M N Sheppard

Royal Brompton and Harefield NHS Foundation Trust, Harefield, England, United Kingdom

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Publications (47)195.37 Total impact

  • Histopathology 12/2008; 53(5):614-7. · 2.86 Impact Factor
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    ABSTRACT: Carcinoid tumours and small cell carcinomas of the lung share many characteristics with normal neuroendocrine cells. While carcinoid tumours contain many dense-cored neurosecretory granules and are frequently argyrophil, small cell carcinomas are poorly granulated and rarely argyrophil, which casts doubt on their neuroendocrine nature. Immunostaining of the enzyme neuron specific enolase (NSE) was recently used to demonstrate the neuroendocrine components of the lung including nerves and neuroendocrine cells. We therefore used NSE immunostaining to investigate neuroendocrine differentiation in 79 lung tumours, including 18 bronchial carcinoids and 31 small cell carcinomas, and compared these results with those obtained with silver stains. Thirteen of the 18 carcinoids were reactive to silver, all other types being negative. NSE-immunoreactivity occurred in 16 carcinoids and 18 small cell carcinomas. None of the squamous cell carcinomas, large cell anaplastic carcinomas and adenocarcinomas examined showed NSE-immucoreactivity. Radioimmunoassay of extractable NSE from 10 fresh lung tumours correlated well with the immunostaining results, demonstrating large amounts in two small cell carcinomas (334 and 517 ng/mg protein) and three carcinoids (152, 908, and 1143 ng/mg protein). Values were much lower for four squamous cell carcinomas (31–44 ng/mg protein) and one large cell anaplastic carcinoma (30 ng/mg protein) and were accounted for by the presence of NSE-positive nerves and neuroendocrine cells in the surrounding lung. NSE immunostaining is a useful marker of neuroendocrine differentiation in lung tumours and should prove particularly valuable in the diagnosis of small cell anaplastic tumours and their metastases.
    Histopathology 04/2007; 8(2):171 - 181. · 2.86 Impact Factor
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    ABSTRACT: We reviewed 45 pulmonary B-cell non-Hodgkin's lymphomas to determine whether their morphology and immunohistochemical features were those of lymphomas arising from mucosa-associated lymphoid tissue (MALT), as described in other sites. The polymerase chain reaction was used to provide further information on clonality. We found that these lymphomas infiltrate the pulmonary interstitium along bronchovascular bundles and interlobular septa, subsequently spilling out into airspaces and finally destroying the alveolar architecture of the lung. Central hyaline sclerosis and vascular infiltration were common features. All lymphomas stained CD20 positive and were accompanied by variable numbers of reactive CD3 positive T-cells. Cytokeratin staining with CAM 5.2 was useful in identifying lymphoepithelial lesions. CD21 staining of follicular dendritic cells revealed germinal centres where they were not recognizable on H & E staining. The polymerase chain reaction was performed on paraffin tissue from 28 patients. Twenty were low grade, of which 12 showed a clonal band and eight stiowed a polyclonal smear pattern. Eight were high grade, of which one revealed a clonal band. Three produced polyclonal smear patterns and four cases were inadequate samples. In one patient who had lymphoma at a second extranodal site, identical bands were identified, evidence for ‘homing’ of lymphoid cells towards mucosal epithelium.
    Histopathology 04/2007; 26(5):395 - 403. · 2.86 Impact Factor
  • A Fletcher, S Y Ho, K P McCarthy, M N Sheppard
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    ABSTRACT: To quantify the variation in fibrosis, fat and muscle within the walls of both ventricles and within the different regions of the heart from six patients dying suddenly of arrhythmogenic right ventricular dysplasia (ARVD) aged 20-60 years. Seven heart regions were examined both macroscopically and histologically using the Picro-Sirius red stain. Quantification of fibrosis, fat and muscle was performed in each region and transmural layer using grid counting. There were macroscopic changes in all examined hearts. A higher percentage of fat with less fibrosis and muscle was observed within the right ventricle of the older patients. The left ventricle had more pathology in the older age group. Statistical differences in pathology in the heart were found. Fat predominated in the epicardial layer in the right and left ventricles of all patients, while the interventricular septum was the least affected. In ARVD, the pathology varies with age in both ventricles, fibrosis being the earliest hallmark of disease, with fatty infiltration evolving later. It should be labelled arrhythmogenic ventricular dysplasia because of biventricular involvement. Histopathologists should therefore sample from whole slices of the heart, so that all the changes can be observed.
