- Email: [email protected]
ADRIAN CONCLUDED
738
their staff would be officers of the regional hospital board, which would take a more active part in the supply organisation and would employ a designated regional supplies officer. The report has been circulated to hospital authorities for comment, with the Minister’s commendation of it as a valuable contribution to an important subject.30 The Minister has excluded from consideration the recommendation to set up a statutory hospital supply board, which was in any case a long-term proposal, and has also not favoured the setting up of supply committees at area level. The rejection of a proposal to set up committees may be unusual, but is not in itself to be
deplored. The members of the Hunt Committee were all professional officers in the various branches of the Ministry and the hospital service, acting in a personal capacity. The report may not be received without reservations, but H.M.c.s in many areas are now convinced of the advantages of joint contracting arrangements into which they entered with suspicion. The implementation of the proposals will depend on the quality and experience of the supplies officers at every level. There can be no greater curse of administration than an inefficient supplies organisation; but the committee has put forward what look like practicable proposals for building up a good one, and the report should be welcomed.
Annotations ADRIAN CONCLUDED
publication of the final report 31 of the Adrian committee, appointed in 1956 " to review the present practice in diagnostic radiology and the use of radiotherapy in non-malignant conditions", marks the end of an enormous task. The final report is brief, the labour was long. Two earlier documents by the committee dealt with mass miniature radiography 32 and the genetic effects of medical X rays.33 Their final pronouncement records the results of what is undoubtedly the largest inquiry yet attempted into the doses received during medical irradiation and their possible somatic effects-that is, possible harm to the patient who is actually irradiated. THE
The committee decided to measure the radiation dose bone-marrow, since this was one of the tissues most susceptible to radiation damage and since leuksemia was one of the important radiation effects to be considered. They concluded that the dose could best be expressed as the mean marrow dose, averaged over the whole active marrow (" at low dose levels, such as those associated with diagnostic radiology, there are theoretical and experimental grounds for believing that the mean dose averaged over all the cells at risk is the one most likely to be relevant to such a radiobiological effect "-namely, the induction of leukxmia). The data available for the calculations were: those furnished by the very large survey made in X-ray departments throughout the country in 1957 and given in to
30. H.M. (66) 69. 31. Radiological Hazards to Patients: Final Office, 1966. 3s. 6d. 32. See Lancet, 1959, i, 975. 33. See ibid. 1960, ii, 1285.
Report.
H.M.
Stationery
the committee’s second report; a vast number of laboratory measurements made on a specially constructed model to determine the relation of skin dose to absorbed dose in underlying marrow cavities; and published details on the distribution of active bone-marrow in the body. The calculated mean marrow doses varied greatly for what was essentially the same type of examination. The " average dose for a single general diagnostic examination’’ (that is, anything except mass miniature radiography, dental radiography, and the diagnostic use of isotopes, was 94 mrad. An examination of the gastrointestinal tract could go as high as 600-1300 mrad and a single chest film as low as 12 mrad. The barium examinations showed a big sex difference for adults, since screening-times were longer for some of the women. The mean marrow doses per examination were : barium meal, males 505 mrad, females 799 mrad; barium enemas, males 528 mrad, females 1062 mrad. From general radiology in N.H.S. and other hospitals the annual mean marrow dose per person of the whole population was 24.4 mrad, to which other mean population doses had to be added as follows:
Of the 22-5 mrad a year from hospital X-rays, barium meals contributed 5-97 mrad (27%), barium swallows and enemas 3-36 mrad (15%), examinations of the spine 3-03 mrad (13-5%), and intravenous pyelography 2-29 mrad (10%). The dose in a single chest examination is small (12 mrad), but the chest is X-rayed so often that the mean annual dose per person was relatively high-namely, 184 mrad (or 8% of the total). Pelvimetry and abdominal examinations during pregnancy accounted for 1.66 mrad (7’3%), and the dose was divided as follows: abdominal examination during pregnancy 1-13 mrad per person per year (mother 0-33, foetus 0.80); pelvimetry 0’53 (mother
0-11, foetus 0-42). What do these doses mean in terms of the risk of leukaemia ? The facts from which this key question must be answered are concerned almost entirely with the increased incidence of leukaemia after irradiation of bonemarrow at the level of some hundreds of rads. The committee decided, however, to attempt an estimate of the risk, and they put it this way. The present annual incidence of leukaemia in the United Kingdom is about 50-60 cases per million of the population-in other words, the chance of an individual contracting leukxmia is between 50 and 60 in a million each year. " Expressed in this way, an individual undergoing some 20’average’ X-ray examinations in the course of a lifetime, would have his annual chance of contracting leukaemia eventually raised (if at all) by at most 2 per million above the level of about 50 to 60 per million for a person having no X-ray examinations." Marrow doses associated with radiotherapy of non-malignant disease were on average much greater than those in radiological examinations, and the average dose for one course of treatment would raise the annual leukaemia risk by an estimated 15 chances per million over a limited period of time. These results support what the committee had to say in the second report.33 No major restrictions were called for in radiological work, but the implementation of the earlier recommendations would materially reduce the dose to the bone-marrow as well as to the gonads. The com-
739
mittee emphasise particularly the restriction of the size of the X-ray beam to the minimum required for the examination and the limitation of all X-ray examinations which mean irradiation of the foetus.
