207
remaining 12, 7(58%) had cholangiocarcinomas and all had cholangiofibrosis. No tumours were found in the groups given D.M.N. or parasites alone. Cholangiofibrosis was found in some animals in the D.M.N. group. The tumours were transplantable in homologous animals. These observations suggest that the combined effects of and liverflukes may play an important role in the genesis of intrahepatic bileduct neoplasms in certain human populations. We feel that cholangiocarcinomas arose in these animals because the D.M.N. caused a malignant transformation of the bileduct epithelial cells which had been altered or stimulated to proliferate by the flukes. The presence of flukes had reduced both the amount of D.M.N. and the duration of the treatment necessary before the appearance of the tumours.5 s
knowledge, cholangiocarcinoma has not been previously reported in young women taking oral contraceptives. our
Mallory Institute of Pathology and Department of Pathology, Boston University Medical Center,
EVELYN F. ELLIS PHILLIP R. GORDON LEONARD S. GOTTLIEB
Boston, Massachusetts 02118, U.S.A.
D.M.N.
Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, and Department of Pathobiology,
Faculty of Science, Mahidol University Mahidol University Bangkok, Thailand
NATTH BHAMARAPRAVATI
PROPHYLACTIC ANTIBIOTICS IN CHOLECYSTECTOMY
SIR,--Galland et a1.1,2 and others3 have discussed the choice of
prophylactic antibiotics to prevent wound infections in abdominal surgery. We have reviewed our past five years’ experience in wound infections associated with cholecystectomies of 2902 cholecystectomy patients. 25 had wound infections after surgery. Of the 1735 patients who did not receive prophylactic antibiotics 24 had wound infections (1.38%) while of the 11677 patients who were given such therapy, only 1 had a wound infection. The most
WITAYA THAMAVIT
"
common
cholecystectomy
were
organisms
isolated from wounds after aureus (60%), Escheri-
Staphyloccocus
TABLE I-WOUND INFECTIONS FOLLOWING CHOLECYSTECTOMY
ORAL CONTRACEPTIVES AND CHOLANGIOCARCINOMA tumours have been reported in who have taken oral contraceptives. We report here an unusual type of carcinoma of the liver in a woman who had taken the pill. A 29-year-old woman, married with two normal children, presented with a 2-month history of malaise and a 1-week history of right-upper-quadrant crampy pain. For 22 months before the conception of her second child she had taken ’Norlestrin 2.5/50’ (2.5 mg norethindrone acetate and 50 lay ethinylrestradiol). Physical examination was normal. Ultrasound and liver-spleen scan showed multiple solid defects in the liver. HBSAg test was negative. At laparotomy she was found to have multiple tumour nodules throughout the liver. No other abnormalities were found in the abdominal cavity. Open biopsy of a single hepatic nodule was interpreted as
SiR,-Malignant hepatic
women
adenocarcinoma, moderately differentiated. Investigations
HOSPITAL
at
revealed carcinoembryonic antigen levels from 43 to 79 ng/ml serum with normal alpha-fetoranging protein but did not identify a primary source of tumour other than the liver. The patient was put on a drug regimen for unknown primary tumours and received cyclophosphamide, doxorubicin, carmustine (bis-chloroethyl nitrosourea), and
another
TABLE II-IN-VITRO SENSITIVITY TO ANTIBIOTICS AT HARTFORD
hospital
5-fluorocytosine. 2 months after surgery, chest metastases.
X-ray revealed pulmonary Jaundice and ascites developed, and the patient
became septic. She died 3 months after diagnosis. Necropsy revealed multiple, large, firm tumour nodules in the liver, mainly in the left lobe, with several small metastases to the lungs and regional and hilar lymph-nodes. A careful search revealed no other primary source of tumour, and the tumour histology was that of a cholangiocarcinoma with dense fibrous stroma. Tumour-free sections of liver showed no underlying hepatic disease. Cholangiocarcinoma comprises approximately 20% of primary hepatic malignancies. It generally develops in an otherwise normal liver, with a less striking male predominance than in hepatocellular carcinoma, which arises in cirrhotic livers in approximately 80% of cases.’ Cholangiocarcinoma has its peak incidence in the 6th decade; it is rare in the 3rd decade.2,3 To 5. Tomatis, L., Magee, P. N., Shubik, P. J. natn. Cancer. Inst. 1964, 33, 341. 1. Purtilo, D. T., Gottlieb, L. S. Cancer, 1973, 32, 458. 2. Edmondson, H. A. Tumors of Liver and Intrahepatic Bile Ducts; p. 80. Armed Forces Institute of Pathology, Washington, D.C., 1958. 3. Okuda, K., and others. Cancer, 1977, 39, 232.
