251
Initial work suggests that plasma-&bgr;-T.G. may prove a useful index of platelet involvement in thrombotic diseases,1.5-18 and a commercial radioimmunoassay kit is now available. On p. 235 and p. 238, groups from Oxford and Sheffield report attempts to assess in-vivo platelet activation or sequestration in diabetic patients. In both series the mean plasma-[3-T.G. concentration seemed to be higher in diabetic patients than in controls. The Oxford workers found no correlation between the plasma-p-T.G. and the extent or activity of diabetic complications; thus, the raised p-T.G. was probably not secondary to the complications associated with tissue damage. Such a conclusion is supported by the particularly interesting findings of the Sheffield group; plasma-p-T.G. was raised in newly diagnosed untreated diabetics, but it tended to fall after six weeks of therapy (diet alone or diet and oral hypoglycoemic agents. These results certainly support the notion that platelet function is commonly abnormal in diabetes. But they conflict with those of a somewhat similar study reported by the Edinburgh group,19 who found no difference in plasma-p-T.G. levels between controls and diabetic patients with complications. In the Edinburgh study the control group was problematical, showing considerable skewing due to the occasional high values; this feature may represent, in part, the difficulties in obtaining a satisfactory blood-sample on every occasion and in processing blood adequately before the radioimmunoassay. (North of the Border, there may be suggestions that the striking diminution in plasma-&bgr;-r.G. once diabetics were properly controlled [Shefheld data] merely indicated that, in general, Edinburgh patients were better controlled.) There was one obvious technical difference between the investigations reported in this issue and that from Edinburgh. The Edinburgh workers used an anticoagulant mixture which included prostaglandin El (a potent anti-aggregating agent), whereas Oxford and Sheffield used the Amersham kit, which has the same anticoagulant formulation except that prostaglandin is omitted. This raises the interesting possibility that the true circulating plasma levels of &bgr;-T.G. may indeed be normal in most diabetic patients and that the recorded increases (Sheffield and Oxford) resulted from invitro p-T.G. release after venepuncture. This invitro release could be regarded as further evidence of a potential platelet hyperactivity in diabetic patients which is blocked in the presence of prosta-
logical fluids.14
14. Bolton, A. E.,
Ludlam, C. A., Moore, S., Pepper, D. S., Cash, J. D. Br. J. Hœmat. 1976, 33, 233. 15. Ludlam, C. A., Bolton, A. E., Moore, S., Cash, J. D. Lancet, 1975, ii, 259. 16. Redman, C. W. G., Allington, M. J., Bolton, F. G., Stirrat, G. M. ibid. 1977, ii, 248. 17 Denham, M. J., Fisher, M., James, G., Hassan, M. ibid. 1977, i, 1154. 18. Pepper, D. S., Ludlam, C. A. in Platelets and Thrombosis; p. 145. New York, 1977.
19. Campbell, J. W., Dawes, J., Fraser, D. M., Pepper, D. S., Clarke, Duncan, L. J. P., Cash, J. D. Diabetes, 1977, 26, 1175.
Whichever way these results are potentially important. The next step is to look at serial samples from diabetic patients and controls, since interpretation of a single J3-T.G. value can be difficult. Although the Edinburgh study was essentially negative there were 2 patients, out of the 56 studied, who had unequivocally raised plasma--T.G. concentrations. 1 of these patients was studied on four further occasions over several weeks and the abnormality persisted.
