A J Lees

UCL Eastman Dental Institute, Londinium, England, United Kingdom

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Publications (342)2994.74 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), β-amyloid 1-42 (Aβ42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and β (soluble amyloid precursor protein (sAPP)α, sAPPβ) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies. 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.
    Journal of Neurology Neurosurgery & Psychiatry 01/2015; DOI:10.1136/jnnp-2014-309562 · 6.81 Impact Factor

  • Journal of Neurology Neurosurgery & Psychiatry 02/2012; 83(3):e1-e1. DOI:10.1136/jnnp-2011-301993.40 · 6.81 Impact Factor

  • Journal of Neurology Neurosurgery & Psychiatry 02/2012; 83(3):e1-e1. DOI:10.1136/jnnp-2011-301993.162 · 6.81 Impact Factor

  • Journal of Neurology Neurosurgery & Psychiatry 02/2012; 83(3):e1-e1. DOI:10.1136/jnnp-2011-301993.161 · 6.81 Impact Factor
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    ABSTRACT: Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.
    NeuroImage 02/2012; 59(3):2035-44. DOI:10.1016/j.neuroimage.2011.10.016 · 6.36 Impact Factor
  • Y. Asi · Z. Ahmed · A.J. Lees · T. Revesz · J.L. Holton ·

    Parkinsonism & Related Disorders 01/2012; 18:S43. DOI:10.1016/S1353-8020(11)70247-4 · 3.97 Impact Factor
  • E H Reynolds · D G Healy · A J Lees ·
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    ABSTRACT: Through Edward Reynolds' collaboration with Samuel Alexander Kinnier Wilson's (SAKW) son, James, on Babylonian neurology and psychiatry, and his contact with James' nephew, Jim, grandson of SAKW, a remarkable film of patients with movement disorders, made by SAKW in the mid-1920s, has come to light. The 20-min silent film with captions by SAKW includes patients with senile tremor, Parkinson's disease and postencephalitic parkinsonism, hemiballismus, Huntington's chorea, Sydenham's chorea, hysterical palsy and tremor, multiple sclerosis, and progressive lenticular degeneration. Most of the patients are filmed in the square outside the National Hospital. The British Film Institute dates the film to 1924 and the captions to 1925. The case records of 6 of the 14 patients, who were admitted to the National Hospital, Queen Square, under the care of Dr. SAKW have been identified and summarized. SAKW may have been stimulated and facilitated to make this film through his personal contact with Charlie Chaplin with whom he stayed at his Californian estate, probably in the summer of 1924. The first films of neurological patients were made in Europe and USA at the beginning of the 20th century, although most have perished. This may be one of the oldest examples from UK. It is also notable for the inclusion of Wilson's disease and a brief shot of SAKW himself.
    Movement Disorders 12/2011; 26(14):2453-9. DOI:10.1002/mds.23536 · 5.68 Impact Factor
  • Z Ahmed · Y.T. Asi · A Sailer · A.J. Lees · H Houlden · T Revesz · J.L. Holton ·
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    ABSTRACT: Z. Ahmed, Y. T. Asi, A. Sailer, A. J. Lees, H. Houlden, T. Revesz and J. L. Holton (2012) Neuropathology and Applied Neurobiology38, 4–24 The neuropathology, pathophysiology and genetics of multiple system atrophy Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies, due to the presence of abnormal α-synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.
    Neuropathology and Applied Neurobiology 11/2011; 38(1):4-24. DOI:10.1111/j.1365-2990.2011.01234.x · 3.93 Impact Factor
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    ABSTRACT: Several in vitro studies have suggested levodopa (L-dopa) to be toxic to dopaminergic neurons and that it can modulate the aggregation process of α-synuclein. We investigated the relationship between cumulative lifetime dose of l-dopa and nigral neuronal count and Lewy body (LB) pathology in Parkinson disease (PD). Density of pigmented neurons was measured unilaterally in a single section of substantia nigra (SN) with delineation of the dorsal and ventral tiers in 96 cases of PD with well-documented clinical records relating to antiparkinsonian drug treatment. Cortical and nigral LB densities were determined using a morphometric approach. Mean lifetime dose of L-dopa correlated significantly (p < 0.001) with duration of PD in the entire study population (n = 96) and it was not possible to disentangle their individual effect. This was not the case in a subgroup analysis of younger onset patients with a longer duration of PD (n = 40) who showed no significant correlation between L-dopa and total SN neuronal density (p = 0.07), after adjustment for duration of illness. There was, however, a lower neuronal density in the ventral (p = 0.02) but not in the dorsal (p = 0.27) tier detected with the cumulative dose of L-dopa. We found no difference in L-dopa dose between Braak PD stages (p = 0.58). Furthermore, the subgroup analysis showed no relationship of L-dopa dose to either cortical (p = 0.47) or nigral (p = 0.48) LB density. Chronic use of L-dopa in PD does not enhance progression of PD pathology as far as can be determined by our observations with SN neuronal counts and LB densities.
    Neurology 09/2011; 77(15):1420-6. DOI:10.1212/WNL.0b013e318232ab4c · 8.29 Impact Factor
  • L Silveira-Moriyama · A J Lees ·