RUSSELL’S VIPER AND THE CASCADE
IN 1750 Patrick Russell went to Turkey and thereafter spent twenty years in the Middle East; he studied plague
and was allowed to wear a turban (an honour seldom conferred on Europeans). He then returned to Edinburgh
Italy, where Felice Fontana, the physiologist, was studying the effects of viper venom on the blood of rabbits. His findings were startling: intravenous injection of venom caused immediate coagulation of the blood, stopping the circulation and instantly killing the animal. In 1781 Russell, at the age of 55, sailed for India, where he made a great study of snakes. Some years later he wrote a large illustrated book about them.’1 So far as the of two these history relates, paths pioneers did not but both would been have cross, surely delighted if they had known that the venom of the viper named after Russell was destined two centuries later to clarify the obscurities of human blood coagulation. In a fascinating account,2 Macfarlane now unfolds the story of why it took thirty years to reach the answer to the deceptively simple question," How does Russell’s viper venom clot blood ? -an answer which finally led to the cascade theory of coagulation.3 In 1904 many years of wrangling and confusion about blood clotting were apparently resolved by the theory of Schmidt and Morawitz, postulating fibrin formation by interaction of the four factors-thromboplastin, prothrombin, calcium, and fibrinogen. This theory survived nearly fifty years, although it did not explain the clotting defect in hxmophilia. In 1911 Addis4 showed that adding a small amount of acid-precipitated fraction from normal plasma rectified clotting of haemophilic blood. By the classical theory this fraction should be prothrombin, via
"
"
"
Addis inferred that prothrombin was defective in haemophilia; but when prothrombin was shown to be normal in hxmophilic blood his experiments were forgotten. Twenty-six years later Patek and Taylormade almost identical experiments, but they called the active fraction " antihaemophilic globulin " and received universal acclaim. Meanwhile Macfarlane had already shown that venom from Russell’s viper was much more effective than thrombin in clotting haemophilic blood, and he was using it to treat haemophilic patients. 6 A venom-lecithin mixture was found to be a more potent thromboplastin than either substance used alone, and the mixture was adopted for the one-stage prothrombin-time test in the control of anticoagulant therapy. But some patients with safe prothrombin levels as estimated by the venom technique began to bleed, and when checked with brain thrombopbstin their blood was found to have almost no prothrombin. These anomalies were only partly explained by demonstration of a fifth clotting factor (factor v) 7 ; so
1 Russell, P. An vol. II, 1801.
Account of Indian
Serpents.
London: vol. I, 1796;
2 Macfarlane, R. G. Oxf. med. Sch. Gaz. 1965, 17, 100. 3 See Lancet, 1964, ii, 135. 4 Addis, T. J. Path. Bact. 1911, 15, 427. Patek, A. J., Taylor, F. H. L. J. clin. Invest. 1937, 16, 6 Macfarlane, R. G., Barnett, B. Lancet, 1934, ii, 985. 7 Owren, P. A. Acta med. scand. 1947, suppl. 194, 1.
but after development of the thromboplastin-generation test, several new factors could be measured quantitatively—XII (Hageman factor) sensitive to surface contact, xi (plasma-thromboplastin antecedent), ix (Christmas factor), vill (antihaemophilic globulin), and x. The mechanism of prothrombin activation could now be classified into an extrinsic system, involving tissue factor and factor vil, and an intrinsic system involving factors XII, xi, ix, and VIII. Factors v and x and phospholipid and calcium were common to both systems-and were apparently required for the action of Russell’s viper venom. But which of these substances was important for this activity? The answer came from using antivenom to limit the reaction-time of the venom: the--venom reacted only with factor x.9 Esnouf and Williams 10 11 then put the whole reaction on a biochemical basis by purifying both the venom coagulant fraction and factor x. And where does the intrinsic counterpart of Russell’s viper venom come from? It was found that factor ix functioned like an enzyme, with factor vm as a substrate, to produce an activator of factor X.12 Indeed, each factor in the intrinsic system was thought to be a proenzyme, and, in clotting, each active enzyme activated the next proenzyme, the process culminating in fibrin formation. Clotting could be regarded as a wave of activation in which each stage amplified the preceding one: the more stages involved the greater the final response. In this " cascade " system8 there are doubts about factor v as a proenzyme, there are positive feed-back mechanisms involving thrombin, and the extrinsic system and the platelets must also be taken into account.13 But the action of Russell’s viper venom seems well established. It has been evolved to act at the highest stage of the amplifier common to both extrinsic and intrinsic systems of vertebrate clotting, and is therefore likely to be shared by most
species.
