Caroline Sewry

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

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Publications (368)1730.53 Total impact

  • C A Sewry
    Neuromuscular Disorders 03/2015; DOI:10.1016/j.nmd.2015.03.009 · 3.13 Impact Factor
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    ABSTRACT: Background: Currently, there is no satisfactory treatment for McArdle disease. Sodium valproate is one of a group of drugs known as histone deacetylase inhibitors (HDACIs) that can affect gene expression by acetylating lysine residues, which in turn has a direct effect on chromatin. A recent clinical trial of the drug in McArdle sheep that were given sodium valproate showed the presence of phosphorylase positive muscle fibres. Aims: The aim of this pilot study is to determine the feasibility of performing a clinical trial of sodium valproate in people with McArdle disease. Methods: 15 subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months. Outcome measurements include cycle ergometry (rating of perceived exertion, oxygen consumption and the respiratory quotient, serum lactate and ammonia levels, maximum heart rate and workload), the number of phosphorylase positive fibres on muscle biopsy pre and post treatment, maximum walking distance measured by the 12 minute walk test, forearm exercise test, blood laboratory parameters, quality of life questionnaire, symptom diary and side effect diary. Results: We expected an improvement in functional capacity in patients treated with sodium valproate in association with an increase in phosphorylase expression in muscle fibres. Conclusion: This pilot study might be the initial step in exploring a novel treatment option for patients with McArdle disease. Funder: Muscular Dystrophy Campaign
    Neuromuscular Disorders 03/2015; 25(S1):S32. · 3.13 Impact Factor
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    ABSTRACT: We present follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame. Copyright © 2015 Elsevier B.V. All rights reserved.
    Neuromuscular Disorders 02/2015; 25(5). DOI:10.1016/j.nmd.2015.02.003 · 3.13 Impact Factor
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    ABSTRACT: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. © 2015 American Academy of Neurology.
    Neurology 01/2015; DOI:10.1212/WNL.0000000000001269 · 8.30 Impact Factor
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    ABSTRACT: Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower ex- tremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible ‘hot spot’ mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that prefer- entially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.
    Brain 01/2015; DOI:10.1093/brain/awu356 · 10.23 Impact Factor
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    ABSTRACT: To assess the natural history of congenital myopathies (CMs) due to different genotypes. Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012. Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling. © 2014 American Academy of Neurology.
    Neurology 11/2014; 84(1). DOI:10.1212/WNL.0000000000001110 · 8.30 Impact Factor
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    ABSTRACT: We formed a multi-institution collaboration in order to compare dystrophin quantification methods, reach a consensus on the most reliable method, and report its biological significance in the context of clinical trials.
    Neurology 10/2014; DOI:10.1212/WNL.0000000000001025 · 8.30 Impact Factor
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    ABSTRACT: McArdle disease is due to an absence of the enzyme muscle glycogen phosphorylase and results in significant physical impairment in humans. We hypothesised that sodium valproate, an HDAC inhibitor, might have the ability to up-regulate the enzyme. We treated McArdle sheep with sodium valproate given enterically at 20-60mg/kg body wt. Compared with untreated control animals, there was increased expression of phosphorylase in muscle fibres. The response was dose dependent and reached a maximum 2 hours after the application and increased with repeated applications. Improvement in mobility could not be demonstrated. These findings suggest that sodium valproate is a potential therapeutic treatment for McArdle disease.