    Neurology 07/2011; 77(4):310-1. DOI:10.1212/WNL.0b013e318227065d · 8.29 Impact Factor
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    ABSTRACT: Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post-mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real-time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi-quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD.
    Neuropathology and Applied Neurobiology 06/2011; 37(7):777-90. DOI:10.1111/j.1365-2990.2011.01187.x · 3.93 Impact Factor
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    ABSTRACT: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10 −3 . We found significant previously unidentified signals (P < 5 × 10 −8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. PSP is a rare neurodegenerative movement disorder clinically char­ acterized by falls, axial rigidity, vertical supranuclear gaze palsy, bradykinesia and cognitive decline. Though PSP is rare (with a prevalence of 3.1–6.5 per 100,000 people 1), after Parkinson's disease, PSP is the second most common cause of degenerative parkinsonism 2 . PSP is a tauopathy with abnormal accumulation of tau protein within neurons as neurofibrillary tangles, primarily in the basal ganglia, diencephalon and brainstem, with neuronal loss in the globus pallidus, subthalamic nucleus and substantia nigra. Abnormal tau also accumulates within oligodendroglia and astrocytes 3 . In Alzheimer's disease, even though all affected indivi­ duals have neurofibrillary tangles, Aβ plaques are closely tied to the primary disease process, and, thus, Alzheimer's disease is a sec­ ondary tauopathy. PSP is a primary tauopathy because tau is the major abnormal protein observed. Both environmental insults and inherited factors contribute to the risk of developing tauopathies 4 . Repetitive brain trauma, associated with certain sports, can cause Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy
    Nature Genetics 06/2011; 43(7):699. · 29.35 Impact Factor
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    ABSTRACT: The transcription factor ΔFosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and ΔFosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/ΔFosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/ΔFosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/ΔFosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/ΔFosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of ΔFosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
    Journal of Parkinson's Disease 01/2011; 1(4):347-57. DOI:10.3233/JPD-2011-11068 · 1.91 Impact Factor
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    ABSTRACT: Background Although conventional MRI (cMRI) has been reported to show specific abnormalities in parkinsonism, the diagnosis of the underlying pathology can be challenging. We report the radiological diagnostic accuracy, and the sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of cMRI abnormalities in a pathologically confirmed cohort of Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal degeneration (CBD). Method cMRI of donors to a neurological brain bank was reviewed by two experienced neuroradiologists blinded to clinical details. Images were systematically reviewed for the presence of specific reported abnormalities. Results 48 pathologically confirmed cases (23 PSP, 6 PD, 13 MSA and 6 CBD) and nine controls were studied. The final clinical diagnosis was supported in 68% and the radiological diagnosis in 60%. Using cMRI 55% of PSP, 67% of PD, and 77% of MSA were correctly identified. In this study the Hummingbird sign has 68% sensitivity, 100% specificity and PPV for PSP and the Hot Cross Bun has 62% sensitivity, 100% specificity and PPV for MSA. Conclusion The confirmation that using cMRI key diagnostic features with very high specificity and PPV have low sensitivity endorses the development of newer MR techniques (e.g., high field diffusion tensor imaging) as useful biomarkers early in disease.
    Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e57. DOI:10.1136/jnnp.2010.226340.161 · 6.81 Impact Factor
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    ABSTRACT: Approximately 10% of patients diagnosed clinically with early Parkinson's disease (PD) have normal dopaminergic functional imaging (SWEDDs-scans without evidence of dopaminergic deficit). A subgroup of SWEDDs are those with asymmetric tremor resembling parkinsonian tremor. Clinical and pathophysiological features which could help distinguish SWEDDs from PD have not been explored. We therefore studied clinical details in 25 tremulous SWEDDs patients in comparison to 25 tremor-dominant. Electrophysiological tremor parameters and response to a cortical plasticity protocol using paired associative stimulation (PAS) was studied in nine patients with SWEDDs, nine with PD, eight with segmental dystonia and eight with essential tremor (ET). Despite clinical overlap, lack of true bradykinesia, presence of dystonia, and head tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs and presence of nonmotor symptoms favoured PD. The combination of re-emergent tremor and highest tremor amplitude at rest was characteristic of PD tremor. SWEDDs and segmental dystonia patients exhibited an exaggerated response to the PAS protocol, in contrast to a subnormal response in PD and a normal response in ET. We conclude that despite clinical overlap, there are features that can help distinguish between PD and SWEDDs. The underlying pathophysiology of SWEDDs differs from PD but has similarities with primary dystonia.
    Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e22. DOI:10.1136/jnnp.2010.226340.22 · 6.81 Impact Factor
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    ABSTRACT: A 63-year old male presented with a 3-year history of worsening mobility due to difficulty maintaining balance and deterioration in his hearing. He had a past medical history of ankylosing spondylitis treated with radiotherapy and NSAIDs. Cranial nerve examination revealed anosmia, bidirectional gaze-evoked nystagmus and jerky pursuit eye movements. Hearing and taste were impaired and his speech was slurred. He had gross truncal ataxia, an unsteady wide-based gait and bilateral Babinski reflexes. Otological testing revealed sensorineural deafness and absent acoustic brain stem evoked responses. Vestibular assessment confirmed bilateral vestibular failure (positive Halmagyi head thrust test and absent caloric responses). T2-weighted MRI was diagnostic; it illustrated low signal along the surface of the cerebellar folia, the brainstem, throughout the Sylvian fissure, the midline sagittal sulcus and along the length of the spinal cord. This was in keeping with haemosiderin deposition and a diagnosis of superficial siderosis. Despite full cerebral and spinal angiography and venography no source of bleeding was found. The patient was started on Trientine chelation therapy. Superficial siderosis has never previously been reported in conjunction with ankylosing spondylitis (AS). The possible underlying mechanism may be AS-associated dural ectasia with inflamed meningitic vessels prone to chronic venous bleeding (Abstract POC08 Figure 1). Abstract POC08 Figure 1.
    Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e36-7. DOI:10.1136/jnnp.2010.226340.78 · 6.81 Impact Factor
  • Z Ahmed · S J Tabrizi · A Li · H Houlden · A Sailer · A J Lees · T Revesz · J L Holton ·

