334
substantially greater than that acceptable with a prophylactic regimen, especially for patients who require many other drugs. Clindamycin is also effective in treatment of P carinii pneumonia and has been suggested as a possible prophylactic agent in patients at high risk of this common AIDS-associated opportunistic infection.8 The population we studied was at high risk of P carinii pneumonia as well as TE; our findings therefore suggest that clindamycin would also be poorly tolerated as a prophylactic regimen for that disorder. Pyrimethamine cannot be recommended for prophylaxis against TE simply on the basis that clindamycin will not do. The pyrimethamine arm of our trial continues. This study was supported by a contract from the National Institute of Allergy and Infectious Diseases. We thank Dr J. Neaton, Mr J. Gerard, Dr S. Milwee, Dr W. Rida, Dr D. C. Wright, Dr M. Carlyn, Dr S. Slome, and Dr B. Fireman for their help in completing this study. Community Programs for Clinical Research on AIDS: Bronx-Lebanon Hospital Centre (Dr J. A. Ernst, Dr 1. Grant, Dr C. Fornilda); Community Consortium (Dr C. L. Brosgart, Dr W. J. Fessel, Dr W. F. Owen); Henry Ford Hospital (Dr E. Fisher, Dr N. Markowitz, Dr L. Saravolatz); North Jersey Community Research Initiative (Ms H. Brown, Ms V. Taylor); AIDSS Research Consortium of Atlanta, Inc (Dr C. Lopez, Dr M. Tanner); Research and Education Group (Ms C. Salveson, Dr J. H. Sampson); Comprehensive AIDS Alliance of Detroit (Dr L. Crane); Hill Health Corporation (Dr S-H. Lam); Chicago Community Program for Clinical Research on AIDS (Dr R. Luskin-Hawk); Delaware Community Program for Clinical Research on AIDS (Dr W. J. Holloway); Richmond AIDS Consortium (Mr R. T. Higginson); Louisiana Community AIDS Research Program (Dr J. Osterberger); Harlem AIDS Treatment Group (Ms L. Macey); Denver Community Program for Clinical Research on AIDS (Ms C. Mesard); Clinical Directors Network of Region II (Dr T. Meyers); Addition Research and Treatment Corporation (Dr J. Rawls).
REFERENCES 1. Luft BJ, Remington JS. Toxoplasmic encephalitis. J Infect Dis 1988; 157: 1-6. 2. Grant IH, Gold JWM, Rosenblum M, Niedzwiecki D, Armstrong D. Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS. AIDS 1990; 4: 519-21. 3. Matherson S, Doumon E, Garakhanian S, Leport C, Detruchis P, Gaudebout C. Prevalence of toxoplasmosis in 365 AIDS and ARC patients before and during zidovudine treatment. VIth International Conference on AIDS, 1990, San Francisco. Abstr no Th.B.476. 4. Eliaszewicz M, Lecomte I, De Sa M, East Parisian CISIH group. Relation between decreasing seric CD4lymphocyte count and outcome of toxoplasmosis in AIDS patients: a basis for primary prophylaxis. VIth International Conference on AIDS, 1990, San Francisco. Abstr no Th.B.481. 5. Dannemann BR, McCutchan JA, Israelski DM, et al. Treatment of toxoplasmic encephalitis in patients with AIDS: a randomized trial
comparing pyrimethamine plus clindamycin
to
pyrimethamine plus
sulfonamides. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1990, Atlanta GA. Abstr mo 1159. 6. Pedrol E, Gonzalez-Clemente JM, Gatell JM, et al. Central nervous system toxoplasmosis in AIDS patients: efficacy of an intermittent maintenance therapy. AIDS 1990; 4: 511-17. 7. Leport C, Bastuji-Garin S, Perronne C, et al. An open study of the pyrimethamine-clindamycin combination in AIDS patients with brain toxoplasmosis. J Infect Dis 1989; 160: 557-58. 8. Toma E, Fournier S, Poisson M, Morisset R, Phaneuf D, Vega C. Clindamycin with primaquine for Pneumocystis carinii pneumonia. Lancet 1989; i: 1046-48.
