:10.1038/jid.2012.95 · 6.37 Impact Factor
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    ABSTRACT: Stem cells derived from adipose tissue are a potentially important source for autologous cell therapy and disease modeling, given fat tissue accessibility and abundance. Critical to developing standard protocols for therapeutic use is a thorough understanding of their potential, and whether this is consistent among individuals, hence, could be generally inferred. Such information is still lacking, particularly in children. To address these issues, we have used different methods to establish stem cells from adipose tissue (adipose-derived stem cells [ADSCs], adipose explant dedifferentiated stem cells [AEDSCs]) from several pediatric patients and investigated their phenotype and differentiation potential using monolayer and micromass cultures. We have also addressed the overlooked issue of selective induction of cartilage differentiation. ADSCs/AEDSCs from different patients showed a remarkably similar behavior. Pluripotency markers were detected in these cells, consistent with ease of reprogramming to induced pluripotent stem cells. Significantly, most ADSCs expressed markers of tissue-specific commitment/differentiation, including skeletogenic and neural markers, while maintaining a proliferative, undifferentiated morphology. Exposure to chondrogenic, osteogenic, adipogenic, or neurogenic conditions resulted in morphological differentiation and tissue-specific marker upregulation. These findings suggest that the ADSC "lineage-mixed" phenotype underlies their significant plasticity, which is much higher than that of chondroblasts we studied in parallel. Finally, whereas selective ADSC osteogenic differentiation was observed, chondrogenic induction always resulted in both cartilage and bone formation when a commercial chondrogenic medium was used; however, chondrogenic induction with a transforming growth factor β1-containing medium selectively resulted in cartilage formation. This clearly indicates that careful simultaneous assessment of bone and cartilage differentiation is essential when bioengineering stem cell-derived cartilage for clinical intervention.
    STEM CELLS TRANSLATIONAL MEDICINE 05/2012; 1(5):384-95. DOI:10.5966/sctm.2012-0009 · 3.60 Impact Factor
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    ABSTRACT: Lipofibromatosis is a rare benign fibrofatty tumor of childhood. The typical presentation of this tumor is as a poorly demarcated and slow-growing mass involving the subcutaneous or deep soft tissues. Lipofibromatosis was first described in 2000, and since then, a small number of cases have been reported in the literature. We report a case of a 19-month-old boy who presented with a swelling of the anterior aspect of the right knee since birth, which had increased in size out of proportion with his growth. Magnetic resonance imaging was extremely useful because it showed the lipomatous nature of the mass, narrowing the differential diagnosis to the pediatric fibrofatty soft tissue tumors. The histologic biopsy revealed the specific diagnosis of lipofibromatosis. We describe the radiologic and pathologic features of this entity and discuss the differential diagnosis in a young child with a fat-containing limb mass.
    Journal of Pediatric Surgery 05/2012; 47(5):1028-31. DOI:10.1016/j.jpedsurg.2012.02.009 · 1.31 Impact Factor