D Geraint James

SERUM ANGIOTENSIN-CONVERTING ENZYME (SACE) IN SARCOIDOSIS AND OTHER GRANULOMATOUS DISORDERS

Serum angiotensin-converting enzyme (SACE) activity was significantly higher in 90 patients with sarcoidosis (55 +/- [S.D.] 23 nmol min-1 ml-1) than in 80 healthy controls (34 +/- 9 nmol min-1 ml-1). Steroid therapy modified SACE activity; 60 sarcoidosis patients who were not being treated with steroids had significantly higher enzyme activities (58 +/- 24 nmol min-1 ml-1) than 30 steroid-treated sarcoidosis patients (40 +/- 19 nmol min-1 ml-1). In 50% of the non-steroid treated sarcoidosis patients SACE activity was more than 2 S.D. above the mean value for the controls. SACE activity was measured in 22 tuberculous patients (38 +/- 14 nmol min-1 ml-1), 20 leprosy patients (34 +/- 9 nmol min-1 ml-1), 31 with primary biliary cirrhosis (44 +/- 20 nmol min-1 ml-1), 26 with inflammatory bowel disease (31 +/- 9 nmol min-1 ml-1), 8 with hepatic granulomatous disease, 5 with Hodgkins disease, and 2 with schistosomiasis. The combined false-positive rate for these non-sarcoidosis patients was 10%. Serial SACE assays provide useful information on the course of sarcoidosis and response to steroid treatment.

Bone and Joint Sarcoidosis

ARCOIDOSIS is a multisystem disorder of unknown etiology, most commonly affecting young adults and presenting most frequently with bilateral bilar lymphadenopatby, pulmonary infiltration, and skin or eye lesions. The diagnosis is established most securely when clinico-radiographic findings are supported by histologic evidence of widespread noncaseating epitheloid cell granulomas in more than one organ or a positive Kveim-Siltzbach skin test. This skin test also reflects activity of the disease. Immunologic features are depression of delayed-type hypersensitivity, indicating T-cell anergy, and raised serum immunoglobulins, indicating B-cell overactivity. There may also be hypercalciuria with or without hypercalcemia. The course and prognosis correlate with the mode of onset; an acute onset with erythema nodosum usually heralds a self-limiting course with spontaneous resolution, while an insidious onset may be followed by relentless progressive fibrosis. Corticosteroids relieve symptoms and suppress inflammation and granuloma formation. ETIOLOGY The cause of sarcoidosis is unknown, so theories abound. Oranuloma formation is the final common pathway of several different and unrelated disorders. We do not know whether sarcoidosis is one disease resulting from one cause or whether it is a multicausal syndrome. Claims that it is an infection are longstanding and the most popular infective agents have been mycobacteria, fungi, and viruses. There has been speculation concerning a transmissible agent from human sarcoid tissue into foot pads of mice, but similar changes occur with control nonsarcoid lymph node tissue. 1 Even human foreskin fibroblast has been used for tissue culture of sarcoid lymph nodes but no viral cytopathic effect was observed. 2 The occasional occurrence of familial sarcoidosis suggests possible genetic influences. We have observed 16 families, among which 33 persons had sarcoidosis. The group comprised nine brother sister, four mother offspring, and one uncle-niece relationship, and it was also noted in husband and wife once. The clinical, radiographic, and other features of the disorder are similar in familial and sporadic sarcoidosis, but the course of one sister was considerably worse than that of her brother, suggesting adverse hormonal factors. Four of these families were from the West Indies, suggesting a racial predisposition to familial sarcoidosis. Turiaf has also noted a greater incidence in French West Indians from Marti

Lupus pernio: a clinico‐radiological study of thirty‐five cases

Thirty‐five patients with lupus pernio were observed in a series of 818 patients with clinical and histological evidence of sarcoidosis. This analysis provides the natural history of lupus pernio and its associated clinico‐radiographic features. There was intrathoracic involvement in 74% of patients, upper respiratory tract disease in 54%, reticulo‐endothelial involvement in 54%, bone cysts in 43%, and ocular lesions in 37%. It predominated in West Indies‐born women. Histological confirmation was easily obtained by nasal mucosal biopsy and this could be repeated serially to evaluate the response to various treatments. Nasal bone radiographs showed destruction of the nasal bones, porosis and alteration in bone texture. Peripheral bone cysts were evident in 50% of patients who were radiographed, and in about 50%, of these patients, the cysts were found in both hands and feet.

