Sejal Saglani

Imperial College London, Londinium, England, United Kingdom

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Publications (78)609.35 Total impact

  • Clare M Lloyd, Sejal Saglani
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    ABSTRACT: The triad of epithelial derived cytokines, IL-25, IL-33 and TSLP are important for the initiation and development of pulmonary immune responses to environmental stimuli. Data from experiments using mouse models provide compelling evidence for their involvement in both innate and adaptive immunity to drive type-2 responses, allergic inflammation and airway remodelling. These cytokines are known to be expressed in human lung tissue and immune cells, however their involvement in mediating allergic pulmonary responses in patients is less clear than in murine models of disease. This article focuses on evidence for the role of IL-25, IL-33 and TSLP in human allergic disease and discusses their potential as therapeutic targets for severe asthma. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current Opinion in Immunology 06/2015; 34. DOI:10.1016/j.coi.2015.02.001 · 7.87 Impact Factor
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    ABSTRACT: Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model. Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age. Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels. Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 04/2015; DOI:10.1136/thoraxjnl-2014-205280 · 8.56 Impact Factor
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    ABSTRACT: The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence. Copyright ©ERS 2015.
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    ABSTRACT: The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13(+) innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13(+) ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2(-/-) mice lacking a functional receptor for IL-33. Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 01/2015; 179. DOI:10.1016/j.jaci.2014.11.039 · 11.25 Impact Factor
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    Journal of Allergy and Clinical Immunology 11/2014; 135(3). DOI:10.1016/j.jaci.2014.09.044 · 11.25 Impact Factor
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    ABSTRACT: Associations between early deficits of lung function, infant airway disease, and outcome at school age in symptomatic infants are still unclear. To report follow-up data on a unique cohort of children investigated invasively in infancy to determine predictive value of airway disease for school-aged respiratory outcomes. Fifty-three infants previously studied using bronchoscopy and airway conductance were approached at 8 years of age. Symptoms, lung volumes, and airway responsiveness were reassessed. Data on lifetime purchase of asthma medication were obtained. Lung function was compared with that of 63 healthy nonasthmatic children. Forty-seven children were reevaluated. Physician-diagnosed asthma was present in 39 children (83%). Twenty-five children (53%) had current and 14 children (30%) had past asthma. No pathologic feature in infancy correlated with any outcome parameter. As expected, study children had significantly reduced lung function and increased airway responsiveness compared with healthy controls, and very early symptoms were risk factors for reduced lung function. Current asthma was associated with reduced infant lung function and parental asthma. Reduced lung function in infancy was associated with purchase of inhaled corticosteroids when 6 to 8 and 0 to 8 years of age. The lack of predictive value of any pathologic measure in infancy, reported here for the first time to our knowledge, demonstrates that pathologic processes determining the inception of asthma, which are as yet undescribed, are different from the eosinophilic inflammation associated with ongoing disease. Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 10/2014; 114(2). DOI:10.1016/j.anai.2014.09.019 · 2.75 Impact Factor
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    ABSTRACT: Few data are available about the inflammatory cytokine profile of bronchoalveolar lavage (BAL) from young children with frequent wheeze. The first aim was to investigate the BAL cellular and cytokine profiles in infants with recurrent lower respiratory symptoms in whom bronchoscopy was indicated for clinical symptom evaluation. The second aim was to relate the BAL results with the histological findings of the endobronchial carina biopsies. Thirty-nine infants (median age 0.9 years) underwent lung function testing by whole-body plethysmography prior to the bronchoscopy. The BAL differential cell counts and cytokine levels were quantified. These findings were compared with the histological findings of the endobronchial carina biopsies. The differential cytology reflected mainly that described for healthy infants with lymphocyte counts at the upper range level. A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement membrane was found. Detectable levels of pro-inflammatory cytokine proteins IL-1β, IL-17A, IL-18, IL-23, and IL-33 were found, whereas levels of Th2-type cytokine proteins were low. Frequent wheeze was the only clinical characteristic significantly related to detectable combined pro-inflammatory cytokine profile. Lung function did not correlate with any cytokine. A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement thickness was found. Detectable production of pro-inflammatory cytokines associated positively with frequent wheeze.