glandin E . viewed, they
are
REWARMING FOR ACCIDENTAL HYPOTHERMIA DEATH in accidental hypothermia usually results from cardiac arrest or ventricular fibrillation. Surface rewarming has restored people to normal health as long as an hour after cardiac arrest during severe hypothermia.’ This can be done slowly in warm air or quickly in warm water.2,3 Even when there is ventricular fibrillation or asystole, normal rhythm may return spontaneously, but cardiac massage at half the normal rate is probably wise in such cases-if a trained person is on hand to do it. Likewise, artificial ventilation is desirable if spontaneous breathing is absent. Whether the patient is in, or merely approaching, hypothermic cardiac arrest there is obviously some theoretical advantage in applying the rewarming heat directly to the heart or other parts of the body core rather than to the surface. Many such methods have been suggested. An article from Canada4 describes peritoneal dialysis, haemodialysis, and cardiopulmonary bypass as "relatively simple methods of internal rewarming that are readily available in most hospitals". These methods have all been successfully used to revive hypothermic patients, but they all carry the risk of infection and other damage to the patient, particularly if they are carried out under emergency conditions. Cardiopulmonary bypass may have a place under very special circumstances-for example, when a severely hypothermic patient is already in a hospital fully equipped and prepared for extracorporeal circulation and repeatedly reverts to ventricular fibrillation after attempts at conversion to normal rhythm. Then it does provide an effective way in which the circulation can be restored and the patient simultaneously rewarmed. But even in such extreme cases, effective cardiac massage and pulmonary ventilation, combined with surface rewarming, may have as much chance of success with less trauma to the patient. If the patient may need defibrillation, free warm water is clearly undesirable; then surface heat can be supplied by hot-water bottles, or a rubber blanket or suit through which warm water circulates. The less drastic methods of "core" rewarming include heating by intragastric balloon and warming of inspired air.6 Insertion of an intragastric balloon carries the same risk as laryngeal intubation and other forms of irritation of the upper airway: it can induce reflex car1. Niazi, S. A., Lewis, F. J. Ann. Surg. 1958, 147, 264. 2. Alexander, L. Combined Intelligence Objectives Subcommittee,
item 24, file nos. 26-37, 1946. 3. Golden, F. St. C. Proc. R. Soc. Med. 1973, 66, 1058. 4. Soung, L. S., Swank, L., Ing, T. S., Said, R. A., Goldman, J. W., Perez, J.,
Geis, W. P. Can. med. Ass J. 1977, 117, 1415. B.
F.,
5. Marcus, P. Aviat. Space envir. Med. (in the press). 6. Lloyd, E. L. Br. J. Anœsth 1973, 45, 41.
252 diac slowing and so precipitate ventricular fibrillation. With inspired-air rewarming the amount of heat which can be transferred is small; the air cannot safely be made hotter than 44°C,’ and this allows heat transfer at the rate of only a few percent of the patient’s own metabolic heat production. In well controlled experiments at the Institute of Aviation Medicine,s warm inspired air had no significant effect on deep body temperature. If the control of gas temperature is reliable the procedure is safe and non-invasive, but its effectiveness seems to be very low. There is no statistical evidence that the death-rate is lower with any one method of rewarming than another, but we do know that rapid surface rewarming in a hot bath is highly effective in reviving victims of acute immersion hypothermia;2.3 for victims of slower cooling on the hills, in whom blood volume is likely to have fallen so that rapid rewarming can produce acute hypotension, slower rewarming in air is probably the safest method-as also in hypothermia complicating disease or old age. It is a good general principle not to use difficult and dangerous treatments when a simple and effective one is already available. In some very special cases, radical methods of circulatory rewarming probably offer the best chance of recovery, but for routine use the established methods of surface rewarming have obvious advantages in effectiveness, simplicity of use, and lack of trauma to the patient. 8 At present no method for routine use offers clear advantages over surface rewarming. ANTIGENIC STIMULATION AND MYELOMA