chia coli (16%), Klebsiella (12.5%), Serratia (4%), and mixed infections (7.5%). The same organism was cultured from the bile and the wound in 24% of cases. The number of days which elapsed before wound infection was clinically apparent upon the organisms--e.g., Staph. aureus, E. coli, and Klebsiella wound infections usually occurred 1 week after surgery but infection with Serratia or multiple organisms occurred nearly 2 weeks after surgery (table I). All antibiotics (1 g of a cephalosporin, 1 g of ampicillin, or 80 mg of gentamicin) were given by intravenous bolus injection immediately before operation. In the protected group, cephalosporins were the most popular prophylactic antibiotics (72%) and cephazolin was the predominant cephalosporin used (94%). Ampicillin was used in 24% of the patients, and gentamicin in the remaining 4%. The single Staph. aureus wound infection in the prophylactic-treated group was in a patient treated with ampicillin-perhaps not surprisingly since we find that only 19% of Staph. aureus are sensitive to ampicillin. The in-vitro sensitivity to antibiotics of organisms isolated in the past 5 years from cholecystectomy wound infections are
depended
1.
Galland, R. B., Saunders, J. H., Mosley, J. C., Darrell, J. H. Lancet, 1977, ii, 1043. 2. Galland, R. B., Saunders, J. H., Darrell, J. H. ibid. p. 304. 3. Pollock, A. V., Evans, M. ibid. p. 408.
208 n. The anti-staphylococcal activity of the cephalosporins may explain their usefulness in preventing Staph. aureus wound infections.4 Although cephalosporins were in general less effective against gram-negative organisms than the aminoglycosides, there was no wound infection in any patient pretreated with cephalosporins. Gentamicin seems to be a logical alternative to the cephalosporins for biliary-tract prophylaxis since both Staph. aureus and E., coli are completely inhibited by this antibiotic. Gentamicin may be able to prevent infection after biliary-tract surgery because it penetrates gallbladder-wall tissue.’ A single, parenteral, preoperative dose of an antibiotic is thus the optimal prophylactic regimen for preventing wound infections associated with cholecystectomy.6 The prophylactic regimen need not be continued for more than 24 h after surgery since wound infections originate during the operation.’ The choice of an antibiotic for prophylaxis should take into account the drug’s in-vivo or in-vitro activity against the presumed pathogens and the drug should be able to penetrate the target tissues-e.g., the wound or gallbladder wall-in adequate concentration for the duration of the operation. Cephalosporins are a logical choice in biliary-tract surgery because they are active against Staph. aureus and most coliform bacteria. Ampicillin has only limited activity against these organisms but is indicated when the enterococcus is the presumed pathogen.8 Gentamicin is more consistently active against the usual coliform bacteria than are the cephalosporins and, in addition, is active against staphylococci;9 it is thus a reasonable alternative to the cephalosporins for the prophylaxis of patients undergoing cholecystectomy. 10
shown in table
Division of Infectious Diseases and Departments of Internal Medicine and Surgery, Hartford Hospital, Hartford, Connecticut 06115, U.S.A.
BURKE A. CUNHA LUDWIG J. PYRTEK RICHARD QUINTILIANI
LABORATORY-PREPARED REAGENTS OR COMMERCIAL KITS
SiR,-Mr Richardson’s article’ is of interest since it is now fashionable to explore less costly (or better) methods of acquiring much-used hospital laboratory reagents. However, there are dangers in making unrealistic claims for economy in homemade products. For example, in ascribing costs to preparation of "in house" reagents Richardson made no allowance for fixed overheads such as rent, heat, light, and power. Capital investment and the need for eventual replacement of equipment should also be allowed for. The Protein Fractionation Centre has been collaborating with the biochemistry department of the Victoria Infirmary Glasgow to produce a bovine serum for clinical control purposes, and there is little doubt that products made in this way are cheaper than the commercial equivalent. Producing for a "home" market makes it possible to adjust constituents to user specification and to prepare special batches for specific purposes.