Sarcoidosis of the upper respiratory tract (SURT)

A series of eight hundred and eighteen patients with histologically-confirmed multisystem sarcoidosis was analysed; within this series were 53 (6 per cent) patients with sarcoidosis of the upper respiratory tract (SURT). Two-thirds presented with predominantly upper respiratory tract symptoms when the systemic disorder was minimal or unrecognized. Women were affected twice as often as men. SURT is commonly associated with lupus pernio and other manifestations of chronic fibrotic sarcoidosis, and it follows the same indolent course. When granulomas are found on biopsy of the upper respiratory tract, there should be a management plan to determine whether they are due to multisystem sarcoidosis or other granulomatous disorders including tuberculosis, Wegeners granulomatosis and leprosy. About one-half of patients with SURT will need oral steroids, either alone or in combination with topical steroids or chloroquine.

IMMUNOLOGY OF SARCOIDOSIS

The cardinal immunologic changes in sarcoidosis consist of depression of delayed-type hypersensitivity, hyperreactive circulating antibody responses and the Kveim-Siltzbach skin test phenomenon. Depression of delayed-type hypersensitivity is demonstrated by skin tests using tuberculin, mumps, pertussis, trichophytin, oidiomycin, dinitrochlorobenzene and Californian keyhole limpet hemocyanin. The cultured lymphocytes from patients with depression of delayed-type hypersensitivity react poorly to phytohemagglutinin, and there is a close correlation between anergy of lymphocytes in culture and by cutaneous anergy. In vivo cutaneous anergy mirrors in vitro cellular hyporeactivity. Other technics used to expose immunologic defects in peripheral lymphocytes of patients with sarcoidosis include tests of T and B cell function, rosetie formation and migration inhibition. Whereas there is cutaneous anergy and impaired cellular immunity in patients with sarcoidosis, the reverse holds for circulating factors. There are increased circulating immunoglobulin levels, increased circulating antibody levels to Epstein-Barr, herpes simplex, rubella, measles and parainfluenza viruses, increase antibody response to mismatched blood and occasional false-positive Wassermann reactions, but there is no increase in circulating autoan tibodies. There is no evidence that patients with sarcoidosis belong predominantly to any particular histocompatibility locus. Worldwide figures for the Kveim-Siltzbach skin test are presented. They provide evidence of its specificity in various international series. The causes of nonspecific reactions are discussed.

Kveim Revisited, Reassessed

ON the hypothesis that sarcoidosis, like lymphogranuloma, might be a virus disease, Williams and Nickerson1 employed a skin test for its diagnosis. A piece of skin sarcoid tissue, suspended in six ...

Sarcoidosis: Past, present, and future concepts

Abstract This brief review of important landmarks in the history of sarcoidosis presents current concepts of clinical and radiologic features, histology, and immunology, and considers future directions in study of its elusive etiology and possible lines of treatment. The clinical picture draws particular attention to erythema nodosum as a marker of the onset of the disease and lupus pernio as a marker of persistence and as an excellent experimental model for evaluating therapy. Our view of the histology of the sarcoid granulomas has been clarified by the use of monoclonal antibodies and histochemistry. By this means, we are now able to recognize the uniforms of the soldiers participating in the sarcoid granuloma battleground. Immunology highlights the interplay between T cell subsets, B cells, macrophages, and their clinical mediators. Our main future objective—to unravel the cause(s) of sarcoidosis—will also help us toward more rational scientific lines of treatment, thereby banishing troublesome complications: pulmonary, cardiac, renal failure, and blindness.

John Coakley Lettsom's Welsh connections.

John Coakley Lettsom (1744–1815), the Quaker physician, lived and worked in London but two of his daughters married brothers of the Elliot family, from Carmarthenshire. His wife was a member of the Miers family, who also had connections with Wales. This paper traces these connections.

Hutchinson's disorders.