ADDRESSES. Department of Medicine, University of California San Francisco and Medical Service, San Francisco General Hospital (M. A Jacobson, MD); San Francisco Community Consortium on AIDS, California (C Child, RN); Tulane University, New Orleans, Louisiana (C L. Besch, MD); Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (R Hafner, MD, L. Deyton, MD) Division of Biostatistics, University of P D. N Minnesota, Matts, PhD, Minneapolis (J Wentworth, MPH) and R. O. W. Sciences, Bethesda, Maryland, (K. Muth, MS) USA. Correspondence to Dr L. Deyton, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6003 Executive Boulevard, Bethesda, Maryland 20892, USA
sulphate in haemodialysis
Dermatan
Experimental work suggests that dermatan sulphate has potential as an antithrombotic agent: it can
inhibit
venous
thrombi yet has less effect upon
bleeding than heparin. While heparin functions as an anticoagulant primarily by its ability to accelerate the action of the plasma protein inhibitor antithrombin III, dermatan sulphate acts selectively through a structurally related inhibitor, heparin co-factor II, to inhibit thrombin. We have done a series of dosefinding studies of the use of dermatan sulphate as an
anticoagulant/antithrombotic agent in patients on maintenance haemodialysis. Dermatan sulphate proved to be an effective anticoagulant in this setting.
Rapid and effective anticoagulation is essential during extracorporeal circulation, the usual agent being heparin. Heparin and its low molecular weight derivatives interact with antithrombin III (ATIII), achieving rapid inhibition of thrombin formation and of other coagulation proteinases.1 The main complication is bleeding, which heparin could induce by its effect upon coagulation, by an inhibitory effect upon platelets, or by an increase in capillary permeability.2 The last two potential mechanisms may be related to the very high charge density of this glycosaminoglycan (GAG). Blood contains a second inhibitor of thrombin, heparin cofactor II (HCII), which is structurally related to ATIIL3 Uniquely, its inhibitory action is accelerated by the GAG dermatan sulphate. Dermatan sulphate has lower charge density than heparin, has less effect upon standard coagulation tests, and causes less bleeding in animal models-yet it still functions as an antithrombotic agent in experimental thrombosis.5-7 To find out if dermatan sulphate might be an alternative to heparin clinically, we have done dose-ranging studies in patients with end-stage renal failure on maintenance haemodialysis. At the renal unit, Charing Cross Hospital, London, dermatan sulphate (MF 701; Mediolanum Farmaceutici, Milan) was administered to patients on 5-6 h dialyses with cuprophane hollow-fibre dialysers. The three studies to be reported here were randomised, crossover comparisons in six to eight patients of dermatan sulphate and individualised (optimal) doses of heparin. In the first study bolus injections of 3 mg/kg body weight and 6 mg/kg dermatan sulphate were compared with a bolus plus infusion regimen of heparin. These injections of dermatan sulphate enabled patients to dialyse for a mean of 4-6 h and 5-3 h, respectively, before visible clotting in the bubble trap required administration of additional anticoagulant (heparin) for the procedure to be completed. The mean duration of dialysis on heparin for these patients was 5-9 h. In a second study, administration of dermatan sulphate as a bolus plus infusion (3 mg/kg plus 0-6 mg/kg per h given over the duration of the dialysis) was also not quite effective, 9 mean duration of dialysis of 4-3 h as compared with 5-7 h for the heparin
335
regimen. However, in the third study, a bolus of 5 mg/kg plus 1 mg/kg per h of infusion over 5 h permitted trouble-free dialysis for a mean of 5-7 h. There were no adverse effects (such as bleeding) caused by the infusions of dermatan sulphate and only small effects upon the kaolincephalin clotting time (KCCT) (mean 100-160 s), in contrast to the greatly prolonged KCCT (mean always > 300 s) obtained with the heparin infusions. Similar studies
were
done
at
the Academic Medical
Centre, Amsterdam. In the first two studies, bolus injections