,
NITROUS OXIDE
THE nitrous oxide produced at the British Oxygen Company’s works at Brentford was contaminated with nitrogen dioxide because-this is almost certain-a reaction vessel was overheated and thereafter elaborate safety precautions failed, under a series of extraordinary coincidences, to detect what had happened. The company has issued a prompt and frank statement admitting liability for the incident, in which two patients died.14 The trouble, it seems, was confined to a day on either side of Aug. 21 (a Sunday) and to a period of 1-2 hours. Nitrous oxide is manufactured commercially by heating
240°C, and the gases evolved are scrubbed, exposed alumina, and liquefied to remove unwanted contaminants, including the highly poisonous nitrogen dioxide. Overheating of the ammonium nitrate would produce more of the dioxide, but normally that would not matter. Unfortunately the purification process failed and so did the tests for detecting contamination. The two chief tests rely on watching solutions through which gas is bubbled and which change from colourless to pink if the gas is contaminated. The reagent consists
ammonium nitrate
to
to
8. 9. 10. 11. 12.
133. 13. 14.
Biggs, R., Douglas, A. S. J. clin. Path. 1953, 6, 23. Macfarlane, R. G. Br. J. Hœmat. 1961, 7, 496. Esnouf, M. P., Williams, W. J. Biochem. J. 1962, 84, 62. Williams, W. J., Esnouf, M. P. ibid. p. 52. Macfarlane, R. G., Biggs, R., Ash, B. J., Denson, K. W. Hœmat. 1964, 10, 530. Macfarlane, R. G. Thromb. Diath. hœm. 1966, 15, 591. See Lancet, Sept. 17, 1966, p. 628.
E.
Br. J.
their staff would be officers of the regional hospital board, which would take a more active part in the supply organisation and would employ a designated regional supplies officer. The report has been circulated to hospital authorities for comment, with the Minister’s commendation of it as a valuable contribution to an important subject.30 The Minister has excluded from consideration the recommendation to set up a statutory hospital supply board, which was in any case a long-term proposal, and has also not favoured the setting up of supply committees at area level. The rejection of a proposal to set up committees may be unusual, but is not in itself to be
deplored. The members of the Hunt Committee were all professional officers in the various branches of the Ministry and the hospital service, acting in a personal capacity. The report may not be received without reservations, but H.M.c.s in many areas are now convinced of the advantages of joint contracting arrangements into which they entered with suspicion. The implementation of the proposals will depend on the quality and experience of the supplies officers at every level. There can be no greater curse of administration than an inefficient supplies organisation; but the committee has put forward what look like practicable proposals for building up a good one, and the report should be welcomed.
Annotations ADRIAN CONCLUDED
publication of the final report 31 of the Adrian committee, appointed in 1956 " to review the present practice in diagnostic radiology and the use of radiotherapy in non-malignant conditions", marks the end of an enormous task. The final report is brief, the labour was long. Two earlier documents by the committee dealt with mass miniature radiography 32 and the genetic effects of medical X rays.33 Their final pronouncement records the results of what is undoubtedly the largest inquiry yet attempted into the doses received during medical irradiation and their possible somatic effects-that is, possible harm to the patient who is actually irradiated. THE
The committee decided to measure the radiation dose bone-marrow, since this was one of the tissues most susceptible to radiation damage and since leuksemia was one of the important radiation effects to be considered. They concluded that the dose could best be expressed as the mean marrow dose, averaged over the whole active marrow (" at low dose levels, such as those associated with diagnostic radiology, there are theoretical and experimental grounds for believing that the mean dose averaged over all the cells at risk is the one most likely to be relevant to such a radiobiological effect "-namely, the induction of leukxmia). The data available for the calculations were: those furnished by the very large survey made in X-ray departments throughout the country in 1957 and given in to
30. H.M. (66) 69. 31. Radiological Hazards to Patients: Final Office, 1966. 3s. 6d. 32. See Lancet, 1959, i, 975. 33. See ibid. 1960, ii, 1285.