    Histopathology 04/2006; 48(4):445-52. · 2.86 Impact Factor
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    A Fabre, M N Sheppard
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    ABSTRACT: To evaluate non-atherosclerotic cardiac deaths in the UK population aged over 15 years including elderly patients and to highlight the concept of the structurally normal heart in sudden death. Pathological data were collected prospectively for sudden adult deaths referred by UK coroners. 453 cases of sudden death from 1994 to 2003 (278 men (61.4%) and 175 women (38.6%), age range 15-81 years) were reviewed. Males predominated in both age groups (< or = 35 years, > 35 years). More than half of the hearts (n = 269, 59.3%) were structurally normal. In the other 40.7%, cardiac abnormalities were noted, which included: (1) cardiomyopathies (23%) such as idiopathic fibrosis, left ventricular hypertrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular dysplasia; (2) inflammatory disorders (8.6%) including lymphocytic myocarditis and cardiac sarcoidosis; (3) non-atheromatous abnormalities of coronary arteries (4.6%); (4) valve diseases; and (5) miscellaneous and rare causes. The concept of the structurally normal heart in sudden death and the need for histological examination to detect underlying disease is highlighted. Relatives need to be referred for cardiological and genetic screening in cases of normal hearts found at necropsy.
    Heart (British Cardiac Society) 03/2006; 92(3):316-20. · 5.01 Impact Factor
  • M.N. Sheppard, A.G. Nicholson
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    ABSTRACT: Cystic fibrosis (CF) is one of the commonest lethal inherited conditions among Caucasians. It affects multiple organ systems and exhibits a range of clinical problems of varying severity. Life expectancy has improved in recent years as treatment regimes have become more intensive, but current treatments are expensive, often time consuming and may affect quality of life. New treatments for the pulmonary disease are under clinical trial and include antiproteases, amiloride, a sodium channel blocker, DNase and gene therapy. The gene for cystic fibrosis was identified in 1989 and this together with the emerging technology of gene therapy heralded a new dawn for the treatment of genetic disease. The lung is considered an ideal organ to target due to ease of access, but subsequent research has shown that the airway surface provides an efficient barrier to topically applied gene transfer agents. A number of Phase I clinical safety trials were carried out through the 1990s and provided proof of concept evidence that delivery of DNA by either viral or non-viral means was safe though not clinically efficacious. Current research is now focusing more on the barriers faced by delivery agents, with the aim that more efficient gene delivery will lead to a gene therapy for cystic fibrosis. The histopathologist is rarely called upon to make the initial diagnosis as cystic fibrosis is usually diagnosed clinically, being characterized by chronic bronchopulmonary infection, malabsorption due to pancreatic insufficiency and a high sweat-sodium concentration on sweat testing. Most information concerning both macroscopic and microscopic findings in cystic fibrosis has come from autopsy studies, so the pathological features are often extreme. However, with increasing survival of patients with cystic fibrosis, we are seeing more subtle changes in other organs and in addition, more aggressive drug therapy, gene therapy and lung transplantation are bringing with them new disease entities and complications.
    Current Diagnostic Pathology. 01/2006;
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    ABSTRACT: The diagnosis of small cell lung carcinoma (SCLC) on bronchial biopsy is often problematical as a result of intense crush artefact. Several antibodies are now available to help in the diagnosis of SCLC and their value was assessed in this clinical situation. Twenty cases of SCLC and 10 control cases (one non-Hodgkin lymphoma, three non-small cell carcinomas, one follicular reactive hyperplasia, and five chronic non-specific inflammations) with extensive crush artefact were stained using antibodies to CD56, MNF116, thyroid transcription factor 1 (TTF-1), and CD45. All SCLCs showed strong positive staining for CD56 in 75-100% of recognisable tumour cells, even in areas where there was extensive crush artefact. Eighteen of 20 cases were positive for TTF-1 and 16 of 20 were positive for MNF116 in the tumour cells, but both of these antibodies showed little or no staining in areas of crush artefact. Control cases comprising lymphoid cells were positive for CD45 in areas of crush artefact, but all cases of SCLC were negative. CD56, along with markers for cytokeratins-TTF-1, and CD45-are useful in the diagnosis of SCLC in biopsies with extensive crush artefact and can help confirm the diagnosis in cases where features are equivocal.