sulphate (2-0, 2-5, and 3-0 mg/kg) were with individualised heparin treatment by boluses compared of 3000-6000 IU and continuous infusions of 1200-2400 IU per h in ten stable chronic haemodialysis patients. A cuprophane plate type dialyser was used (duration of dialysis 3-4 h). After dialysis, the extracorporeal circuit was inspected for clot formation by an independent investigator. All 24 dialysis procedures were completed successfully, except for that of one patient who had the lowest dose and who had a thrombotic obstruction 90 min after the start of the procedure. Significant clot formation (large thrombotic patches within dialyser plate and/or clots within bubble catcher) was observed in one patient on each dermatan dose, no significant clot formation occurred with heparin. The third Amsterdam study was a randomised, crossover comparison of bolus injections of 4-5 mg/kg and 6-0 mg/kg dermatan sulphate with heparin treatment. Thirteen chronic stable haemodialysis patients were dialysed with a cuprophane hollow-fibre dialyser for 3-0-4-5 h. All dialyses were completed successfully. There was no significant difference in clot formation in the extracorporeal circuit between the 6-0 mg/kg dermatan sulphate and heparin, whereas with 4-5 mg/kg significantly more clots were observed in the extracorporeal circuit. No serious bleeding events or other significant adverse events occurred in the three studies, and laboratory findings were comparable with those in the London studies. While there are differences in dialysis duration and procedure at the two centres, which lead to some differences in perceived dose requirements for clot-free dialysis, both groups have demonstrated that dermatan sulphate is an effective anticoagulant in haemodialysis. They confirm that it is possible to achieve anticoagulation in man through the HCII pathway of thrombin inhibition, rather than through action on ATIII. The ability to use agents with reduced charge density and with reduced effect upon the KCCT to achieve effective protection against clot formation, raises the possibility of reduced effect on bleeding and may stimulate interest in the HCII pathway as a therapeutic option. of dermatan
REFERENCES 1. Bjork I, Olson S, Shore J. Molecular mechanisms of the accelerating effect of heparin on the reactions between antithrombin and clotting proteinases. In: Lane DA, Lindahl U, eds. Heparin, chemical and biological properties, clinical applications. London: Edward Arnold, 1989: 229-55. 2. Hirsh J. From unfractionated heparins to low molecular weight heparins. Acta Chirurg Scand 1990; 556 suppl: 42-50. 3.Tollefsen DM, Blank MK. Detection of a new heparin-dependent inhibitor of thrombin in human plasma. JClin Invest 1981; 68: 589-96. 4. Tollefsen DM, Pestka CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulphate. J Biol Chem 1983; 258: 6713-16. 5. Okwusidi J, Falcone M, Van Ryn McKenna J, Hirsh J, Ofosu FA, Buchanan MR. In vivo catalysis of thrombin inhibition by antithrombin III or heparin cofactor II and antithrombotic effects: differential effects of unfractionated heparin and dermatan sulphate. Thromb Haemorrh Disorders 1990; 1: 77-80. 6. Van Ryn McKenna J, Gray E, Weber E. Ofosu FA, Buchanan MR. Effects of sulphated polysaccharides on inhibition of thrombus formation initiated by different stimuli. Thromb Haemost 1989; 61:7-9.
7. Fernandez F, Van Ryn J, Ofosu F, Hirsh J, Buchanan M. The haemorrhagic and antithrombotic effects of dermatan sulphate. Br J Haematol 1989; 64: 309-17.
ADDRESSES. Departments of Haematology and Medicine, Charing Cross and Westminster Hospital and Medical School, London, UK (Prof D A Lane, PhD, K. Ryan, MRCP, H. Ireland, PhD, J R. Curtis, FRCP); Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research and Department of Nephrology, Academic Medical Centre, Amsterdam (M. T. Nurmohamed, MD, R. T. Krediet, MD, Prof J. W. ten Cate, MD); and Diatel Amsterdam, Dialysis Centre, Amsterdam, Netherlands (M C. Roggekamp, MD, P Stevens, MD). Correspondence to Prof D. A. Lane, Department of Haematology, Charing Cross and Westminster Medical School, London W6 8RF, UK.