Report.
H.M.
Stationery
the committee’s second report; a vast number of laboratory measurements made on a specially constructed model to determine the relation of skin dose to absorbed dose in underlying marrow cavities; and published details on the distribution of active bone-marrow in the body. The calculated mean marrow doses varied greatly for what was essentially the same type of examination. The " average dose for a single general diagnostic examination’’ (that is, anything except mass miniature radiography, dental radiography, and the diagnostic use of isotopes, was 94 mrad. An examination of the gastrointestinal tract could go as high as 600-1300 mrad and a single chest film as low as 12 mrad. The barium examinations showed a big sex difference for adults, since screening-times were longer for some of the women. The mean marrow doses per examination were : barium meal, males 505 mrad, females 799 mrad; barium enemas, males 528 mrad, females 1062 mrad. From general radiology in N.H.S. and other hospitals the annual mean marrow dose per person of the whole population was 24.4 mrad, to which other mean population doses had to be added as follows:
Of the 22-5 mrad a year from hospital X-rays, barium meals contributed 5-97 mrad (27%), barium swallows and enemas 3-36 mrad (15%), examinations of the spine 3-03 mrad (13-5%), and intravenous pyelography 2-29 mrad (10%). The dose in a single chest examination is small (12 mrad), but the chest is X-rayed so often that the mean annual dose per person was relatively high-namely, 184 mrad (or 8% of the total). Pelvimetry and abdominal examinations during pregnancy accounted for 1.66 mrad (7’3%), and the dose was divided as follows: abdominal examination during pregnancy 1-13 mrad per person per year (mother 0-33, foetus 0.80); pelvimetry 0’53 (mother
0-11, foetus 0-42). What do these doses mean in terms of the risk of leukaemia ? The facts from which this key question must be answered are concerned almost entirely with the increased incidence of leukaemia after irradiation of bonemarrow at the level of some hundreds of rads. The committee decided, however, to attempt an estimate of the risk, and they put it this way. The present annual incidence of leukaemia in the United Kingdom is about 50-60 cases per million of the population-in other words, the chance of an individual contracting leukxmia is between 50 and 60 in a million each year. " Expressed in this way, an individual undergoing some 20’average’ X-ray examinations in the course of a lifetime, would have his annual chance of contracting leukaemia eventually raised (if at all) by at most 2 per million above the level of about 50 to 60 per million for a person having no X-ray examinations." Marrow doses associated with radiotherapy of non-malignant disease were on average much greater than those in radiological examinations, and the average dose for one course of treatment would raise the annual leukaemia risk by an estimated 15 chances per million over a limited period of time. These results support what the committee had to say in the second report.33 No major restrictions were called for in radiological work, but the implementation of the earlier recommendations would materially reduce the dose to the bone-marrow as well as to the gonads. The com-
739
mittee emphasise particularly the restriction of the size of the X-ray beam to the minimum required for the examination and the limitation of all X-ray examinations which mean irradiation of the foetus.
RUSSELL’S VIPER AND THE CASCADE
IN 1750 Patrick Russell went to Turkey and thereafter spent twenty years in the Middle East; he studied plague
and was allowed to wear a turban (an honour seldom conferred on Europeans). He then returned to Edinburgh
Italy, where Felice Fontana, the physiologist, was studying the effects of viper venom on the blood of rabbits. His findings were startling: intravenous injection of venom caused immediate coagulation of the blood, stopping the circulation and instantly killing the animal. In 1781 Russell, at the age of 55, sailed for India, where he made a great study of snakes. Some years later he wrote a large illustrated book about them.’1 So far as the of two these history relates, paths pioneers did not but both would been have cross, surely delighted if they had known that the venom of the viper named after Russell was destined two centuries later to clarify the obscurities of human blood coagulation. In a fascinating account,2 Macfarlane now unfolds the story of why it took thirty years to reach the answer to the deceptively simple question," How does Russell’s viper venom clot blood ? -an answer which finally led to the cascade theory of coagulation.3 In 1904 many years of wrangling and confusion about blood clotting were apparently resolved by the theory of Schmidt and Morawitz, postulating fibrin formation by interaction of the four factors-thromboplastin, prothrombin, calcium, and fibrinogen. This theory survived nearly fifty years, although it did not explain the clotting defect in hxmophilia. In 1911 Addis4 showed that adding a small amount of acid-precipitated fraction from normal plasma rectified clotting of haemophilic blood. By the classical theory this fraction should be prothrombin, via
"
"
"
Addis inferred that prothrombin was defective in haemophilia; but when prothrombin was shown to be normal in hxmophilic blood his experiments were forgotten. Twenty-six years later Patek and Taylormade almost identical experiments, but they called the active fraction " antihaemophilic globulin " and received universal acclaim. Meanwhile Macfarlane had already shown that venom from Russell’s viper was much more effective than thrombin in clotting haemophilic blood, and he was using it to treat haemophilic patients. 6 A venom-lecithin mixture was found to be a more potent thromboplastin than either substance used alone, and the mixture was adopted for the one-stage prothrombin-time test in the control of anticoagulant therapy. But some patients with safe prothrombin levels as estimated by the venom technique began to bleed, and when checked with brain thrombopbstin their blood was found to have almost no prothrombin. These anomalies were only partly explained by demonstration of a fifth clotting factor (factor v) 7 ; so
