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HEPARIN AND MAST CELLS
1466 HEPARIN AND MAST CELLS
SIR,-Professor Garrett and Dr Osman (Nov 1, p 1046) conclude that our hypothesis on the localisation of heparin in mast cells (Sept 27, p 718) may be untenable. They state that there is no real evidence of mast cell subpopulations in man as opposed to rodents. This assertion seems wrong for the glycosaminoglycan content of mast cells (the feature relevant to our argument) since chondroitin sulphate E proteoglycan (rather than heparin) has been shown to be present in mast cells cultured from human colonic mucosa.1 Moreover, a recent report shows haemostasis in the gastric mucosa to be sensitive to heparin anticoagulation, unlike that of the general vasculature which is sensitive to platelet active agents.2 This would also accord with our proposal. Garrett and Osman’s second comment arises out of a study on mast cell tryptase digestion of fibrinogen and from which a suggestion is made that this protease has an anticoagulant role.3 However, a concentration of 5 tg/n-11 of tryptase trebled the clotting time of a fibrinogen solution after almost 2 h digestion3whereas 5 Ilg/ml of heparin will render whole plasma more or less unclottable instantaneously. M. F. SCULLY V. ELLIS V. V. KAKKAR
Thrombosis Research Unit,
King’s College Hospital, London SE5 8RX
1. Eliakim R, Gilead L, Ligumsky M, Okon E, Rachmilewitz D, Razin E. Histamine and chondroitin sulfate E proteoglycan released by cultured human colonic mucosa: Indication for possible presence of E mast cells. Proc Natl Acad Sci USA 1986; 83: 461-64. 2. Whittle BJR, Kaufmann GL Jr, Moncada S. Hemostatic mechanisms independent of platelet aggregation arrest gastric mucosal bleeding. Proc Natl Acad Sci USA 1986; 83: 5683-87. 3. Schwartz LB, Bradford TR, Littman BH, Wintroub BU. The fibrinogenolytic activity of purified tryptase from human lung mast cells. J Immunol 1985; 135: 2762-67.
HUMAN PAPILLOMAVIRUS TYPE 16 DNA AT BIOPSY OF GINGIVAL HYPERPLASIA AFTER CARDIAC TRANSPLANTATION.
given a heart transplant at Anti-rejection therapy was cyclosporin 18 mg/kg body weight (trough serum levels being 692-1103, average 887 ng/ml) and azothioprine 125 mg daily for 30 days. No steroids were given. Acyclovir (800 mg) was given prophylactically for 3 months. On day 25 the patient complained of sore gums. Examination on day 32 revealed a striking overgrowth of the gingiva, especially on the palatal side of the upper incisors and labially on the lower incisors. The gingiva were firm, granular and pale pink. The overgrowth steadily increased, and one year post-transplant gingival biopsy was done. The histological report was "a thickened squamous mucosa overlying a fibrotic and SIR,-A 43-year-old
woman was
Harefield Hospital in 1984.
merely coincided with a cyclosporin-induced gingival overgrowth. Patients whose cell-mediated immunity is compromised have an increased incidence of warts, which puts them considerably more at risk of HPV-induced neoplasia of the skin and mucosa. Virus Reference Laboratory, Central Public Health Laboratory, London NW9 5HT
PATRICIA E. GIBSON
Department of Dentistry, Harefield Hospital, Harefield, Middlesex
MARTIN S. SEYMOUR
Syrjanen K, Happonen RP, Syrjanen S, Calonius B. Human papilloma virus HPV antigens and local immunologic reactivity in oral squamous cell tumours and hyperplasias. Scand J Dent Res 1984; 92: 358-70. 2. Durst M, Gissmann L, Ikenberg H, zur Hausen H. Papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA 1983; 80: 3812-15. 3. Naghashfar Z, Sawada E, Kutcher MJ, et al. Identification of genital tract Virol 1985; papillomaviruses HPV-6 and HPV-16 in warts of the oral cavity. Med J 1.
17: 313-24. 4. Brandsma JL,
Steinberg BM, Abramson AL, Winkler B. Presence of human papillomavirus type 16 related sequences in verrucous carcinoma of the larynx. Cancer Res 1986; 46: 2185-88. 5. Stremlau A, Gissmann L, Ikenberg H, et al. Human papillomavirus type 16 related DNA in an anaplastic carcinoma of the lung. Cancer 1985; 55: 1737-40. 6. Wysocki GP, Gretzinger HA, Laupacis A, et al. Fibrous hyperplasia of the gingiva; side effect of cyclospirin A therapy. Oral Surg 1983; 55: 274-78. 7. Rateitshak-Plus EM, Hefti A, Lortscher R, Thiel G Initial observation that cyclosporin A induces gingival enlargement in man J Clin Periodont 1983; 10: 237-46 8.