    Journal of Clinical Pathology 10/2005; 58(9):978-80. · 2.44 Impact Factor
  • D K Tansey, Z Aly, M N Sheppard
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    ABSTRACT: Fibrofatty replacement of the right ventricle wall, often with associated inflammation, is the hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare but established cause of sudden cardiac death in young adults. Fatty infiltration of the right ventricle alone without fibrosis may also occur but its relation to sudden death is not well established. In this study we assessed the amount of epicardial and intramyocardial fat in the right ventricle of 'normal' hearts from subjects who had died of non-cardiac causes. Hearts (n = 148) were examined from 81 males and 67 females, with an age range of 6 months to 68 years, who had died of non-cardiac causes. The extent and distribution of right ventricular epicardial and intramyocardial fat was assessed macro- and microscopically, respectively. The majority of hearts (85%) contained at least some intramyocardial fat with significantly more fat replacement noted in the right ventricles of older subjects and in females than in males. There was no significant fibrosis or inflammation in any of the 148 cases. Variable amounts of intramyocardial fat may be seen in the right ventricle of subjects dying of non-cardiac related causes. Care should be taken not to confuse this relatively common simple fatty infiltration with ARVC.
    Histopathology 02/2005; 46(1):98-104. · 2.86 Impact Factor
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    ABSTRACT: A 44-year-old woman presented with poorly controlled asthma and nodular radiological changes. A VATS lung biopsy confirmed talc granulomatous disease possibly related to her previous work as a dental technician. A detailed occupational history is mandatory. Talc granulomatous disease is one important alternative diagnosis in poorly controlled asthma.
    Grand Rounds. 12/2004; 5:1-3.
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    A S John, R H Mohiaddin, M N Sheppard
    Heart (British Cardiac Society) 10/2004; 90(9):1102. · 5.01 Impact Factor
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    Mary N Sheppard
    BMJ (online) 03/2004; 328(7436):406. · 17.22 Impact Factor
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    ABSTRACT: Case history An asymptomatic 8-week-old male infant was referred for assessment. A prenatal ultrasound had been suggestive of a congenital cystic adenomatoid malformation (CCAM). Fol- lowing delivery, he had a plain chest radiograph (fig. 1) and went on to have a computed tomography (CT) scan of the thorax (fig. 2), which showed an extrapulmonary mass close to the vertebral column. He proceeded to have magnetic resonance imaging of the thorax to look for intraspinal extension. The appearances were not anticipated, in that the lesion appeared to be intrapulmonary with no extension into the mediastinum, spinal canal or chest wall. The diaphragm was reported as being intact and separating the lesion from the abdominal cavity. There were no abnormal vessels reported. These features were in keeping with an intrapul- monary cystic lesion and the infant was referred for a surgical opinion. As the infant remained well, surgery was deferred until the child was 1-yr old. A routine pre-operative CT scan (fig. 3) was performed on the day before the planned surgery followed by a barium swallow (fig. 4). A surgical procedure for what
    European Respiratory Journal 03/2004; 23(2):347-51. · 6.36 Impact Factor
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    ABSTRACT: Cystic fibrohistiocytic tumour of the lung is a rare proliferative process. Its histogenesis is uncertain, but evidence suggests that some cases represent metastatic disease from apparently indolent skin lesions, namely cellular fibrous histiocytomas. This study presents four cases and reviews the literature concerning this pattern of disease and its aetiology. All patients were male (age range 35-54 years). Two presented with recurrent haemoptysis. Two cases had histories of cutaneous fibrohistiocytic lesions in the chest wall, excised 10 and 23 years prior to presentation with lung disease. Imaging data showed multiple bilateral cystic lung lesions in all four patients with nodular cavitating opacities seen on high-resolution computed tomography scans. Microscopy showed variably dilated thin-walled cystic airspaces lined by cuboidal epithelium and an underlying layer of mildly pleomorphic spindle cells with slightly wavy morphology and storiform architecture, admixed with inflammatory cells. Tumour cells stained for CD68 in three of four cases. All cases were negative for CD34. All patients were alive with disease, although one required pneumonectomy for intractable haemoptysis. This study and a review of published cases show that the majority of cystic fibrohistiocytic tumours of the lung probably represent metastases from cellular fibrous histiocytomas. However, rare cases may be either primary in origin or the primary site remains occult; the term cystic fibrohistiocytic tumour remains appropriate for such cases.