1 Foster M. Preface to Lectures on the History of Physiology during the Sixteenth, Seventeenth and Eighteenth Centuries. Cambridge: Cambridge University Press, 1924. The Lane Lectures were delivered at Cooper College, San Francisco, California in 1900. The book became a classic of its kind 2 Belongings 1. Circumstances connected with a person or thing; relations with another person or thing. The Compact Edition of the Oxford English Dictionary volume 1, Oxford University Press, 1979:198 3 Dale H. Sir Michael Foster, – KC.B., F.R.S. A Secretary of the Royal Society. Notes and Records of the Royal Society of London 1964;19:10–32. The complete bibliography of Michael Foster is included 4 Unattributed. Obituary. Sir Michael Foster, K.C.B., M.D., F.R.S., formerly Professor of Physiology in the University of Cambridge. British Medical Journal 1907;i:349–51 5 Gaskell WH. Sir Michael Foster, 1836–1907. Obituary Notices. Proceedings of the Royal Society of London 1907;80:lxxi–lxxxi 6 Langley JN. Sir Michael Foster. In: Memoriam. Journal of Physiology, London 1907;35:233–46 7 Foster M. Thomas Henry Huxley. Obituary Notices. Proceedings of the Royal Society of London 1895;59:xlvi–lxvi 8 Langley JN (op. cit. ref. 6): p. 234 9 Foster M. On the effects produced by freezing on the physiological properties of muscles. Proceedings of the Royal Society of London 1859–60;10:523–8. Communicated by Dr Sharpey, Sec RS 10 Desmond A. Thomas Henry Huxley. In: Matthews HCG, Harrison B, eds. Oxford Dictionary of National Biography, Oxford: Oxford University Press, 2004;25:103. Bishop Samuel Wilderforce asked Huxley whether he was descended from apes on his grandfather’s or grandmother’s side. Huxley replied that he would ‘rather have a miserable ape for a grandfather’ than a man ‘possessed of great means of influence and yet who employs ... that influence for the mere purpose of introducing ridicule into a grave scientific discussion’ 11 Foster M. On the existence of glycogen in the tissues of certain Entozoa. Proceedings of the Royal Society of London 1865;14:543–6. Communicated by Professor Huxley 12 Sharpey-Schafer E. History of the Physiological Society during its First Fifty Years (1876–1926). London: Cambridge University Press, 1927 13 Ibid.: p. 18 14 Harley George (1829–96). In: Brown GH, ed. Munk’s Roll. Lives of the Fellows of the Royal College of Physicians of London 1826–1925; volume 4. London: Royal College of Physicians, 1955:141 15 Huxley TH. Science and Education Essays. New York: D Appleton & Company, 1898:127 16 Unattributed. (op. cit. ref. 4): p. 351 17 Sharpey-Schafer Edward Albert (1850–1935). In: Porter R, consulting editor. The Hutchinson Dictionary of Scientific Biography. 2nd edn. Oxford: Helicon Press, 1994:618–9. Schafer named one of his sons after his mentor Sharpey. After the First World War in which both sons were killed, he affixed the name Sharpey to his own. Schafer was Professor of Physiology at Edinburgh University (1899–1933) and was knighted in 1913 18 Foster M. Coutts Trotter. Obituary. Nature, London 1887;37:153–4 19 Sykes AH. Foster and Sharpey’s Tour of Europe. Notes and Records of the Royal Society of London 2000;54:47–52 20 Langley JN. (op. cit. ref. 6): p. 238 21 Foster M. Claude Bernard (Master of Medicine Series). London: T. Fisher Unwin, 1899:p.vii 22 Ibid.: p. 80 23 Sharpey-Schafer E (op. cit. ref. 12): pp. 24–5 24 Unattributed. Obituary. Sir Michael Foster, K.C.B., M.D. Lond., D.C.L., LL.D., D.Sc., F.R.S. Lancet 1907;i:397–401 25 Foster M, Balfour FM. The Elements of Embryology. Part 1. London: MacMillan & Company, 1874 26 Foster M. Text Book of Physiology. London: MacMillan & Co, 1877 27 Langley JN (op. cit. ref. 6): p. 240 28 Sturdy S. Sir John Scott Burdon Sanderson (1828–1905). In: Matthews HCG, Harrison B, eds. Oxford Dictionary of National Biography. Oxford: Oxford University Press, 2004;48:875–8 Burdon-Sanderson left University College, London in 1882 to become first Waynflete Professor of Physiology at Oxford (1882– 95). In 1895 he was appointed Regius Professor of Medicine at Oxford (1895–1903); he became a baronet in 1899 29 Klein E, Burdon-Sanderson J, Foster M, Lauder Brunton T. In: Burdon-Sanderson J, ed. Handbook for the Physiological Laboratory. London: J & A Churchill, 1873 30 Romano TM. Sir Michael Foster (1836–1907). In: Matthews HCG, Harrison B, eds. Oxford Dictionary of National Biography. Oxford: Oxford University Press, 2004;20:520–3 31 Thomson L. Original development of the Medical Research Council. British Medical Journal 1963;ii:1290 32 Dale H (op. cit. ref. 3): p. 28 33 Gaskell WH (op. cit. ref. 5): p. lxxxi 226 Journal of Medical Biography Volume 16 November 2008

Sir Herbert Isambard Owen (1850-1927).

Isambard Owen, born in Chepstow to a Welsh father, studied at Cambridge and St Georges Hospital where he qualified in 1875 and was later physician and Dean. In 1904 he moved to Newcastle-upon-Tyne as Principal of Armstrong College. He left in 1909 to become Bristol Universitys Vice-Chancellor, retiring in 1921. Although not resident in Wales he was an ardent Welshman. After joining the Cymmrodorion Society in 1877 he became involved in the struggle to improve primary and secondary education in Wales, partly by promoting use of the Welsh language in schools. His main contribution to Welsh academic life was in the foundation of the University of Wales and, later, of the medical school in Cardiff. He wrote the Universitys Charter and from 1895 until 1910 was its Senior Deputy Chancellor – and stand-in for two Princes of Wales (later Edward VII and George V) who served as Chancellor.