    10/2014; 4:35. DOI:10.1186/2045-7022-4-35
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    ABSTRACT: Background Associations between vitamin D status and childhood asthma are increasingly reported, but direct causation and mechanisms underlying an effect remain unknown. We investigated the effect of early-life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD). Methods In utero and early-life vitamin D deficiency was achieved using a vitamin D-deficient diet for female mice during the third trimester of pregnancy and lactation. Offspring were weaned onto a vitamin D-deficient or vitamin D-replete diet, and exposure to intranasal house dust mite (HDM) or saline was commenced from day 3 of life for up to 6weeks, when airway hyper-responsiveness (AHR), airway inflammation and remodelling were assessed. ResultsNeonatal mice that had in utero and early-life vitamin D deficiency had significantly increased pulmonary CD3(+)CD4(+)T1ST2(+) cells and reduced CD4(+)IL-10(+) cells. This effect was enhanced following HDM exposure. AHR in HDM-exposed mice was unaffected by vitamin D status. Introduction of vitamin D into the diet at weaning resulted in a significant reduction in serum IgE levels, reduced pulmonary eosinophilia and peri-bronchiolar collagen deposition. Conclusion Peri-natal vitamin D deficiency alone has immunomodulatory effects including Th2 skewing and reduced IL-10-secreting T regulatory cells, exaggerated with additional allergen exposure. Vitamin D deficiency in early life does not affect AHR, but contributes to disease severity with worse eosinophilic inflammation and airway remodelling. Importantly, supplementation with vitamin D improves both of these pathological abnormalities.
    Allergy 06/2014; 69(10). DOI:10.1111/all.12465 · 6.00 Impact Factor
  • Sejal Saglani
    Thorax 05/2014; 69(10). DOI:10.1136/thoraxjnl-2014-205561 · 8.56 Impact Factor
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    ABSTRACT: Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.
    Nature medicine 05/2014; 20(6). DOI:10.1038/nm.3568 · 28.05 Impact Factor
  • Andrew Bush, Jonathan Grigg, Sejal Saglani
    BMJ (online) 02/2014; 348:g15. DOI:10.1136/bmj.g15 · 16.38 Impact Factor
  • Sejal Saglani, Clare M Lloyd
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    ABSTRACT: The importance and functional contribution of eosinophils to the pathogenesis of severe asthma was questioned when adult studies reported neutrophilic inflammation and Th17 cells were central to disease. Eosinophilic inflammation, atopic sensitization and airway remodelling are the hallmark features of severe asthma in children. Contrary to adult reports, neutrophils, Th17 and Th2 cytokines are rarely detected in children with severe disease who are prescribed high-dose steroids. Type 2 innate lymphoid cells (ILCs), which are induced by the epithelial cytokine interleukin (IL)-33, and also release the Th2 cytokines IL-5 and IL-13, have been shown to be important in mediating asthma, and specifically, ILCs have a role in mediating eosinophil homeostasis. A direct link between IL-33, airway remodelling and steroid resistance in paediatric severe asthma suggests the steroid-resistant eosinophilia may be mediated by ILCs rather than classical Th2 lymphocytes. Data from children with severe asthma have shown that findings from adults cannot be translated to children, and that steroid-resistant eosinophilic inflammation appears central to the pathogenesis of paediatric disease. Age-appropriate experimental models and use of airway samples from children are critical to understanding the underlying mechanisms and identifying novel therapeutic targets.
    Current Opinion in Allergy and Clinical Immunology 02/2014; DOI:10.1097/ACI.0000000000000045 · 3.66 Impact Factor
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    ABSTRACT: Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children. Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1α,25-dihydroxyvitamin D3. Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p<0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p<0.001) and decreasing IL-13 (p<0.001) but unexpectedly enhanced IL-17A production in all groups-most strikingly in the STRA cohort (p<0.001). The inclusion of the active form of vitamin D, 1α,25-dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p<0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p<0.01). These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA.