activity in monoclonal immunoglobulins clues to the pathogenesis of myeloma. Until may provide a few years ago, attention was focused on autoantibody activities.’ For instance, more than 5% of monoclonal macroglobulins are antibodies to IgG,2 and one interpretation is that autoantibody-synthesising clones are especially prone to malignant transformation. But myeloma proteins can also possess activity against extrinsic antigens,2,3 and possibly these are more relevant to pathogenesis. Some myeloma proteins have antistreptolysin-0 (A.S.O) activity, and the clinical history may be informative. Kalliomaki and others4 have just reported such a case. A patient with myeloma had a lifelong history of factitious dermatitis, probably with chronic streptococcal skin infection. In 1961 the A.s.O titre was 6400 i.u./ml; and in 1975, when the myeloma globulin was detected, it was 52 200. They refer also to an earlier reports of a myeloma patient aged 38 whose monoclonal protein possessed A.s.O activity and who had had three episodes of rheumatic fever in childhood. Last year, Lustermans and Klein6 reported two patients with monoclonal A.s.O antibodies but no overt evidence of myeloma ; both had a history reminiscent of rheumatic fever. In one the monoclonal fraction was detected only a few ANTIBODY
7. Shanks, C. A., Marsh, H. M. ibid. p. 522. 8. Keatinge, W. R. Practitioner, 1977, 219, 183. 1. Metzger, H. Am. J. Med. 1969, 47, 837. 2. Seligmann, M., Brouet, J. C. Semin. Hemat. 1973, 10, 163. 3. Potter, M. in Multiple Myeloma and Related Disorders, vol. 1 (edited by H. A. Azar and M. Potter). Hagerstown, 1973. 4. Kalliomäki, J. L., Granfors, K., Toivanen, A. Clin. Immun. Immunopath.
1978, 9, 22. 5. Seligmann, M., Danon, 6. Lustermans, A T., Klein,
F., Basch, A., Bernard, J. Nature, 1968, 220, 711. F. J. clin. Path. 1977, 30, 851.
months after the
onset
of symptoms, and this is
not
in-
compatible with the hypothesis of a monoclonal immune that, whenever an titre persists after antibiotic treatment, the search should be on for monoclonal antibodies. Do some "benign" monoclonal gammopathies eventually progress to myeloma? Salmon and Seligmann’ have proposed a two-hit hypothesis for the development of myeloma. The first hit, by some antigen, would lead (perhaps only in genetically disposed hosts) to premalignant monoclonal B-cell proliferation. The second hit would be the oncogenic or mutagenic stimulus leading to neoplastic growth of a susceptible subclone. In support of their hypothesis they cited work in Balb/c mice, in which myeloma is readily induced but which are resistant to myeloma when reared germ-free,8 and the case of a patient who received two injections of antitetanus horse serum 6 years apart, and 30 years later had a myeloma with monoclonal IgG specifically active against horse iX2-macroglobulin.9 Since myeloma growth follows a gompertzian curve and is rapid at sub-clinical level," the long period between antigenic stimulation and occurrence of myeloma implied the existence of a preneoplastic stage. The antibodies in monoclonal immunoglobulins can be clinically harmful - and not merely those specific for auto-antigens. For instance, myeloma was diagnosed in a patient who had been on riboflavin-containing vitamins for three months, and the circulating monoclonal protein had riboflavin-binding activity which caused striking xanthoderma and xanthotrichia.11 In another patient, sudden death was caused by immunological interaction between monoclonal IgM and an intravenous divalent X-ray contrast medium.12 Further work on the nature and role of previous stimulation may provide insight into the cell proliferation of myeloma and other B-cell disorders. response. Lustermans and Klein urge
unusually high A.s.O
MECILLINAM
antibiotic
newly released in the penicillins but has certain novel properties. Other penicillins are synthesised from aminopenicillanic acid, and its antibacterial spectrum is different.’ Whereas most penicillins have considerable activity against gram-positive organisms and are generally less active against the gram-negative, the reverse is true of mecillinam. There is no useful activity against staphylococci or streptococci but Escherichia coli (including many ampicillin-resistant strains) and Klebsiella spp. are susceptible to as little as 0.01to 0.1 mg/l.’ Proteus spp. are less uniform in their sensitivity and Pseudomonas aeruginosa and Bacteroides are resistant. In-vitro testing of this antibiotic is difficult since the activity seems to be influenced by inoculum size and the nature of the medium. This leads to the next major difference between mecillinam and the penicillins. Usually MECILLINAM, U.K., is related
an
to
the
7. Salmon, S. E., Seligmann, M. Lancet, 1974, ii, 1230. 8. Potter, M. Semin. Hemat. 1973, 10, 19. 9. Seligmann, M., Sassy, C., Chevalier, A. J. Immun. 1973, 110, 85. 10. Sullivan, P. W., Salmon, S. E. J. clin. Invest. 1972, 51, 1697. 11. Farhangi, M., Osserman, E. F. New Engl. J. Med. 1976, 294, 177. 12. Harboe, M., Følling, I., Haugen, O. A., Bauer, K. Lancet, 1976, ii, 285. 1. Reeves, D. S. J. Antimicrob. Chemother. 1977, 3, suppl. B, p. 5.