    Neuromuscular Disorders 10/2014; 25(2). DOI:10.1016/j.nmd.2014.10.002 · 3.13 Impact Factor
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    ABSTRACT: Specific antibodies are vital research tools in the fight against neuromuscular disease, but no single antibody can perform all the necessary functions. Over a period of 20 years, we have produced large numbers of well-characterized antibodies for studies of the most common neuromuscular diseases (Duchenne/Becker and Emery-Dreifuss muscular dystrophies, spinal muscular atrophy and myotonic dystrophy). This MDA Monoclonal Antibody (mAb) resource currently contains over 350 different mAbs, including 150 exon-specific dystrophin mAbs. The antibody panels are currently used by the research community (a) for assessing the outcome of gene therapy, cell therapy, drug therapy or oligonucleotide therapy trials (e.g. dystrophin switch-on or alternative splicing) (b) for animal or cellular model systems to look for novel drug treatments (e.g. SMN or utrophin up-regulation) or novel approaches to gene/protein replacement, and (c) for basic research into understanding disease pathogenesis with the eventual aim of discovering novel treatment targets (e.g. muscleblind and msh3 in myotonic dystrophy). All mAbs are freely available for academic research, subject to an agreed form of acknowledgement in any publications. We now describe the most recent additions to the resource, including new mAbs against nebulin and nesprins 1 and 2. Technical advice freely available from the resource, including datasheets and protocols for producing and applying mAbs, will also be presented. The resource website can be found at
    Neuromuscular Disorders 10/2014; 24(s 9–10):802. DOI:10.1016/j.nmd.2014.06.041 · 3.13 Impact Factor
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    ABSTRACT: We generated a novel monoclonal antibody, DAG-6F4, against alpha-dystroglycan which immunolabels the sarcolemma in human muscle biopsies. Its seven amino-acid epitope, PNQRPEL, was identified using phage-displayed peptides and is located immediately after the highly-glycosylated mucin domain of alpha-dystroglycan. On Western blots of recombinant alpha-dystroglycan, epitope accessibility was reduced, but not entirely prevented, by glycosylation. DAG-6F4 immunolabelling was markedly reduced in muscle biopsies from Duchenne muscular dystrophy patients consistent with disruption of the dystroglycan complex. In a range of dystroglycanopathy patients with reduced/altered glycosylation, staining by DAG-6F4 was often less reduced than staining by IIH6 (antibody against the glycan epitope added by LARGE and commonly used to identify glycosylated alpha-dystroglycan). Whereas IIH6 was reduced in all patients, DAG-6F4 was hardly changed in a LARGE patient, less reduced than IIH6 in limb-girdle muscular dystrophy type 2I, but as reduced as IIH6 in some congenital muscular dystrophy patients. Although absence of the LARGE-dependent laminin-binding site appears not to affect alpha-dystroglycan stability at the sarcolemma, the results suggest that further reduction in aDG glycosylation may reduce its stability. These studies suggest that DAG-6F4 may be a useful addition to the antibody repertoire for evaluating the dystroglycan complex in neuromuscular disorders.
    Neuromuscular Disorders 09/2014; 25(1). DOI:10.1016/j.nmd.2014.09.005 · 3.13 Impact Factor
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    ABSTRACT: We report an eleven year old girl with early motor difficulties initially diagnosed with a peripheral neuropathy in another hospital based on abnormal electrophysiological findings. Our clinical assessment did not highlight obvious clinical features supporting a peripheral neuropathy but evidence of mild proximal weakness. Electrophysiological studies performed at our hospital revealed evidence of a sensorimotor demyelinating polyneuropathy with possible axonal involvement. Brain MRI revealed subtle white matter signal abnormalities, interpreted as nonspecific. Given the patient’s proximal weakness and a mildly elevated serum creatine kinase, we performed a muscle biopsy. The muscle had mildly dystrophic features and subtly depleted laminin α2 expression. There was diffusely upregulated laminin α5 expression, and depletion of laminin α2 in intramuscular motor nerves, which made us suspect a partial laminin α2 (merosin) deficiency. Muscle MRI showed predominant posterior and medial compartments involvement. The patient was found to have autosomal recessively inherited double heterozygous LAMA2 mutations. This case illustrates the mild end of the partial merosin deficiency phenotypic spectrum, and highlights how careful assessment of laminin α2 expression in intramuscular motor nerves can be a helpful diagnostic clue in partial merosin deficiency.
    Neuromuscular Disorders 08/2014; 24(8). DOI:10.1016/j.nmd.2014.05.008 · 3.13 Impact Factor
  • Caroline A Sewry, Hans H Goebel
    Neuromuscular Disorders 08/2014; DOI:10.1016/j.nmd.2014.07.007 · 3.13 Impact Factor
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    ABSTRACT: The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but CMS genetic screening was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, with a partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this.
    Neuromuscular Disorders 08/2014; 24(8). DOI:10.1016/j.nmd.2014.05.003 · 3.13 Impact Factor
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    ABSTRACT: Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anti-cholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission.