    Thorax 12/2013; 69(6). DOI:10.1136/thoraxjnl-2013-203421 · 8.56 Impact Factor
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    ABSTRACT: Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.
    Allergy 12/2013; 68(12):1520-31. DOI:10.1111/all.12275 · 6.00 Impact Factor
  • Thorax, A115; 11/2013
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    Clare M Lloyd, Sejal Saglani
    Nature medicine 08/2013; 19(8):976-7. DOI:10.1038/nm.3296 · 28.05 Impact Factor
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    Sejal Saglani
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    ABSTRACT: Viral aetiology, host susceptibility (in particular allergic predisposition and sensitization), and illness severity, timing and frequency all appear to contribute as synergistic factors to the risk of developing asthma. Experimental models have shown both innate and adaptive immune responses contribute to this risk with lung inflammatory cells showing marked differences in phenotype and function in young compared with older animals, and these differences are further enhanced following virus infection. Findings to date strongly suggest that the impact of infant and preschool viral infections on the maturing immune system and developing lung that subsequently result in an asthma phenotype occur during a critical susceptibility period, and in a genetically susceptible host. There are currently no therapeutic strategies that allow primary or secondary prevention of asthma following early life viral respiratory infections in high-risk children, thus a focus on understanding the mechanisms of progression from viral wheezing in infants and preschool children to asthma development are urgently needed. This review summarizes the data reporting the role of the two most common viruses, that is, respiratory syncytial virus and human rhinovirus, that result in asthma development, comparing risk factors for disease progression, and providing insight into strategies that might be adopted to prevent asthma development.
    08/2013; 1(4):139-150. DOI:10.1177/2049936113497202
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    ABSTRACT: BACKGROUND: TH2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown. OBJECTIVE: We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. METHODS: IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2(-/-) mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified. RESULTS: Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2(-/-) mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA. CONCLUSION: IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
    The Journal of allergy and clinical immunology 06/2013; DOI:10.1016/j.jaci.2013.04.012 · 11.25 Impact Factor
  • Alexandra Adams, Sejal Saglani
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    ABSTRACT: Asthma continues to be one of the greatest burdens to healthcare resources throughout the developed world. In most cases, good symptom control can be achieved with low-dose inhaled corticosteroids, and can be cared for in the primary and secondary healthcare systems. However, there is a group in whom control is not achieved despite high-dose inhaled corticosteroids and maximal add-on therapies; these are children with problematic severe asthma that should be referred to a specialist team for further investigation and management. In this review we aimed to provide an evidence-based guide for pediatricians providing care for children with asthma in secondary healthcare settings. The review focuses on a proposed investigation and management strategy for children aged between 6 and 16 years with problematic severe asthma, and is supported as far as possible by evidence from the literature. We first address recent advances in nomenclature and then discuss our proposed course of investigation and management of these children. Distinction of children with true, severe, therapy-resistant asthma from those with asthma that is difficult to treat because of unaddressed underlying modifiable factors is critical and is discussed in detail.
    Paediatric Drugs 04/2013; 15(3). DOI:10.1007/s40272-013-0025-5 · 1.72 Impact Factor

Publication Stats

1k Citations
609.35 Total Impact Points

Institutions

  • 2005–2015
    • Imperial College London
      • Section of Leukocyte Biology
      Londinium, England, United Kingdom
  • 2004–2014
    • Royal Brompton and Harefield NHS Foundation Trust
      • Department of Paediatrics
      Harefield, England, United Kingdom
    • Royal Berkshire NHS Foundation Trust
      Reading, England, United Kingdom
  • 2012–2013
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 2010
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2006
    • University of Helsinki
      • Department of Pediatrics
      Helsinki, Uusimaa, Finland
  • 2001
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia