277 often responds well to intensive intravenous fluids, correction of electrolytes, steroids, and withdrawal of antibiotics. We thank Mr A. W.
Hargreaves for assistance
in
publishing this
case.
Salford Royal Hospital, Manchester M60 9EP
J. A. C. THORPE
changes were statistically significant. There in the control group. changes significant Indomethacin may thus interfere with p-blockers by its hypertensive activity rather than by modifying the synthesis of prostaglandins upon which the p-blockers depend. tively.
All of these
were no
A. NYSENBAUM Servicio de Nefrologia, Cuidad Sanitaria de la Seguridad Social
1° de Octubre, Madrid, Spain
ACTIVE THERAPEUTIC MOIETY OF SULPHASALAZINE
,
SiR,-The efficacy of sulphasalazine in ulcerative colitis has been established in several well-controlled trials. After ingestion most of the drug reaches the colon where it is completely split by bacteria into sulphapyridine and 5-aminosalicylic acid (5-A.S.A.). Sulphasalazine is most effective at the site of breakdown. This suggests that a metabolite rather than the parent compound is responsible for the drug’s activity. To determine the therapeutically active moiety of sulphasalazine, suppositories of sulphapyridine (300 mg), 5-A.S.A. (200 mg), or placebo were given to patients with idiopathic proctitis. We did not give sulphasalazine suppositories because the drug is split into sulphapyridine and 5-A.S.A. in the rectum also. The study was double blind, and the patients were allotted at random to one of the three types of suppository. The patients took two suppositories per day for four weeks. Sigmoidoscopy was done before and after the trial. The preliminary results, after inclusion of thirty patients in the trial, are as follows (remission being defined as complete disappearance of clinical symptoms and a normal rectal mucosa at sigmoidoscopy) :
These results accord with those of Azad Khan
et
al.l
the number of patients is small, our results support the view that 5-A.S.A. is the therapeutically active moiety of
Although
sulphasalazine. Division of Gastroenterology, Department ofMedicine, and Department of Pharmacy, St Radboud Hospital,
University of Nijmegen, Nijmegen, Netherlands, and Department of Statistical Consultation, University of Nijmegen
P. A. M. VAN HEES J. H. M. VAN TONGEREN
J. H. BAKKER H. J. J. VAN LIER
INDOMETHACIN AND &bgr;-BLOCKERS IN HYPERTENSION
SiR,—Durao et al. showed that indomethacin modified the effect of p-blockers on arterial pressure in hypertension. We have foundaa reactive increase in prostaglandin activity in 13 patients with essential hypertension all with normal renal function. 6 volunteers were controls. After 3 days on indomethacin (150 mg/day), the mean arterial pressure in the hypertensive group increased from a basal mean value of 118i9 mm Hg to 131±8 mm Hg. Weight increased from a mean basal value of 72± 14 kg to 74+14 kg. The glomerular filtrate and the renal plasma-flow, measured as the creatinine clearance and p-aminohippuric acid clearance, decreased from 95+20 and 612±120 ml/min, respectively, to 78±24 and 499±140 ml/min, respectively. The plasma-renin activity and plasma-aldosterone decreased from 12+10 ng/ml/3h and 14±66 ng/dl respectively to 4±3 ng/ml/3h and 8-9±6 ng/dl respec1. Azad Khan, A. K., Pins, J., Truelove, S. C. Lancet, 1977, ii, 892. 2. Durão, V., Prata, M. M., Gonçalves, L. M. P. Lancet, 1977, ii, 1005.
3. Barrientos, A., Alcazar, J. M., Ruilope, L., Jarillo, D., Rodicio, J. L. Abstracts of meeting of Spanish Society of Nephrology. San Sebastian,
1977, p. 111.
A. BARRIENTOS V. ALCAZAR L. RUILOPE
D. JARILLO J. L. RODICIO
PLATELET AGGREGATION INDUCED BY SWINE INFLUENZA VACCINE
SIR,-Rivard and Potier propose that platelet aggregates induced in some elderly people vaccinated with swine influenza vaccine in the United States may have caused some sudden deaths from heart-disease. Their proposal is interesting but we question whether the platelet aggregation was related to the neuraminidase activity of the virus. We have been studying the effects of neuraminidase and of viruses with neuraminidase activity on platelet function ;2-4 we find that purified neuraminidase does not cause a platelet-release reaction nor induce platelet aggregation. We did not find that desialylated platelets aggregated spontaneously in homologous plasma, and it seems likely that the spontaneous aggregation observed by Hovigs is attributable to impurities in the neuraminidase preparations available in 1965, or to the platelet preparation procedures in use at that time. However, we have found that platelets from which membrane sialic acid has been removed by neuraminidase show slightly enhanced sensitivity to platelet-aggregating agents.3 In experiments with animals, these platelets are rapidly removed from the circulation. Influenza A virus PR8 (which has neuraminidase activity) also removes surface sialic acid from platelets without inducing the release reaction or causing aggregation.4 In animals platelets which have been exposed to this virus and returned to the circulation also do not survive in the circulation. Therefore it may be that the reports of thrombocytopenia in association with influenzaare attributable to removal of platelet membrane sialic acid by influenza virus. In contrast, there are some viruses (such as Newcastle disease virus) which have neuraminidase activity but also induce the platelet-release reaction and platelet aggregation.4 Viruses with multiple effects of this nature probably induce thrombocytopenia by causing platelet-aggregate formation in the circulation and also by removing platelet-membrane sialic acid. It seems likely that the swine influenza vaccine studied by Rivard and Potier induced platelet aggregation in vitro through a mechanism unrelated to its neuraminidase activity. We have tested the bivalent influenza virus vaccine produced by Connaught Laboratories, Downsview, Ontario (lot no. 2807-1) and found that it caused extensive biphasic aggregation of washed human platelets and release of 60% of the contents of the amine storage granules (see table). The aggregating activity was abolished by dialysis and could be restored by adding the preservative in the vaccine (0.01% thimerosal 1. 2.
Rivard, G. E., Potier, M. Lancet, 1977, ii, 302. Turpie, A. G. G., Chernesky, M. A., Larke, R. P. B., Packham, M. A., Mustard, J. F. Lab. Invest. 1973, 28, 575. 3. Greenberg, J., Packham, M. A., Cazenave, J.-P., Reimers, H.-J., Mustard, J. F. ibid. 1975, 32, 476. 4. Scott, S., Reimers, H.-J., Chernesky, M., Greenberg, J. P., Kinlough-Rathbone, R., Packham, M. A., Mustard, J. F. Circulation, 1976, 54, 199. 5. Hovig, T. Thromb. Diath. hœmorrh. 1965, 13, 84. 6. Jamieson, G. A., Pepper, D. S. in The Circulating Platelet (edited by S. A. Johnson); p. 189. New York, 1971. 7. Mustard, J. F., Perry, D. W., Ardlie, N. G., Packham, M. A. Br. J. Hœmat. 1972, 22, 193. 8. Leone, G., Boni, P., Vincenti, A. Thrombos. Hæmostas. 1976, 35, 249. 9. Kinlough-Rathbone, R. L., Packham, M. A., Mustard, J. F. Thromb. Res. 1976, 9, 669.
278 The biochemical and antibiotic susceptibility tests were done with media supplemented with 0.001% pyridoxal hydrochloride. Therefore, these strains of Strep. mitior should be referred
EFFECT OF COMPONENTS OF INFLUENZA VIRUS VACCINE ON HUMAN
PLATELETS*
to as
"pyridoxal-dependent" not "pyridoxine-dependent". e
School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, U.S.A.
ROBERTA B. CAREY
CEREBRAL VENTRICULAR SIZE IN CHRONIC SCHIZOPHRENIA
*Human platelet suspension in ’Tyrode’ solution containing 0.35% albumin and apyrase.’ Platelets were prelabelled with 14C-serotonin for measurement of release of amine storage granule contents3and with 51Cr for measurement of loss of cytoplasmic constituents.9 Aggregation was recorded with a Payton aggregation module (Payton As-
sociates, Rexdale, Ontario). Concentrations listed the platelet suspension.
are
final concentrations after all additions
to
[thiomersal]). The preservative itself caused platelet aggregation and the release of 40-50% of the contents of the amine storage granules (see table). Leone et a1.8 have also reported that a concentration of thimerosal as low as 20 fLmol/l causes platelet aggregation in human platelet-rich plasma. Since the concentration of thimerosal in the aggregation experiments of Rivard and Potier would have been 25 mol/1 it seems likely that the aggregation they observed was, at least in part, caused by the preservative. It is also possible that other impurities in the vaccine may be capable of causing or contributing to platelet aggregation or that the strains of influenza virus in the vaccine may act like Newcastle disease virus and have several effects on the platelets. It is unlikely that the neuraminidase activity of the vaccine is responsible for its platelet-aggregating effects. It also seems improbable, in our opinion, that subcutaneous or intramuscular injection of 0.5 ml of vaccine would cause sufficient virsemia to produce platelet aggregates in the circulation. S. SCOTT J. F. MUSTARD Department of Pathology, M. CHERNESKY McMaster University, R. L. KINLOUGH-RATHBONE Hamilton, Ontario L85 4J9, Canada Department of Biochemistry,
University ofToronto
SiR,—The correspondence which followed the report of Johnstone et at.’ that the ventricular size of chronic institutionalised schizophrenic patients was larger than that found in a control group included several explanations of the result and highlighted the need for further studies.3.4 During the past three years, eleven patients with a clinical diagnosis of schizophrenia have been examined by computerised tomography (c.T.) at the National Hospital and an assessment of the Evans index2 was made. These patients were referred either from a psychiatric hospital where they were resident or from a general practitioner and the main reason for referral was to exclude organic disease. The diagnosis of schizophrenia was made either by a referring psychiatrist or by psychiatrists at’the National Hospital. Details of these patients and the results of their c.T. scans are given in the table. In each case the Evans index fell within the normal range (
Hargreaves for assistance
in
publishing this
case.
Salford Royal Hospital, Manchester M60 9EP
J. A. C. THORPE
changes were statistically significant. There in the control group. changes significant Indomethacin may thus interfere with p-blockers by its hypertensive activity rather than by modifying the synthesis of prostaglandins upon which the p-blockers depend. tively.
All of these
were no
A. NYSENBAUM Servicio de Nefrologia, Cuidad Sanitaria de la Seguridad Social
1° de Octubre, Madrid, Spain
ACTIVE THERAPEUTIC MOIETY OF SULPHASALAZINE
,
SiR,-The efficacy of sulphasalazine in ulcerative colitis has been established in several well-controlled trials. After ingestion most of the drug reaches the colon where it is completely split by bacteria into sulphapyridine and 5-aminosalicylic acid (5-A.S.A.). Sulphasalazine is most effective at the site of breakdown. This suggests that a metabolite rather than the parent compound is responsible for the drug’s activity. To determine the therapeutically active moiety of sulphasalazine, suppositories of sulphapyridine (300 mg), 5-A.S.A. (200 mg), or placebo were given to patients with idiopathic proctitis. We did not give sulphasalazine suppositories because the drug is split into sulphapyridine and 5-A.S.A. in the rectum also. The study was double blind, and the patients were allotted at random to one of the three types of suppository. The patients took two suppositories per day for four weeks. Sigmoidoscopy was done before and after the trial. The preliminary results, after inclusion of thirty patients in the trial, are as follows (remission being defined as complete disappearance of clinical symptoms and a normal rectal mucosa at sigmoidoscopy) :