Initial work suggests that plasma-&bgr;-T.G. may prove a useful index of platelet involvement in thrombotic diseases,1.5-18 and a commercial radioimmunoassay kit is now available. On p. 235 and p. 238, groups from Oxford and Sheffield report attempts to assess in-vivo platelet activation or sequestration in diabetic patients. In both series the mean plasma-[3-T.G. concentration seemed to be higher in diabetic patients than in controls. The Oxford workers found no correlation between the plasma-p-T.G. and the extent or activity of diabetic complications; thus, the raised p-T.G. was probably not secondary to the complications associated with tissue damage. Such a conclusion is supported by the particularly interesting findings of the Sheffield group; plasma-p-T.G. was raised in newly diagnosed untreated diabetics, but it tended to fall after six weeks of therapy (diet alone or diet and oral hypoglycoemic agents. These results certainly support the notion that platelet function is commonly abnormal in diabetes. But they conflict with those of a somewhat similar study reported by the Edinburgh group,19 who found no difference in plasma-p-T.G. levels between controls and diabetic patients with complications. In the Edinburgh study the control group was problematical, showing considerable skewing due to the occasional high values; this feature may represent, in part, the difficulties in obtaining a satisfactory blood-sample on every occasion and in processing blood adequately before the radioimmunoassay. (North of the Border, there may be suggestions that the striking diminution in plasma-&bgr;-r.G. once diabetics were properly controlled [Shefheld data] merely indicated that, in general, Edinburgh patients were better controlled.) There was one obvious technical difference between the investigations reported in this issue and that from Edinburgh. The Edinburgh workers used an anticoagulant mixture which included prostaglandin El (a potent anti-aggregating agent), whereas Oxford and Sheffield used the Amersham kit, which has the same anticoagulant formulation except that prostaglandin is omitted. This raises the interesting possibility that the true circulating plasma levels of &bgr;-T.G. may indeed be normal in most diabetic patients and that the recorded increases (Sheffield and Oxford) resulted from invitro p-T.G. release after venepuncture. This invitro release could be regarded as further evidence of a potential platelet hyperactivity in diabetic patients which is blocked in the presence of prosta-
logical fluids.14
14. Bolton, A. E.,
Ludlam, C. A., Moore, S., Pepper, D. S., Cash, J. D. Br. J. Hœmat. 1976, 33, 233. 15. Ludlam, C. A., Bolton, A. E., Moore, S., Cash, J. D. Lancet, 1975, ii, 259. 16. Redman, C. W. G., Allington, M. J., Bolton, F. G., Stirrat, G. M. ibid. 1977, ii, 248. 17 Denham, M. J., Fisher, M., James, G., Hassan, M. ibid. 1977, i, 1154. 18. Pepper, D. S., Ludlam, C. A. in Platelets and Thrombosis; p. 145. New York, 1977.
19. Campbell, J. W., Dawes, J., Fraser, D. M., Pepper, D. S., Clarke, Duncan, L. J. P., Cash, J. D. Diabetes, 1977, 26, 1175.