Failure to detect cytomegalovirus DNA in pancreas in type 2 diabetes
attempted to confirm the finding of cytomegalovirus (CMV) nucleic acid sequences in pancreas sections from patients with type 2 diabetes in a large population since this finding has major implications for the pathogenesis of the disorder. A highly sensitive nested polymerase chain reaction method was developed to detect the immediateearly CMV gene in DNA extracted from waxWe have
embedded tissue sections. We could not confirm the previous findings; CMV DNA was not detected in pancreas sections from 43 type 2 diabetic patients or from 38 non-diabetic age-matched subjects, although the method detected CMV DNA, even in very low concentrations, in positive controls.
higher prevalence of cytomegalovirus (CMV) nucleic acid sequences in pancreas sections from patients with type 2 diabetes than in sections from non-diabetic subjects. Independent confirmation of this finding is important because of its implications for the pathogenesis of type 2 diabetes. We have attempted such Lohr and Oldstonel
reported
a
confirmation. At the renal unit, Charing Cross Hospital, London, dermatan sulphate (MF 701; Mediolanum Farmaceutici, Milan) was administered to patients on 5-6 h dialyses with cuprophane hollow-fibre dialysers. The three studies to be reported here were randomised, crossover comparisons in six to eight patients of dermatan sulphate and individualised (optimal) doses of heparin. In the first study bolus injections of 3 mg/kg body weight and 6 mg/kg dermatan sulphate were compared with a bolus plus infusion regimen of heparin. These injections of dermatan sulphate enabled patients to dialyse for a mean of 4-6 h and 5-3 h, respectively, before visible clotting in the bubble trap required administration of additional anticoagulant (heparin) for the procedure to be completed. The mean duration of dialysis on heparin for these patients was 5-9 h. In a second study, administration of dermatan sulphate as a bolus plus infusion (3 mg/kg plus 0-6 mg/kg per h given over the duration of the dialysis) was also not quite effective, 9 mean duration of
substantially greater than that acceptable with a prophylactic regimen, especially for patients who require many other drugs. Clindamycin is also effective in treatment of P carinii pneumonia and has been suggested as a possible prophylactic agent in patients at high risk of this common AIDS-associated opportunistic infection.8 The population we studied was at high risk of P carinii pneumonia as well as TE; our findings therefore suggest that clindamycin would also be poorly tolerated as a prophylactic regimen for that disorder. Pyrimethamine cannot be recommended for prophylaxis against TE simply on the basis that clindamycin will not do. The pyrimethamine arm of our trial continues. This study was supported by a contract from the National Institute of Allergy and Infectious Diseases. We thank Dr J. Neaton, Mr J. Gerard, Dr S. Milwee, Dr W. Rida, Dr D. C. Wright, Dr M. Carlyn, Dr S. Slome, and Dr B. Fireman for their help in completing this study. Community Programs for Clinical Research on AIDS: Bronx-Lebanon Hospital Centre (Dr J. A. Ernst, Dr 1. Grant, Dr C. Fornilda); Community Consortium (Dr C. L. Brosgart, Dr W. J. Fessel, Dr W. F. Owen); Henry Ford Hospital (Dr E. Fisher, Dr N. Markowitz, Dr L. Saravolatz); North Jersey Community Research Initiative (Ms H. Brown, Ms V. Taylor); AIDSS Research Consortium of Atlanta, Inc (Dr C. Lopez, Dr M. Tanner); Research and Education Group (Ms C. Salveson, Dr J. H. Sampson); Comprehensive AIDS Alliance of Detroit (Dr L. Crane); Hill Health Corporation (Dr S-H. Lam); Chicago Community Program for Clinical Research on AIDS (Dr R. Luskin-Hawk); Delaware Community Program for Clinical Research on AIDS (Dr W. J. Holloway); Richmond AIDS Consortium (Mr R. T. Higginson); Louisiana Community AIDS Research Program (Dr J. Osterberger); Harlem AIDS Treatment Group (Ms L. Macey); Denver Community Program for Clinical Research on AIDS (Ms C. Mesard); Clinical Directors Network of Region II (Dr T. Meyers); Addition Research and Treatment Corporation (Dr J. Rawls).