These results accord with those of Azad Khan
et
al.l
the number of patients is small, our results support the view that 5-A.S.A. is the therapeutically active moiety of
Although
sulphasalazine. Division of Gastroenterology, Department ofMedicine, and Department of Pharmacy, St Radboud Hospital,
University of Nijmegen, Nijmegen, Netherlands, and Department of Statistical Consultation, University of Nijmegen
P. A. M. VAN HEES J. H. M. VAN TONGEREN
J. H. BAKKER H. J. J. VAN LIER
INDOMETHACIN AND &bgr;-BLOCKERS IN HYPERTENSION
SiR,—Durao et al. showed that indomethacin modified the effect of p-blockers on arterial pressure in hypertension. We have foundaa reactive increase in prostaglandin activity in 13 patients with essential hypertension all with normal renal function. 6 volunteers were controls. After 3 days on indomethacin (150 mg/day), the mean arterial pressure in the hypertensive group increased from a basal mean value of 118i9 mm Hg to 131±8 mm Hg. Weight increased from a mean basal value of 72± 14 kg to 74+14 kg. The glomerular filtrate and the renal plasma-flow, measured as the creatinine clearance and p-aminohippuric acid clearance, decreased from 95+20 and 612±120 ml/min, respectively, to 78±24 and 499±140 ml/min, respectively. The plasma-renin activity and plasma-aldosterone decreased from 12+10 ng/ml/3h and 14±66 ng/dl respectively to 4±3 ng/ml/3h and 8-9±6 ng/dl respec1. Azad Khan, A. K., Pins, J., Truelove, S. C. Lancet, 1977, ii, 892. 2. Durão, V., Prata, M. M., Gonçalves, L. M. P. Lancet, 1977, ii, 1005.
3. Barrientos, A., Alcazar, J. M., Ruilope, L., Jarillo, D., Rodicio, J. L. Abstracts of meeting of Spanish Society of Nephrology. San Sebastian,
1977, p. 111.
A. BARRIENTOS V. ALCAZAR L. RUILOPE
D. JARILLO J. L. RODICIO
PLATELET AGGREGATION INDUCED BY SWINE INFLUENZA VACCINE
SIR,-Rivard and Potier propose that platelet aggregates induced in some elderly people vaccinated with swine influenza vaccine in the United States may have caused some sudden deaths from heart-disease. Their proposal is interesting but we question whether the platelet aggregation was related to the neuraminidase activity of the virus. We have been studying the effects of neuraminidase and of viruses with neuraminidase activity on platelet function ;2-4 we find that purified neuraminidase does not cause a platelet-release reaction nor induce platelet aggregation. We did not find that desialylated platelets aggregated spontaneously in homologous plasma, and it seems likely that the spontaneous aggregation observed by Hovigs is attributable to impurities in the neuraminidase preparations available in 1965, or to the platelet preparation procedures in use at that time. However, we have found that platelets from which membrane sialic acid has been removed by neuraminidase show slightly enhanced sensitivity to platelet-aggregating agents.3 In experiments with animals, these platelets are rapidly removed from the circulation. Influenza A virus PR8 (which has neuraminidase activity) also removes surface sialic acid from platelets without inducing the release reaction or causing aggregation.4 In animals platelets which have been exposed to this virus and returned to the circulation also do not survive in the circulation. Therefore it may be that the reports of thrombocytopenia in association with influenzaare attributable to removal of platelet membrane sialic acid by influenza virus. In contrast, there are some viruses (such as Newcastle disease virus) which have neuraminidase activity but also induce the platelet-release reaction and platelet aggregation.4 Viruses with multiple effects of this nature probably induce thrombocytopenia by causing platelet-aggregate formation in the circulation and also by removing platelet-membrane sialic acid. It seems likely that the swine influenza vaccine studied by Rivard and Potier induced platelet aggregation in vitro through a mechanism unrelated to its neuraminidase activity. We have tested the bivalent influenza virus vaccine produced by Connaught Laboratories, Downsview, Ontario (lot no. 2807-1) and found that it caused extensive biphasic aggregation of washed human platelets and release of 60% of the contents of the amine storage granules (see table). The aggregating activity was abolished by dialysis and could be restored by adding the preservative in the vaccine (0.01% thimerosal 1. 2.