Whichever way these results are potentially important. The next step is to look at serial samples from diabetic patients and controls, since interpretation of a single J3-T.G. value can be difficult. Although the Edinburgh study was essentially negative there were 2 patients, out of the 56 studied, who had unequivocally raised plasma--T.G. concentrations. 1 of these patients was studied on four further occasions over several weeks and the abnormality persisted.
glandin E . viewed, they
are
REWARMING FOR ACCIDENTAL HYPOTHERMIA DEATH in accidental hypothermia usually results from cardiac arrest or ventricular fibrillation. Surface rewarming has restored people to normal health as long as an hour after cardiac arrest during severe hypothermia.’ This can be done slowly in warm air or quickly in warm water.2,3 Even when there is ventricular fibrillation or asystole, normal rhythm may return spontaneously, but cardiac massage at half the normal rate is probably wise in such cases-if a trained person is on hand to do it. Likewise, artificial ventilation is desirable if spontaneous breathing is absent. Whether the patient is in, or merely approaching, hypothermic cardiac arrest there is obviously some theoretical advantage in applying the rewarming heat directly to the heart or other parts of the body core rather than to the surface. Many such methods have been suggested. An article from Canada4 describes peritoneal dialysis, haemodialysis, and cardiopulmonary bypass as "relatively simple methods of internal rewarming that are readily available in most hospitals". These methods have all been successfully used to revive hypothermic patients, but they all carry the risk of infection and other damage to the patient, particularly if they are carried out under emergency conditions. Cardiopulmonary bypass may have a place under very special circumstances-for example, when a severely hypothermic patient is already in a hospital fully equipped and prepared for extracorporeal circulation and repeatedly reverts to ventricular fibrillation after attempts at conversion to normal rhythm. Then it does provide an effective way in which the circulation can be restored and the patient simultaneously rewarmed. But even in such extreme cases, effective cardiac massage and pulmonary ventilation, combined with surface rewarming, may have as much chance of success with less trauma to the patient. If the patient may need defibrillation, free warm water is clearly undesirable; then surface heat can be supplied by hot-water bottles, or a rubber blanket or suit through which warm water circulates. The less drastic methods of "core" rewarming include heating by intragastric balloon and warming of inspired air.6 Insertion of an intragastric balloon carries the same risk as laryngeal intubation and other forms of irritation of the upper airway: it can induce reflex car1. Niazi, S. A., Lewis, F. J. Ann. Surg. 1958, 147, 264. 2. Alexander, L. Combined Intelligence Objectives Subcommittee,
item 24, file nos. 26-37, 1946. 3. Golden, F. St. C. Proc. R. Soc. Med. 1973, 66, 1058. 4. Soung, L. S., Swank, L., Ing, T. S., Said, R. A., Goldman, J. W., Perez, J.,
Geis, W. P. Can. med. Ass J. 1977, 117, 1415. B.