The centre operates in five divisions of which one is the production division. Thus the cost element for staffing must allow for labour, supervision, and support services such as engineering, quality control, and administration. It seems probable that in Richardson’s analysis the margin of 32%, for the most profitable comparison between "in house" and "bought-in" kits at 4.
Nightingale,
C.
H., Greene, D. S., Quintiliani, R. J. pharm. Sci. 1975, 64,
1899. 5. 6. 7. 8. 9. 10. 1.
Cunha, B. A., Quintiliani, R. Abstr. Soc. Microbiol. 1977, 77, 15. Strachan, C. J. L. and others. Br. med. J. 1977, i, 1254. Burke, J. F. Surgery, 1961, 1961, 50, 161. Pyrtek, L. J., Bartus, S. A. Surgery Gynec. Obstet. 1967, 125, 101. Richards, F., McCall, C., Cox, C. J. Am. med. Ass. 1971, 215, 1297. Cunha, B. A., Klimek, J. J., Quintiliani, R. Curr. Ther. Res. 1976, 19, Richardson, R. W. Lancet, 1977, ii, 1273.
the 200-per-day level for serum-aspartate-transaminase, is not sufficient to cover all overheads. This criticism is not intended to be destructive of the basic thesis that the N.H.S. should prepare in-house reagents. The N.H.S. has vast resources which could support projects of this type; however, at this stage all costing should be very conservative. There is obvious merit in being able to claim that inhouse preparation is less costly, but in the initial stages it is more valuable to discover that it is not more costly than commercial sources and, if possible, of better quality. Economic viability tends to be a matter of scale and, whilst questioning the validity of the conclusion drawn by Richardson, we have no doubt that, on a larger scale, in-house preparation could be very profitable. Perhaps several laboratories could combine to produce a range of reagents, each at a scale to satisfy a regional need. Basically, that is what the Scottish trial represents, except that the inclusion of the Protein Fractionation Centre in the project injects non-commercial, N.H.S. financed industrial processing technology and skills for operating at scales well beyond the scope of almost all hospital laboratories. Single-source reagents or quality-control material must be independently tested by centres which employ primary methods of standardisation before they are released. Protein Fractionation Centre, Scottish National Blood Transfusion Edinburgh EH17 7QT
Service,
Biochemistry Department, Victoria Infirmary, Glasgow G42 9TY
JOHN G. WATT ANDREW P. KENNY
HEPARIN-INDUCED DECREASE IN CIRCULATING ANTITHROMBIN III
SIR,-Marciniak and Gockerman reported that heparin, when present in the blood of patients for prolonged periods, reduced circulating antithrombin-III (A.T. III) levels.l However, they do not indicate the duration of heparin treatment in the twenty-two patients in whom A.T. m levels were being measured. It would seem that in five patients heparin was continued for 5-6 days. A.T. III, measured as antigen and as functional binding capacity, fell for 3-4 days and then levelled out. What would happen to the A.T. in if heparin were continued
for longer? hospital many patients with postoperative deep thrombosis are given intravenous heparin by constant infusion for much longer than the traditional 7-10 days, often until the maximum clinical improvement has been achieved. Control is monitored by twice-daily thrombin-times. Heparin requirements-sufficient to maintain the thrombin-time in the "therapeutic range" of 25-55 s (giving a ratio of 2:4. 5)--often increase for several days, usually less than 7, and after a steady period of a few more days may then decrease. The requirements then become steady, the dose varying from patient to patient. I have always assumed that heparin requirements are inversely proportional to A.T. III, though A.T. III has not been measured sequentially. My observation would be explained by a fall in A.T. 111 in the early days of heparin therapy, as reported by Marciniak and Gockerman, followed by a rise and then a steady state. One patient with iliofemoral deep venous thrombosis had increasing heparin requirements through her first week on treatment. Intravenous heparin was then stopped and she had a clinical extension of her thrombosis. Heparin was re-introduced and her requirements fell steadily over the next week, when she was able to come off intravenous treatment without further trouble. The implications of these observations are clearly important as they may well have a bearing on the ideal time for heparinisation of any particular patient, at present an unknown quanIn this
venous
529. 1.