1 Russell, P. An vol. II, 1801.
Account of Indian
Serpents.
London: vol. I, 1796;
2 Macfarlane, R. G. Oxf. med. Sch. Gaz. 1965, 17, 100. 3 See Lancet, 1964, ii, 135. 4 Addis, T. J. Path. Bact. 1911, 15, 427. Patek, A. J., Taylor, F. H. L. J. clin. Invest. 1937, 16, 6 Macfarlane, R. G., Barnett, B. Lancet, 1934, ii, 985. 7 Owren, P. A. Acta med. scand. 1947, suppl. 194, 1.
but after development of the thromboplastin-generation test, several new factors could be measured quantitatively—XII (Hageman factor) sensitive to surface contact, xi (plasma-thromboplastin antecedent), ix (Christmas factor), vill (antihaemophilic globulin), and x. The mechanism of prothrombin activation could now be classified into an extrinsic system, involving tissue factor and factor vil, and an intrinsic system involving factors XII, xi, ix, and VIII. Factors v and x and phospholipid and calcium were common to both systems-and were apparently required for the action of Russell’s viper venom. But which of these substances was important for this activity? The answer came from using antivenom to limit the reaction-time of the venom: the--venom reacted only with factor x.9 Esnouf and Williams 10 11 then put the whole reaction on a biochemical basis by purifying both the venom coagulant fraction and factor x. And where does the intrinsic counterpart of Russell’s viper venom come from? It was found that factor ix functioned like an enzyme, with factor vm as a substrate, to produce an activator of factor X.12 Indeed, each factor in the intrinsic system was thought to be a proenzyme, and, in clotting, each active enzyme activated the next proenzyme, the process culminating in fibrin formation. Clotting could be regarded as a wave of activation in which each stage amplified the preceding one: the more stages involved the greater the final response. In this " cascade " system8 there are doubts about factor v as a proenzyme, there are positive feed-back mechanisms involving thrombin, and the extrinsic system and the platelets must also be taken into account.13 But the action of Russell’s viper venom seems well established. It has been evolved to act at the highest stage of the amplifier common to both extrinsic and intrinsic systems of vertebrate clotting, and is therefore likely to be shared by most
species.
,
NITROUS OXIDE
THE nitrous oxide produced at the British Oxygen Company’s works at Brentford was contaminated with nitrogen dioxide because-this is almost certain-a reaction vessel was overheated and thereafter elaborate safety precautions failed, under a series of extraordinary coincidences, to detect what had happened. The company has issued a prompt and frank statement admitting liability for the incident, in which two patients died.14 The trouble, it seems, was confined to a day on either side of Aug. 21 (a Sunday) and to a period of 1-2 hours. Nitrous oxide is manufactured commercially by heating
240°C, and the gases evolved are scrubbed, exposed alumina, and liquefied to remove unwanted contaminants, including the highly poisonous nitrogen dioxide. Overheating of the ammonium nitrate would produce more of the dioxide, but normally that would not matter. Unfortunately the purification process failed and so did the tests for detecting contamination. The two chief tests rely on watching solutions through which gas is bubbled and which change from colourless to pink if the gas is contaminated. The reagent consists
ammonium nitrate
to
to
8. 9. 10. 11. 12.
133. 13. 14.
Biggs, R., Douglas, A. S. J. clin. Path. 1953, 6, 23. Macfarlane, R. G. Br. J. Hœmat. 1961, 7, 496. Esnouf, M. P., Williams, W. J. Biochem. J. 1962, 84, 62. Williams, W. J., Esnouf, M. P. ibid. p. 52. Macfarlane, R. G., Biggs, R., Ash, B. J., Denson, K. W. Hœmat. 1964, 10, 530. Macfarlane, R. G. Thromb. Diath. hœm. 1966, 15, 591. See Lancet, Sept. 17, 1966, p. 628.
E.
Br. J.