Nagington J, Gray L. Cyclosporin A immunosuppression, Epstein-Barr antibody, and lymphoma. Lancet 1980; i: 536-37.
END-STAGE RENAL FAILURE IN DIABETES
SIR,-We read with interest the article by Professor Cameron and Dr Challah (Oct 25, p 962) on the treatment of end-stage renal failure due to diabetes. In 1985 we did a short epidemiological survey within the Sunderland district (total population 300 000). Laboratory records for June to November, 1984, were examined retrospectively and 561 patients with renal failure were identified (blood urea 20 mmol/1 or more, serum creatinine 200 jmol/1 or more). Medical records were examined in 467 cases and the most likely cause of renal failure was identified where possible. Of 144 patients with identifiable primary renal disease, 20 (13-9%) had diabetic nephropathy (table). The type I diabetics were younger (mean age 58 years, range 33-63) than the type II patients (67, DETAILS OF
20 PATIENTS WITH RENAL FAILURE DUE TO DIABETIC NEPHROPATHY
chronically inflamed submucosa". 6 months later three samples were taken from the affected gingiva and total DNA was extracted. The samples were denatured and 2 ltg DNA was "spotted" onto a ’Hybond-N’ nylon membrane and hybridised under highly stringent conditions with a 32pradiolabelled human papillomavirus type 16 (HPV 16) probe. Another sample containing 8 J.!g DNA was probed with HPV 6. Both these probes had been excised from the plasmid vector before being radiolabelled. All three samples were negative when probed with HPV 6 but one was strongly positive with the HPV 16 probe. The DNA is now being characterised further. HPV antigens have been found in gingival hyperplasia and oral squamous cell tumours’ in non-immunosuppressed people. HPV 16 is primarily associated with dysplasia and carcinoma of the cervix2 but has also been found in oral warts/ verrucous carcinoma of the larynx,4 and carcinoma of the lung.This is the first time HPV DNA has been found in the oral cavity of a cardiac transplant patient, and may well be the first such finding in any
immunosuppressed patient. Gingival growth is a well-known side-effect of cyclosporin.6,7 This compound inhibits cytotoxic T cells and may impair the immunological control of certain viral infections.8 In this woman, it is not known whether HPV 16 induced the gingival hyperplasia or
Dial=already on dialysis; !HD= cardiac failure AMI = acute myocardial infarction.
due to ischaemic heart
disease;
SIR,-Professor Garrett and Dr Osman (Nov 1, p 1046) conclude that our hypothesis on the localisation of heparin in mast cells (Sept 27, p 718) may be untenable. They state that there is no real evidence of mast cell subpopulations in man as opposed to rodents. This assertion seems wrong for the glycosaminoglycan content of mast cells (the feature relevant to our argument) since chondroitin sulphate E proteoglycan (rather than heparin) has been shown to be present in mast cells cultured from human colonic mucosa.1 Moreover, a recent report shows haemostasis in the gastric mucosa to be sensitive to heparin anticoagulation, unlike that of the general vasculature which is sensitive to platelet active agents.2 This would also accord with our proposal. Garrett and Osman’s second comment arises out of a study on mast cell tryptase digestion of fibrinogen and from which a suggestion is made that this protease has an anticoagulant role.3 However, a concentration of 5 tg/n-11 of tryptase trebled the clotting time of a fibrinogen solution after almost 2 h digestion3whereas 5 Ilg/ml of heparin will render whole plasma more or less unclottable instantaneously. M. F. SCULLY V. ELLIS V. V. KAKKAR
Thrombosis Research Unit,
King’s College Hospital, London SE5 8RX
1. Eliakim R, Gilead L, Ligumsky M, Okon E, Rachmilewitz D, Razin E. Histamine and chondroitin sulfate E proteoglycan released by cultured human colonic mucosa: Indication for possible presence of E mast cells. Proc Natl Acad Sci USA 1986; 83: 461-64. 2. Whittle BJR, Kaufmann GL Jr, Moncada S. Hemostatic mechanisms independent of platelet aggregation arrest gastric mucosal bleeding. Proc Natl Acad Sci USA 1986; 83: 5683-87. 3. Schwartz LB, Bradford TR, Littman BH, Wintroub BU. The fibrinogenolytic activity of purified tryptase from human lung mast cells. J Immunol 1985; 135: 2762-67.