    Histopathology 01/2004; 43(6):556-62. · 2.86 Impact Factor
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    ABSTRACT: Sclerosing haemangiomas typically comprise a mixture of four architectural patterns (papillary, sclerotic, solid and haemorrhagic) and two cell types, eosinophilic cuboidal epithelial lining cells and sheets of rounded cells with either eosinophilic or clear cytoplasm. In most instances, recognition of these architectural and cytological features provides sufficient evidence for diagnosis. This study presents and discusses the histogenesis of four cases where difficulties in diagnosis were encountered, and reports the value of the antibody TTF-1 in making the diagnosis. Four cases with focal areas reminiscent of sclerosing haemangioma were reviewed and immunostained with an antibody panel including antibodies to TTF-1 and surfactant apoprotein A. Of these, one case was classified as sclerosing haemangioma combined with typical carcinoid, in which there was a mediastinal lymph node metastasis solely comprising the solid component of sclerosing haemangioma. The second was classified as an alveolar adenoma with sclerosing haemangioma-like areas. In the remaining two cases, diagnosis was confounded by presentation with predominantly cystic masses, the largest 70 mm in diameter. Immunohistochemically, TTF-1 was of greater value than surfactant apoprotein, in particular in identifying the solid component of sclerosing haemangioma when this was solely present. Sclerosing haemangiomas should be considered in the differential diagnosis of cystic pulmonary masses. They may also present histologically as combined tumours and metastasize to mediastinal nodes, indicating an, albeit low, malignant potential. TTF-1 is a valuable antibody in identifying the presence of a sclerosing haemangioma when typical features are absent.
    Histopathology 12/2002; 41(5):404-13. · 2.86 Impact Factor
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    ABSTRACT: Relapsing polychondritis (RP) is a rare inflammatory multiorgan disorder affecting cartilaginous structures and other connective tissues. Serious cardiovascular complications have been reported in patients with RP, the most frequent being aortic or mitral regurgitation and aortic aneurysms. Aortitis is a very rare complication. An unusual case of active aortitis in a patient with RP, despite intensive immunosuppressive treatment, is described with a special emphasis on the pathological findings.
    Journal of Clinical Pathology 12/2001; 54(11):890-2. · 2.44 Impact Factor
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    ABSTRACT: Epithelial-myoepithelial carcinomas are very rare in the lung, and little is known about the relationship of their histologic features to prognosis. We describe five primary pulmonary epithelial-myoepithelial carcinomas with details on clinical presentation, histology, and immunohistochemical profiles. We also reviewed the literature to detail further their prognosis. The patients' ages ranged from 33 to 57 years (average 51 years). The tumors were all endobronchial and the patients presented with symptoms or imaging features of airway obstruction. The tumors were completely resected; none showed nodal involvement. All five patients are alive and free of disease 4 months to 8 years (average 4.2 years) after surgery. Four tumors showed a mixed pattern of glands lined by a dual layer of cells and solid sheets of either spindle cells or clear cells, the glandular and solid components being present in variable proportions. The fifth tumor comprised purely spindle cells. The mitotic rate was <1/20 high power fields in both the glandular and spindle/clear cell components. In one case there was focal nuclear pleomorphism. The inner layer of the glands stained for cytokeratins and epithelial membrane antigen, and the outer layer for S-100 and smooth muscle actin. In one case the spindle cells stained for CD34. A review of published cases shows the majority of tumors behave in an indolent fashion, the rare aggressive tumors being predominantly myoepitheliomatous. Nevertheless, the term epithelial-myoepithelial carcinoma is preferred because of their malignant potential. A high mitotic rate, tumoral necrosis, and nuclear pleomorphism appear to be adverse prognostic factors.