    Neuropathology and Applied Neurobiology 05/2010; 36(6):551-7. DOI:10.1111/j.1365-2990.2010.01093.x · 3.93 Impact Factor

  • BMJ (online) 03/2010; 340:c1213. DOI:10.1136/bmj.c1213 · 17.45 Impact Factor
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    ABSTRACT: We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.
    Brain 09/2009; 132(Pt 11):2947-57. DOI:10.1093/brain/awp234 · 9.20 Impact Factor
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    ABSTRACT: We performed a mutation screen of NR4A2 (also known as NURR1) in 409 Parkinson's disease (PD) patients. We identified a novel single base substitution in the 5'UTR of the NR4A2 (also known as NURR1) gene (c.-309C>T). We have performed expression studies in neuronal cell lines showing that the c.-309C>T mutation reduces NR4A2 mRNA expression in vitro. We have confirmed this finding in vivo by performing allele specific real-time PCR from brain tissue harbouring the 309C>T mutation and show a 3.48+/-1.62 fold reduction in mRNA expression of the mutant allele compared to wild-type. In addition we have undertaken genome wide expression analysis of the mutant NR4A2 brain and shown underexpressed genes were significantly enriched for gene ontology categories in nervous system development and synaptic transmission and overexpressed genes were enriched for unfolded protein response and morphogenesis. Lastly we have shown that the c.-309C>T mutation abrogates the protective effect of wild-type NR4A2 against apoptopic stress. Our findings indicate the c.-309C>T mutation reduces NR4A2 expression resulting in the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission. These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation.
    Neuroscience Letters 07/2009; 457(2):75-9. DOI:10.1016/j.neulet.2009.03.021 · 2.03 Impact Factor

Publication Stats

30k Citations
2,994.74 Total Impact Points


  • 2008-2015
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2010
    • Bank of England
      Londinium, England, United Kingdom
  • 1991-2008
    • University College London
      • • Institute of Neurology
      • • Department of Molecular Neuroscience
      • • Department of Epidemiology and Public Health
      Londinium, England, United Kingdom
    • Middlesex University, UK
      Londinium, England, United Kingdom
    • New South Wales Institute of Psychiatry
      Sydney, New South Wales, Australia
  • 2002-2004
    • University of London
      • The School of Pharmacy
      Londinium, England, United Kingdom
  • 1992-2003
    • London Research Institute
      Londinium, England, United Kingdom
  • 1986-2001
    • Middlesex Hospital
      मिडलटाउन, Connecticut, United States
  • 2000
    • Saint Mary's Hospital Center
      Montréal, Quebec, Canada
  • 1995
    • Ljubljana University Medical Centre
      Lubliano, Ljubljana, Slovenia
    • University College London Hospitals NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1994
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1993
    • Repatriation General Hospital
      Tarndarnya, South Australia, Australia
  • 1990
    • King's College London
      Londinium, England, United Kingdom
  • 1989
    • Institute of Psychiatry, Kolkata
      Kolkata, West Bengal, India
    • St. Mark's Hospital
      Harrow i London, England, United Kingdom
  • 1985
    • The Whittington Hospital NHS Trust
      Londinium, England, United Kingdom