REFERENCES 1. Luft BJ, Remington JS. Toxoplasmic encephalitis. J Infect Dis 1988; 157: 1-6. 2. Grant IH, Gold JWM, Rosenblum M, Niedzwiecki D, Armstrong D. Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS. AIDS 1990; 4: 519-21. 3. Matherson S, Doumon E, Garakhanian S, Leport C, Detruchis P, Gaudebout C. Prevalence of toxoplasmosis in 365 AIDS and ARC patients before and during zidovudine treatment. VIth International Conference on AIDS, 1990, San Francisco. Abstr no Th.B.476. 4. Eliaszewicz M, Lecomte I, De Sa M, East Parisian CISIH group. Relation between decreasing seric CD4lymphocyte count and outcome of toxoplasmosis in AIDS patients: a basis for primary prophylaxis. VIth International Conference on AIDS, 1990, San Francisco. Abstr no Th.B.481. 5. Dannemann BR, McCutchan JA, Israelski DM, et al. Treatment of toxoplasmic encephalitis in patients with AIDS: a randomized trial
comparing pyrimethamine plus clindamycin
to
pyrimethamine plus
sulfonamides. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1990, Atlanta GA. Abstr mo 1159. 6. Pedrol E, Gonzalez-Clemente JM, Gatell JM, et al. Central nervous system toxoplasmosis in AIDS patients: efficacy of an intermittent maintenance therapy. AIDS 1990; 4: 511-17. 7. Leport C, Bastuji-Garin S, Perronne C, et al. An open study of the pyrimethamine-clindamycin combination in AIDS patients with brain toxoplasmosis. J Infect Dis 1989; 160: 557-58. 8. Toma E, Fournier S, Poisson M, Morisset R, Phaneuf D, Vega C. Clindamycin with primaquine for Pneumocystis carinii pneumonia. Lancet 1989; i: 1046-48.
ADDRESSES. Department of Medicine, University of California San Francisco and Medical Service, San Francisco General Hospital (M. A Jacobson, MD); San Francisco Community Consortium on AIDS, California (C Child, RN); Tulane University, New Orleans, Louisiana (C L. Besch, MD); Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (R Hafner, MD, L. Deyton, MD) Division of Biostatistics, University of P D. N Minnesota, Matts, PhD, Minneapolis (J Wentworth, MPH) and R. O. W. Sciences, Bethesda, Maryland, (K. Muth, MS) USA. Correspondence to Dr L. Deyton, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6003 Executive Boulevard, Bethesda, Maryland 20892, USA
sulphate in haemodialysis
Dermatan
Experimental work suggests that dermatan sulphate has potential as an antithrombotic agent: it can
inhibit
venous
thrombi yet has less effect upon
bleeding than heparin. While heparin functions as an anticoagulant primarily by its ability to accelerate the action of the plasma protein inhibitor antithrombin III, dermatan sulphate acts selectively through a structurally related inhibitor, heparin co-factor II, to inhibit thrombin. We have done a series of dosefinding studies of the use of dermatan sulphate as an
anticoagulant/antithrombotic agent in patients on maintenance haemodialysis. Dermatan sulphate proved to be an effective anticoagulant in this setting.