Marciniak, E., Gockerman, J. P. Lancet, 1977, ii, 581.
remaining 12, 7(58%) had cholangiocarcinomas and all had cholangiofibrosis. No tumours were found in the groups given D.M.N. or parasites alone. Cholangiofibrosis was found in some animals in the D.M.N. group. The tumours were transplantable in homologous animals. These observations suggest that the combined effects of and liverflukes may play an important role in the genesis of intrahepatic bileduct neoplasms in certain human populations. We feel that cholangiocarcinomas arose in these animals because the D.M.N. caused a malignant transformation of the bileduct epithelial cells which had been altered or stimulated to proliferate by the flukes. The presence of flukes had reduced both the amount of D.M.N. and the duration of the treatment necessary before the appearance of the tumours.5 s
knowledge, cholangiocarcinoma has not been previously reported in young women taking oral contraceptives. our
Mallory Institute of Pathology and Department of Pathology, Boston University Medical Center,
EVELYN F. ELLIS PHILLIP R. GORDON LEONARD S. GOTTLIEB
Boston, Massachusetts 02118, U.S.A.
D.M.N.
Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, and Department of Pathobiology,
Faculty of Science, Mahidol University Mahidol University Bangkok, Thailand
NATTH BHAMARAPRAVATI
PROPHYLACTIC ANTIBIOTICS IN CHOLECYSTECTOMY
SIR,--Galland et a1.1,2 and others3 have discussed the choice of
prophylactic antibiotics to prevent wound infections in abdominal surgery. We have reviewed our past five years’ experience in wound infections associated with cholecystectomies of 2902 cholecystectomy patients. 25 had wound infections after surgery. Of the 1735 patients who did not receive prophylactic antibiotics 24 had wound infections (1.38%) while of the 11677 patients who were given such therapy, only 1 had a wound infection. The most
WITAYA THAMAVIT
"
common
cholecystectomy
were
organisms
isolated from wounds after aureus (60%), Escheri-
Staphyloccocus
TABLE I-WOUND INFECTIONS FOLLOWING CHOLECYSTECTOMY
ORAL CONTRACEPTIVES AND CHOLANGIOCARCINOMA tumours have been reported in who have taken oral contraceptives. We report here an unusual type of carcinoma of the liver in a woman who had taken the pill. A 29-year-old woman, married with two normal children, presented with a 2-month history of malaise and a 1-week history of right-upper-quadrant crampy pain. For 22 months before the conception of her second child she had taken ’Norlestrin 2.5/50’ (2.5 mg norethindrone acetate and 50 lay ethinylrestradiol). Physical examination was normal. Ultrasound and liver-spleen scan showed multiple solid defects in the liver. HBSAg test was negative. At laparotomy she was found to have multiple tumour nodules throughout the liver. No other abnormalities were found in the abdominal cavity. Open biopsy of a single hepatic nodule was interpreted as
SiR,-Malignant hepatic
women
adenocarcinoma, moderately differentiated. Investigations
HOSPITAL
at
revealed carcinoembryonic antigen levels from 43 to 79 ng/ml serum with normal alpha-fetoranging protein but did not identify a primary source of tumour other than the liver. The patient was put on a drug regimen for unknown primary tumours and received cyclophosphamide, doxorubicin, carmustine (bis-chloroethyl nitrosourea), and
another
TABLE II-IN-VITRO SENSITIVITY TO ANTIBIOTICS AT HARTFORD
hospital
5-fluorocytosine. 2 months after surgery, chest metastases.
X-ray revealed pulmonary Jaundice and ascites developed, and the patient
became septic. She died 3 months after diagnosis. Necropsy revealed multiple, large, firm tumour nodules in the liver, mainly in the left lobe, with several small metastases to the lungs and regional and hilar lymph-nodes. A careful search revealed no other primary source of tumour, and the tumour histology was that of a cholangiocarcinoma with dense fibrous stroma. Tumour-free sections of liver showed no underlying hepatic disease. Cholangiocarcinoma comprises approximately 20% of primary hepatic malignancies. It generally develops in an otherwise normal liver, with a less striking male predominance than in hepatocellular carcinoma, which arises in cirrhotic livers in approximately 80% of cases.’ Cholangiocarcinoma has its peak incidence in the 6th decade; it is rare in the 3rd decade.2,3 To 5. Tomatis, L., Magee, P. N., Shubik, P. J. natn. Cancer. Inst. 1964, 33, 341. 1. Purtilo, D. T., Gottlieb, L. S. Cancer, 1973, 32, 458. 2. Edmondson, H. A. Tumors of Liver and Intrahepatic Bile Ducts; p. 80. Armed Forces Institute of Pathology, Washington, D.C., 1958. 3. Okuda, K., and others. Cancer, 1977, 39, 232.