    American Journal of Surgical Pathology 12/2001; 25(12):1508-14. · 4.87 Impact Factor
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    ABSTRACT: Anastomosis of the ascending aorta to the right pulmonary artery, the so-called Waterston shunt, was undertaken as a palliative procedure for children with cyanotic congenital heart disease due to obstruction of the pulmonary outflow tract with reduced pulmonary blood flow. We present the clinicopathological correlations in two patients who underwent construction of Waterston shunts as neonates, and subsequently died of ruptured pulmonary aneurysms in adult life. Rupture should, therefore, be recognized as a late complication of this procedure, and be considered in the long-term follow-up of such patients, especially when the shunted lung is hypertensive.
    Cardiology in the Young 02/2001; 11(1):123-7. · 0.95 Impact Factor
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    ABSTRACT: Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.
    Human Pathlogy 11/2000; 31(10):1255-65. · 2.84 Impact Factor
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    ABSTRACT: To present two cases of malignant endobronchial myxoid tumours with a highly distinctive sarcomatoid pattern not previously described at this site, and discuss their histogenesis in relation to previously documented endobronchial neoplasms. Both tumours presented in young adult females and were purely sarcomatoid with interweaving cords of small uniform, rounded or slightly elongated cells lying within a myxoid stroma. The stroma was alcian blue positive, but sensitive to hyaluronidase in both cases. The tumour cells contained a small volume of periodic acid-Schiff-positive eosinophilic cytoplasm and stained positively for vimentin only, but there also was a prominent background population of CD68-positive dendritic cells. Ultrastructural studies showed that the tumour cells contained an excess of rough endoplasmic reticulum, with some of the cisternae appearing dilated, and scalloping of the cell surfaces, although no intracisternal tubules were identified. Although the histological pattern was most reminiscent of extraskeletal myxoid chondrosarcoma, the sensitivity of the stroma to pretreatment with hyaluronidase precluded the diagnosis. However, there were similarities with the sarcomatoid component of malignant salivary gland-type mixed tumours of the lung and this tumour possibly represents a variant of a bronchial gland tumour. Despite this uncertainty over origin, this pattern should be recognized as part of the differential diagnosis of myxoid tumours in the lung, as an apparently indolent type of malignant endobronchial neoplasm.
    Histopathology 11/1999; 35(4):313-8. · 2.86 Impact Factor
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    ABSTRACT: Interstitial pneumonitis in children is very rare and most cases have been classified according to their counterparts in adults, although the term 'chronic pneumonitis of infancy' has recently been proposed for a particular pattern of interstitial lung disease in infants. We reviewed our paediatric cases of interstitial pneumonitis, first, to look at the spectrum of histological patterns found in this age group and, second, to determine whether the classification of such cases in childhood is both appropriate and worthwhile. Twenty-five of 38 open lung biopsies showed an overlapping spectrum of interstitial pneumonitis, including three cases that fulfilled the histological criteria for chronic pneumonitis of infancy. There were 11 cases of reactive pulmonary lymphoid hyperplasia (either lymphoid interstitial pneumonitis or follicular bronchiolitis), five of which were associated with abnormalities of the immune system. Four cases were classified as desquamative interstitial pneumonitis and the remaining seven cases were classified as nonspecific interstitial pneumonitis. There were no cases with the histological features of usual interstitial pneumonitis. Most patients responded to steroids but tended to have a residual deficit in lung function. Mortality appeared to be associated with presentation at a young age. Classification of interstitial pneumonitis according to their adult counterparts is appropriate for this younger age group and can provide valuable information for the clinician. The term 'chronic pneumonitis of infancy' refers to a specific histological pattern, but whether it represents a separate disease or a reflection of pulmonary immaturity remains to be proven.
    Histopathology 10/1998; 33(3):203-11. · 2.86 Impact Factor

Publication Stats

1k Citations
195.37 Total Impact Points

Institutions

  • 2005–2006
    • Royal Brompton and Harefield NHS Foundation Trust
      • Department of Paediatrics
      Harefield, England, United Kingdom
  • 2002
    • Nottinghamshire Healthcare NHS Trust
      Nottigham, England, United Kingdom
  • 2001
    • Imperial College London
      • Department of Medicine
      London, ENG, United Kingdom
  • 1993–1994
    • The Heart Lung Center
      Londinium, England, United Kingdom
  • 1990–1993
    • National Heart, Lung, and Blood Institute
      Maryland, United States