    Neuromuscular Disorders 07/2014; DOI:10.1016/j.nmd.2014.07.005 · 3.13 Impact Factor
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    ABSTRACT: Nesprin-1-giant and nesprin-2-giant regulate nuclear positioning by the interaction of their C-terminal KASH domains with nuclear membrane SUN proteins and their N-terminal calponin-homology domains with cytoskeletal actin. A number of short isoforms lacking the actin-binding domains are produced by internal promotion. We have evaluated the significance of these shorter isoforms using quantitative RT-PCR and western blotting with site-specific monoclonal antibodies. Within a complete map of nesprin isoforms, we describe two novel nesprin-2 epsilon isoforms for the first time. Epsilon isoforms are similar in size and structure to nesprin-1-alpha. Expression of nesprin isoforms was highly tissue-dependent. Nesprin-2-epsilon-1 was found in early embryonic cells, while nesprin-2-epsilon-2 was present in heart and other adult tissues, but not skeletal muscle. Some cell lines lack shorter isoforms and express only one of the two nesprin genes, suggesting that either of the giant nesprins is sufficient for basic cell functions. For the first time, localisation of endogenous nesprin away from the nuclear membrane was shown in cells where removal of the KASH domain by alternative splicing occurs. By distinguishing between degradation products and true isoforms on western blots, it was found that previously-described beta and gamma isoforms are expressed either at only low levels or with a limited tissue distribution. Two of the shortest alpha isoforms, nesprin-1-alpha-2 and nesprin-2-alpha-1, were found almost exclusively in cardiac and skeletal muscle and a highly conserved and alternatively-spliced exon, available in both nesprin genes, was always included in these tissues. These "muscle-specific" isoforms are thought to form a complex with emerin and lamin A/C at the inner nuclear membrane and mutations in all three proteins cause Emery-Dreifuss muscular dystrophy and/or inherited dilated cardiomyopathy, disorders in which only skeletal muscle and/or heart are affected.
    PLoS ONE 04/2014; 9(4):e94380. DOI:10.1371/journal.pone.0094380 · 3.53 Impact Factor
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    ABSTRACT: The current pathological diagnostic criteria for sporadic inclusion body myositis (IBM) lack sensitivity. Using immunohistochemical techniques abnormal protein aggregates have been identified in IBM, including some associated with neurodegenerative disorders. Our objective was to investigate the diagnostic utility of a number of markers of protein aggregates together with mitochondrial and inflammatory changes in IBM. Retrospective cohort study. The sensitivity of pathological features was evaluated in cases of Griggs definite IBM. The diagnostic potential of the most reliable features was then assessed in clinically typical IBM with rimmed vacuoles (n=15), clinically typical IBM without rimmed vacuoles (n=9) and IBM mimics-protein accumulation myopathies containing rimmed vacuoles (n=7) and steroid-responsive inflammatory myopathies (n=11). Specialist muscle services at the John Radcliffe Hospital, Oxford and the National Hospital for Neurology and Neurosurgery, London. Individual pathological features, in isolation, lacked sensitivity and specificity. However, the morphology and distribution of p62 aggregates in IBM were characteristic and in a myopathy with rimmed vacuoles, the combination of characteristic p62 aggregates and increased sarcolemmal and internal major histocompatibility complex class I expression or endomysial T cells were diagnostic for IBM with a sensitivity of 93% and specificity of 100%. In an inflammatory myopathy lacking rimmed vacuoles, the presence of mitochondrial changes was 100% sensitive and 73% specific for IBM; characteristic p62 aggregates were specific (91%), but lacked sensitivity (44%). We propose an easily applied diagnostic algorithm for the pathological diagnosis of IBM. Additionally our findings support the hypothesis that many of the pathological features considered typical of IBM develop later in the disease, explaining their poor sensitivity at disease presentation and emphasising the need for revised pathological criteria to supplement the clinical criteria in the diagnosis of IBM.