Rapid and effective anticoagulation is essential during extracorporeal circulation, the usual agent being heparin. Heparin and its low molecular weight derivatives interact with antithrombin III (ATIII), achieving rapid inhibition of thrombin formation and of other coagulation proteinases.1 The main complication is bleeding, which heparin could induce by its effect upon coagulation, by an inhibitory effect upon platelets, or by an increase in capillary permeability.2 The last two potential mechanisms may be related to the very high charge density of this glycosaminoglycan (GAG). Blood contains a second inhibitor of thrombin, heparin cofactor II (HCII), which is structurally related to ATIIL3 Uniquely, its inhibitory action is accelerated by the GAG dermatan sulphate. Dermatan sulphate has lower charge density than heparin, has less effect upon standard coagulation tests, and causes less bleeding in animal models-yet it still functions as an antithrombotic agent in experimental thrombosis.5-7 To find out if dermatan sulphate might be an alternative to heparin clinically, we have done dose-ranging studies in patients with end-stage renal failure on maintenance haemodialysis. At the renal unit, Charing Cross Hospital, London, dermatan sulphate (MF 701; Mediolanum Farmaceutici, Milan) was administered to patients on 5-6 h dialyses with cuprophane hollow-fibre dialysers. The three studies to be reported here were randomised, crossover comparisons in six to eight patients of dermatan sulphate and individualised (optimal) doses of heparin. In the first study bolus injections of 3 mg/kg body weight and 6 mg/kg dermatan sulphate were compared with a bolus plus infusion regimen of heparin. These injections of dermatan sulphate enabled patients to dialyse for a mean of 4-6 h and 5-3 h, respectively, before visible clotting in the bubble trap required administration of additional anticoagulant (heparin) for the procedure to be completed. The mean duration of dialysis on heparin for these patients was 5-9 h. In a second study, administration of dermatan sulphate as a bolus plus infusion (3 mg/kg plus 0-6 mg/kg per h given over the duration of the dialysis) was also not quite effective, 9 mean duration of dialysis of 4-3 h as compared with 5-7 h for the heparin
335
regimen. However, in the third study, a bolus of 5 mg/kg plus 1 mg/kg per h of infusion over 5 h permitted trouble-free dialysis for a mean of 5-7 h. There were no adverse effects (such as bleeding) caused by the infusions of dermatan sulphate and only small effects upon the kaolincephalin clotting time (KCCT) (mean 100-160 s), in contrast to the greatly prolonged KCCT (mean always > 300 s) obtained with the heparin infusions. Similar studies
were
done
at
the Academic Medical
Centre, Amsterdam. In the first two studies, bolus injections
sulphate (2-0, 2-5, and 3-0 mg/kg) were with individualised heparin treatment by boluses compared of 3000-6000 IU and continuous infusions of 1200-2400 IU per h in ten stable chronic haemodialysis patients. A cuprophane plate type dialyser was used (duration of dialysis 3-4 h). After dialysis, the extracorporeal circuit was inspected for clot formation by an independent investigator. All 24 dialysis procedures were completed successfully, except for that of one patient who had the lowest dose and who had a thrombotic obstruction 90 min after the start of the procedure. Significant clot formation (large thrombotic patches within dialyser plate and/or clots within bubble catcher) was observed in one patient on each dermatan dose, no significant clot formation occurred with heparin. The third Amsterdam study was a randomised, crossover comparison of bolus injections of 4-5 mg/kg and 6-0 mg/kg dermatan sulphate with heparin treatment. Thirteen chronic stable haemodialysis patients were dialysed with a cuprophane hollow-fibre dialyser for 3-0-4-5 h. All dialyses were completed successfully. There was no significant difference in clot formation in the extracorporeal circuit between the 6-0 mg/kg dermatan sulphate and heparin, whereas with 4-5 mg/kg significantly more clots were observed in the extracorporeal circuit. No serious bleeding events or other significant adverse events occurred in the three studies, and laboratory findings were comparable with those in the London studies. While there are differences in dialysis duration and procedure at the two centres, which lead to some differences in perceived dose requirements for clot-free dialysis, both groups have demonstrated that dermatan sulphate is an effective anticoagulant in haemodialysis. They confirm that it is possible to achieve anticoagulation in man through the HCII pathway of thrombin inhibition, rather than through action on ATIII. The ability to use agents with reduced charge density and with reduced effect upon the KCCT to achieve effective protection against clot formation, raises the possibility of reduced effect on bleeding and may stimulate interest in the HCII pathway as a therapeutic option. of dermatan
REFERENCES 1. Bjork I, Olson S, Shore J. Molecular mechanisms of the accelerating effect of heparin on the reactions between antithrombin and clotting proteinases. In: Lane DA, Lindahl U, eds. Heparin, chemical and biological properties, clinical applications. London: Edward Arnold, 1989: 229-55. 2. Hirsh J. From unfractionated heparins to low molecular weight heparins. Acta Chirurg Scand 1990; 556 suppl: 42-50. 3.Tollefsen DM, Blank MK. Detection of a new heparin-dependent inhibitor of thrombin in human plasma. JClin Invest 1981; 68: 589-96. 4. Tollefsen DM, Pestka CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulphate. J Biol Chem 1983; 258: 6713-16. 5. Okwusidi J, Falcone M, Van Ryn McKenna J, Hirsh J, Ofosu FA, Buchanan MR. In vivo catalysis of thrombin inhibition by antithrombin III or heparin cofactor II and antithrombotic effects: differential effects of unfractionated heparin and dermatan sulphate. Thromb Haemorrh Disorders 1990; 1: 77-80. 6. Van Ryn McKenna J, Gray E, Weber E. Ofosu FA, Buchanan MR. Effects of sulphated polysaccharides on inhibition of thrombus formation initiated by different stimuli. Thromb Haemost 1989; 61:7-9.