chia coli (16%), Klebsiella (12.5%), Serratia (4%), and mixed infections (7.5%). The same organism was cultured from the bile and the wound in 24% of cases. The number of days which elapsed before wound infection was clinically apparent upon the organisms--e.g., Staph. aureus, E. coli, and Klebsiella wound infections usually occurred 1 week after surgery but infection with Serratia or multiple organisms occurred nearly 2 weeks after surgery (table I). All antibiotics (1 g of a cephalosporin, 1 g of ampicillin, or 80 mg of gentamicin) were given by intravenous bolus injection immediately before operation. In the protected group, cephalosporins were the most popular prophylactic antibiotics (72%) and cephazolin was the predominant cephalosporin used (94%). Ampicillin was used in 24% of the patients, and gentamicin in the remaining 4%. The single Staph. aureus wound infection in the prophylactic-treated group was in a patient treated with ampicillin-perhaps not surprisingly since we find that only 19% of Staph. aureus are sensitive to ampicillin. The in-vitro sensitivity to antibiotics of organisms isolated in the past 5 years from cholecystectomy wound infections are
depended
1.
Galland, R. B., Saunders, J. H., Mosley, J. C., Darrell, J. H. Lancet, 1977, ii, 1043. 2. Galland, R. B., Saunders, J. H., Darrell, J. H. ibid. p. 304. 3. Pollock, A. V., Evans, M. ibid. p. 408.
208 n. The anti-staphylococcal activity of the cephalosporins may explain their usefulness in preventing Staph. aureus wound infections.4 Although cephalosporins were in general less effective against gram-negative organisms than the aminoglycosides, there was no wound infection in any patient pretreated with cephalosporins. Gentamicin seems to be a logical alternative to the cephalosporins for biliary-tract prophylaxis since both Staph. aureus and E., coli are completely inhibited by this antibiotic. Gentamicin may be able to prevent infection after biliary-tract surgery because it penetrates gallbladder-wall tissue.’ A single, parenteral, preoperative dose of an antibiotic is thus the optimal prophylactic regimen for preventing wound infections associated with cholecystectomy.6 The prophylactic regimen need not be continued for more than 24 h after surgery since wound infections originate during the operation.’ The choice of an antibiotic for prophylaxis should take into account the drug’s in-vivo or in-vitro activity against the presumed pathogens and the drug should be able to penetrate the target tissues-e.g., the wound or gallbladder wall-in adequate concentration for the duration of the operation. Cephalosporins are a logical choice in biliary-tract surgery because they are active against Staph. aureus and most coliform bacteria. Ampicillin has only limited activity against these organisms but is indicated when the enterococcus is the presumed pathogen.8 Gentamicin is more consistently active against the usual coliform bacteria than are the cephalosporins and, in addition, is active against staphylococci;9 it is thus a reasonable alternative to the cephalosporins for the prophylaxis of patients undergoing cholecystectomy. 10
shown in table
Division of Infectious Diseases and Departments of Internal Medicine and Surgery, Hartford Hospital, Hartford, Connecticut 06115, U.S.A.
BURKE A. CUNHA LUDWIG J. PYRTEK RICHARD QUINTILIANI
LABORATORY-PREPARED REAGENTS OR COMMERCIAL KITS
SiR,-Mr Richardson’s article’ is of interest since it is now fashionable to explore less costly (or better) methods of acquiring much-used hospital laboratory reagents. However, there are dangers in making unrealistic claims for economy in homemade products. For example, in ascribing costs to preparation of "in house" reagents Richardson made no allowance for fixed overheads such as rent, heat, light, and power. Capital investment and the need for eventual replacement of equipment should also be allowed for. The Protein Fractionation Centre has been collaborating with the biochemistry department of the Victoria Infirmary Glasgow to produce a bovine serum for clinical control purposes, and there is little doubt that products made in this way are cheaper than the commercial equivalent. Producing for a "home" market makes it possible to adjust constituents to user specification and to prepare special batches for specific purposes.