HUMAN PAPILLOMAVIRUS TYPE 16 DNA AT BIOPSY OF GINGIVAL HYPERPLASIA AFTER CARDIAC TRANSPLANTATION.
given a heart transplant at Anti-rejection therapy was cyclosporin 18 mg/kg body weight (trough serum levels being 692-1103, average 887 ng/ml) and azothioprine 125 mg daily for 30 days. No steroids were given. Acyclovir (800 mg) was given prophylactically for 3 months. On day 25 the patient complained of sore gums. Examination on day 32 revealed a striking overgrowth of the gingiva, especially on the palatal side of the upper incisors and labially on the lower incisors. The gingiva were firm, granular and pale pink. The overgrowth steadily increased, and one year post-transplant gingival biopsy was done. The histological report was "a thickened squamous mucosa overlying a fibrotic and SIR,-A 43-year-old
woman was
Harefield Hospital in 1984.
merely coincided with a cyclosporin-induced gingival overgrowth. Patients whose cell-mediated immunity is compromised have an increased incidence of warts, which puts them considerably more at risk of HPV-induced neoplasia of the skin and mucosa. Virus Reference Laboratory, Central Public Health Laboratory, London NW9 5HT
PATRICIA E. GIBSON
Department of Dentistry, Harefield Hospital, Harefield, Middlesex
MARTIN S. SEYMOUR
Syrjanen K, Happonen RP, Syrjanen S, Calonius B. Human papilloma virus HPV antigens and local immunologic reactivity in oral squamous cell tumours and hyperplasias. Scand J Dent Res 1984; 92: 358-70. 2. Durst M, Gissmann L, Ikenberg H, zur Hausen H. Papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA 1983; 80: 3812-15. 3. Naghashfar Z, Sawada E, Kutcher MJ, et al. Identification of genital tract Virol 1985; papillomaviruses HPV-6 and HPV-16 in warts of the oral cavity. Med J 1.
17: 313-24. 4. Brandsma JL,
Steinberg BM, Abramson AL, Winkler B. Presence of human papillomavirus type 16 related sequences in verrucous carcinoma of the larynx. Cancer Res 1986; 46: 2185-88. 5. Stremlau A, Gissmann L, Ikenberg H, et al. Human papillomavirus type 16 related DNA in an anaplastic carcinoma of the lung. Cancer 1985; 55: 1737-40. 6. Wysocki GP, Gretzinger HA, Laupacis A, et al. Fibrous hyperplasia of the gingiva; side effect of cyclospirin A therapy. Oral Surg 1983; 55: 274-78. 7. Rateitshak-Plus EM, Hefti A, Lortscher R, Thiel G Initial observation that cyclosporin A induces gingival enlargement in man J Clin Periodont 1983; 10: 237-46 8.
Nagington J, Gray L. Cyclosporin A immunosuppression, Epstein-Barr antibody, and lymphoma. Lancet 1980; i: 536-37.
END-STAGE RENAL FAILURE IN DIABETES
SIR,-We read with interest the article by Professor Cameron and Dr Challah (Oct 25, p 962) on the treatment of end-stage renal failure due to diabetes. In 1985 we did a short epidemiological survey within the Sunderland district (total population 300 000). Laboratory records for June to November, 1984, were examined retrospectively and 561 patients with renal failure were identified (blood urea 20 mmol/1 or more, serum creatinine 200 jmol/1 or more). Medical records were examined in 467 cases and the most likely cause of renal failure was identified where possible. Of 144 patients with identifiable primary renal disease, 20 (13-9%) had diabetic nephropathy (table). The type I diabetics were younger (mean age 58 years, range 33-63) than the type II patients (67, DETAILS OF
20 PATIENTS WITH RENAL FAILURE DUE TO DIABETIC NEPHROPATHY
chronically inflamed submucosa". 6 months later three samples were taken from the affected gingiva and total DNA was extracted. The samples were denatured and 2 ltg DNA was "spotted" onto a ’Hybond-N’ nylon membrane and hybridised under highly stringent conditions with a 32pradiolabelled human papillomavirus type 16 (HPV 16) probe. Another sample containing 8 J.!g DNA was probed with HPV 6. Both these probes had been excised from the plasmid vector before being radiolabelled. All three samples were negative when probed with HPV 6 but one was strongly positive with the HPV 16 probe. The DNA is now being characterised further. HPV antigens have been found in gingival hyperplasia and oral squamous cell tumours’ in non-immunosuppressed people. HPV 16 is primarily associated with dysplasia and carcinoma of the cervix2 but has also been found in oral warts/ verrucous carcinoma of the larynx,4 and carcinoma of the lung.This is the first time HPV DNA has been found in the oral cavity of a cardiac transplant patient, and may well be the first such finding in any
immunosuppressed patient. Gingival growth is a well-known side-effect of cyclosporin.6,7 This compound inhibits cytotoxic T cells and may impair the immunological control of certain viral infections.8 In this woman, it is not known whether HPV 16 induced the gingival hyperplasia or
Dial=already on dialysis; !HD= cardiac failure AMI = acute myocardial infarction.
due to ischaemic heart
disease;