7. Fernandez F, Van Ryn J, Ofosu F, Hirsh J, Buchanan M. The haemorrhagic and antithrombotic effects of dermatan sulphate. Br J Haematol 1989; 64: 309-17.
ADDRESSES. Departments of Haematology and Medicine, Charing Cross and Westminster Hospital and Medical School, London, UK (Prof D A Lane, PhD, K. Ryan, MRCP, H. Ireland, PhD, J R. Curtis, FRCP); Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research and Department of Nephrology, Academic Medical Centre, Amsterdam (M. T. Nurmohamed, MD, R. T. Krediet, MD, Prof J. W. ten Cate, MD); and Diatel Amsterdam, Dialysis Centre, Amsterdam, Netherlands (M C. Roggekamp, MD, P Stevens, MD). Correspondence to Prof D. A. Lane, Department of Haematology, Charing Cross and Westminster Medical School, London W6 8RF, UK.
Failure to detect cytomegalovirus DNA in pancreas in type 2 diabetes
attempted to confirm the finding of cytomegalovirus (CMV) nucleic acid sequences in pancreas sections from patients with type 2 diabetes in a large population since this finding has major implications for the pathogenesis of the disorder. A highly sensitive nested polymerase chain reaction method was developed to detect the immediateearly CMV gene in DNA extracted from waxWe have
embedded tissue sections. We could not confirm the previous findings; CMV DNA was not detected in pancreas sections from 43 type 2 diabetic patients or from 38 non-diabetic age-matched subjects, although the method detected CMV DNA, even in very low concentrations, in positive controls.
higher prevalence of cytomegalovirus (CMV) nucleic acid sequences in pancreas sections from patients with type 2 diabetes than in sections from non-diabetic subjects. Independent confirmation of this finding is important because of its implications for the pathogenesis of type 2 diabetes. We have attempted such Lohr and Oldstonel
reported
a
confirmation. At the renal unit, Charing Cross Hospital, London, dermatan sulphate (MF 701; Mediolanum Farmaceutici, Milan) was administered to patients on 5-6 h dialyses with cuprophane hollow-fibre dialysers. The three studies to be reported here were randomised, crossover comparisons in six to eight patients of dermatan sulphate and individualised (optimal) doses of heparin. In the first study bolus injections of 3 mg/kg body weight and 6 mg/kg dermatan sulphate were compared with a bolus plus infusion regimen of heparin. These injections of dermatan sulphate enabled patients to dialyse for a mean of 4-6 h and 5-3 h, respectively, before visible clotting in the bubble trap required administration of additional anticoagulant (heparin) for the procedure to be completed. The mean duration of dialysis on heparin for these patients was 5-9 h. In a second study, administration of dermatan sulphate as a bolus plus infusion (3 mg/kg plus 0-6 mg/kg per h given over the duration of the dialysis) was also not quite effective, 9 mean duration of