Rivard, G. E., Potier, M. Lancet, 1977, ii, 302. Turpie, A. G. G., Chernesky, M. A., Larke, R. P. B., Packham, M. A., Mustard, J. F. Lab. Invest. 1973, 28, 575. 3. Greenberg, J., Packham, M. A., Cazenave, J.-P., Reimers, H.-J., Mustard, J. F. ibid. 1975, 32, 476. 4. Scott, S., Reimers, H.-J., Chernesky, M., Greenberg, J. P., Kinlough-Rathbone, R., Packham, M. A., Mustard, J. F. Circulation, 1976, 54, 199. 5. Hovig, T. Thromb. Diath. hœmorrh. 1965, 13, 84. 6. Jamieson, G. A., Pepper, D. S. in The Circulating Platelet (edited by S. A. Johnson); p. 189. New York, 1971. 7. Mustard, J. F., Perry, D. W., Ardlie, N. G., Packham, M. A. Br. J. Hœmat. 1972, 22, 193. 8. Leone, G., Boni, P., Vincenti, A. Thrombos. Hæmostas. 1976, 35, 249. 9. Kinlough-Rathbone, R. L., Packham, M. A., Mustard, J. F. Thromb. Res. 1976, 9, 669.
278 The biochemical and antibiotic susceptibility tests were done with media supplemented with 0.001% pyridoxal hydrochloride. Therefore, these strains of Strep. mitior should be referred
EFFECT OF COMPONENTS OF INFLUENZA VIRUS VACCINE ON HUMAN
PLATELETS*
to as
"pyridoxal-dependent" not "pyridoxine-dependent". e
School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, U.S.A.
ROBERTA B. CAREY
CEREBRAL VENTRICULAR SIZE IN CHRONIC SCHIZOPHRENIA
*Human platelet suspension in ’Tyrode’ solution containing 0.35% albumin and apyrase.’ Platelets were prelabelled with 14C-serotonin for measurement of release of amine storage granule contents3and with 51Cr for measurement of loss of cytoplasmic constituents.9 Aggregation was recorded with a Payton aggregation module (Payton As-
sociates, Rexdale, Ontario). Concentrations listed the platelet suspension.
are
final concentrations after all additions
to
[thiomersal]). The preservative itself caused platelet aggregation and the release of 40-50% of the contents of the amine storage granules (see table). Leone et a1.8 have also reported that a concentration of thimerosal as low as 20 fLmol/l causes platelet aggregation in human platelet-rich plasma. Since the concentration of thimerosal in the aggregation experiments of Rivard and Potier would have been 25 mol/1 it seems likely that the aggregation they observed was, at least in part, caused by the preservative. It is also possible that other impurities in the vaccine may be capable of causing or contributing to platelet aggregation or that the strains of influenza virus in the vaccine may act like Newcastle disease virus and have several effects on the platelets. It is unlikely that the neuraminidase activity of the vaccine is responsible for its platelet-aggregating effects. It also seems improbable, in our opinion, that subcutaneous or intramuscular injection of 0.5 ml of vaccine would cause sufficient virsemia to produce platelet aggregates in the circulation. S. SCOTT J. F. MUSTARD Department of Pathology, M. CHERNESKY McMaster University, R. L. KINLOUGH-RATHBONE Hamilton, Ontario L85 4J9, Canada Department of Biochemistry,
University ofToronto
SiR,—The correspondence which followed the report of Johnstone et at.’ that the ventricular size of chronic institutionalised schizophrenic patients was larger than that found in a control group included several explanations of the result and highlighted the need for further studies.3.4 During the past three years, eleven patients with a clinical diagnosis of schizophrenia have been examined by computerised tomography (c.T.) at the National Hospital and an assessment of the Evans index2 was made. These patients were referred either from a psychiatric hospital where they were resident or from a general practitioner and the main reason for referral was to exclude organic disease. The diagnosis of schizophrenia was made either by a referring psychiatrist or by psychiatrists at’the National Hospital. Details of these patients and the results of their c.T. scans are given in the table. In each case the Evans index fell within the normal range (