    BMJ Open 04/2014; 4(4):e004552. DOI:10.1136/bmjopen-2013-004552 · 2.06 Impact Factor
  • Neuromuscular Disorders 03/2014; 24:S27. DOI:10.1016/S0960-8966(14)70091-4 · 3.13 Impact Factor
  • Neuromuscular Disorders 03/2014; 24:S11. DOI:10.1016/S0960-8966(14)70033-1 · 3.13 Impact Factor
  • Neuromuscular Disorders 03/2014; 24:S11. DOI:10.1016/S0960-8966(14)70032-X · 3.13 Impact Factor
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    ABSTRACT: Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great clinical and genetic heterogeneity so that achieving an accurate genetic diagnosis has become increasingly challenging, even in the age of next generation sequencing. In this document we review the diagnostic features, differential diagnostic considerations and available diagnostic tools for the various CMD subtypes and provide a systematic guide to the use of these resources for achieving an accurate molecular diagnosis. An International Committee on the Standard of Care for Congenital Muscular Dystrophies composed of experts on various aspects relevant to the CMDs performed a review of the available literature as well as of the unpublished expertise represented by the members of the committee and their contacts. This process was refined by two rounds of online surveys and followed by a three-day meeting at which the conclusions were presented and further refined. The combined consensus summarized in this document allows the physician to recognize the presence of a CMD in a child with weakness based on history, clinical examination, muscle biopsy results, and imaging. It will be helpful in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis.
    Neuromuscular Disorders 01/2014; DOI:10.1016/j.nmd.2013.12.011 · 3.13 Impact Factor

Publication Stats

10k Citations
1,730.53 Total Impact Points


  • 2008–2014
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Dubowitz Neuromuscular Centre (DNC)
      Londinium, England, United Kingdom
    • Royal Holloway, University of London
      • Department of Biological Sciences
      Эгхем, England, United Kingdom
  • 2000–2014
    • Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust
      Oswestry, England, United Kingdom
  • 2008–2013
    • University College London
      • Institute of Child Health
      Londinium, England, United Kingdom
  • 2012
    • Barts Cancer Institute
      Londinium, England, United Kingdom
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 2011
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • University of Helsinki
      • Folkhälsan Institute of Genetics and Department of Medical Genetics
      Helsinki, Province of Southern Finland, Finland
    • London Health Sciences Centre
      London, Ontario, Canada
    • King's College London
      • Department of Clinical Neuroscience
      London, ENG, United Kingdom
  • 2010
    • University of Chicago
      • Department of Human Genetics
      Chicago, Illinois, United States
    • Institute for Child Health Policy (ICHP)
      اورموند بيتش، فلوريدا, Florida, United States
    • University of Cape Town
      • Department of Child and Adolescent Health
      Cape Town, Province of the Western Cape, South Africa
  • 2007–2008
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 1999–2008
    • Imperial College London
      • • Section of Paediatrics
      • • Faculty of Medicine
      Londinium, England, United Kingdom
    • Kuopio University Hospital
      Kuopio, Northern Savo, Finland
  • 2006
    • Ospedale Pediatrico Bambino Gesù
      Roma, Latium, Italy
  • 2004–2006
    • University Hospital Essen
      • Institute of Physiological Chemistry
      Essen, North Rhine-Westphalia, Germany
    • University of Ferrara
      Ferrare, Emilia-Romagna, Italy
    • Royal Perth Hospital
      Perth City, Western Australia, Australia
  • 1994–2005
    • University of Oxford
      Oxford, England, United Kingdom
    • University of Iowa
      Iowa City, Iowa, United States
    • Cornell University
      Итак, New York, United States
  • 1987–2005
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 2003
    • Ministry of Health (Israel)
      Yerushalayim, Jerusalem District, Israel
  • 1996–1999
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom
    • University of Florence
      Florens, Tuscany, Italy
  • 1998
    • University of Greifswald
      Griefswald, Mecklenburg-Vorpommern, Germany
    • University of Pavia
      Ticinum, Lombardy, Italy
  • 1993–1997
    • Royal Berkshire NHS Foundation Trust
      Reading, England, United Kingdom
  • 1995
    • International Centre for Genetic Engineering and Biotechnology
      Trst, Friuli Venezia Giulia, Italy
  • 1985–1995
    • University of London
      Londinium, England, United Kingdom