The centre operates in five divisions of which one is the production division. Thus the cost element for staffing must allow for labour, supervision, and support services such as engineering, quality control, and administration. It seems probable that in Richardson’s analysis the margin of 32%, for the most profitable comparison between "in house" and "bought-in" kits at 4.
Nightingale,
C.
H., Greene, D. S., Quintiliani, R. J. pharm. Sci. 1975, 64,
1899. 5. 6. 7. 8. 9. 10. 1.
Cunha, B. A., Quintiliani, R. Abstr. Soc. Microbiol. 1977, 77, 15. Strachan, C. J. L. and others. Br. med. J. 1977, i, 1254. Burke, J. F. Surgery, 1961, 1961, 50, 161. Pyrtek, L. J., Bartus, S. A. Surgery Gynec. Obstet. 1967, 125, 101. Richards, F., McCall, C., Cox, C. J. Am. med. Ass. 1971, 215, 1297. Cunha, B. A., Klimek, J. J., Quintiliani, R. Curr. Ther. Res. 1976, 19, Richardson, R. W. Lancet, 1977, ii, 1273.
the 200-per-day level for serum-aspartate-transaminase, is not sufficient to cover all overheads. This criticism is not intended to be destructive of the basic thesis that the N.H.S. should prepare in-house reagents. The N.H.S. has vast resources which could support projects of this type; however, at this stage all costing should be very conservative. There is obvious merit in being able to claim that inhouse preparation is less costly, but in the initial stages it is more valuable to discover that it is not more costly than commercial sources and, if possible, of better quality. Economic viability tends to be a matter of scale and, whilst questioning the validity of the conclusion drawn by Richardson, we have no doubt that, on a larger scale, in-house preparation could be very profitable. Perhaps several laboratories could combine to produce a range of reagents, each at a scale to satisfy a regional need. Basically, that is what the Scottish trial represents, except that the inclusion of the Protein Fractionation Centre in the project injects non-commercial, N.H.S. financed industrial processing technology and skills for operating at scales well beyond the scope of almost all hospital laboratories. Single-source reagents or quality-control material must be independently tested by centres which employ primary methods of standardisation before they are released. Protein Fractionation Centre, Scottish National Blood Transfusion Edinburgh EH17 7QT
Service,
Biochemistry Department, Victoria Infirmary, Glasgow G42 9TY
JOHN G. WATT ANDREW P. KENNY
HEPARIN-INDUCED DECREASE IN CIRCULATING ANTITHROMBIN III
SIR,-Marciniak and Gockerman reported that heparin, when present in the blood of patients for prolonged periods, reduced circulating antithrombin-III (A.T. III) levels.l However, they do not indicate the duration of heparin treatment in the twenty-two patients in whom A.T. m levels were being measured. It would seem that in five patients heparin was continued for 5-6 days. A.T. III, measured as antigen and as functional binding capacity, fell for 3-4 days and then levelled out. What would happen to the A.T. in if heparin were continued
for longer? hospital many patients with postoperative deep thrombosis are given intravenous heparin by constant infusion for much longer than the traditional 7-10 days, often until the maximum clinical improvement has been achieved. Control is monitored by twice-daily thrombin-times. Heparin requirements-sufficient to maintain the thrombin-time in the "therapeutic range" of 25-55 s (giving a ratio of 2:4. 5)--often increase for several days, usually less than 7, and after a steady period of a few more days may then decrease. The requirements then become steady, the dose varying from patient to patient. I have always assumed that heparin requirements are inversely proportional to A.T. III, though A.T. III has not been measured sequentially. My observation would be explained by a fall in A.T. 111 in the early days of heparin therapy, as reported by Marciniak and Gockerman, followed by a rise and then a steady state. One patient with iliofemoral deep venous thrombosis had increasing heparin requirements through her first week on treatment. Intravenous heparin was then stopped and she had a clinical extension of her thrombosis. Heparin was re-introduced and her requirements fell steadily over the next week, when she was able to come off intravenous treatment without further trouble. The implications of these observations are clearly important as they may well have a bearing on the ideal time for heparinisation of any particular patient, at present an unknown quanIn this
venous
529. 1.
Marciniak, E., Gockerman, J. P. Lancet, 1977, ii, 581.