F.,
5. Marcus, P. Aviat. Space envir. Med. (in the press). 6. Lloyd, E. L. Br. J. Anœsth 1973, 45, 41.
252 diac slowing and so precipitate ventricular fibrillation. With inspired-air rewarming the amount of heat which can be transferred is small; the air cannot safely be made hotter than 44°C,’ and this allows heat transfer at the rate of only a few percent of the patient’s own metabolic heat production. In well controlled experiments at the Institute of Aviation Medicine,s warm inspired air had no significant effect on deep body temperature. If the control of gas temperature is reliable the procedure is safe and non-invasive, but its effectiveness seems to be very low. There is no statistical evidence that the death-rate is lower with any one method of rewarming than another, but we do know that rapid surface rewarming in a hot bath is highly effective in reviving victims of acute immersion hypothermia;2.3 for victims of slower cooling on the hills, in whom blood volume is likely to have fallen so that rapid rewarming can produce acute hypotension, slower rewarming in air is probably the safest method-as also in hypothermia complicating disease or old age. It is a good general principle not to use difficult and dangerous treatments when a simple and effective one is already available. In some very special cases, radical methods of circulatory rewarming probably offer the best chance of recovery, but for routine use the established methods of surface rewarming have obvious advantages in effectiveness, simplicity of use, and lack of trauma to the patient. 8 At present no method for routine use offers clear advantages over surface rewarming. ANTIGENIC STIMULATION AND MYELOMA
activity in monoclonal immunoglobulins clues to the pathogenesis of myeloma. Until may provide a few years ago, attention was focused on autoantibody activities.’ For instance, more than 5% of monoclonal macroglobulins are antibodies to IgG,2 and one interpretation is that autoantibody-synthesising clones are especially prone to malignant transformation. But myeloma proteins can also possess activity against extrinsic antigens,2,3 and possibly these are more relevant to pathogenesis. Some myeloma proteins have antistreptolysin-0 (A.S.O) activity, and the clinical history may be informative. Kalliomaki and others4 have just reported such a case. A patient with myeloma had a lifelong history of factitious dermatitis, probably with chronic streptococcal skin infection. In 1961 the A.s.O titre was 6400 i.u./ml; and in 1975, when the myeloma globulin was detected, it was 52 200. They refer also to an earlier reports of a myeloma patient aged 38 whose monoclonal protein possessed A.s.O activity and who had had three episodes of rheumatic fever in childhood. Last year, Lustermans and Klein6 reported two patients with monoclonal A.s.O antibodies but no overt evidence of myeloma ; both had a history reminiscent of rheumatic fever. In one the monoclonal fraction was detected only a few ANTIBODY
7. Shanks, C. A., Marsh, H. M. ibid. p. 522. 8. Keatinge, W. R. Practitioner, 1977, 219, 183. 1. Metzger, H. Am. J. Med. 1969, 47, 837. 2. Seligmann, M., Brouet, J. C. Semin. Hemat. 1973, 10, 163. 3. Potter, M. in Multiple Myeloma and Related Disorders, vol. 1 (edited by H. A. Azar and M. Potter). Hagerstown, 1973. 4. Kalliomäki, J. L., Granfors, K., Toivanen, A. Clin. Immun. Immunopath.
1978, 9, 22. 5. Seligmann, M., Danon, 6. Lustermans, A T., Klein,
F., Basch, A., Bernard, J. Nature, 1968, 220, 711. F. J. clin. Path. 1977, 30, 851.
months after the
onset
of symptoms, and this is
not
in-
compatible with the hypothesis of a monoclonal immune that, whenever an titre persists after antibiotic treatment, the search should be on for monoclonal antibodies. Do some "benign" monoclonal gammopathies eventually progress to myeloma? Salmon and Seligmann’ have proposed a two-hit hypothesis for the development of myeloma. The first hit, by some antigen, would lead (perhaps only in genetically disposed hosts) to premalignant monoclonal B-cell proliferation. The second hit would be the oncogenic or mutagenic stimulus leading to neoplastic growth of a susceptible subclone. In support of their hypothesis they cited work in Balb/c mice, in which myeloma is readily induced but which are resistant to myeloma when reared germ-free,8 and the case of a patient who received two injections of antitetanus horse serum 6 years apart, and 30 years later had a myeloma with monoclonal IgG specifically active against horse iX2-macroglobulin.9 Since myeloma growth follows a gompertzian curve and is rapid at sub-clinical level," the long period between antigenic stimulation and occurrence of myeloma implied the existence of a preneoplastic stage. The antibodies in monoclonal immunoglobulins can be clinically harmful - and not merely those specific for auto-antigens. For instance, myeloma was diagnosed in a patient who had been on riboflavin-containing vitamins for three months, and the circulating monoclonal protein had riboflavin-binding activity which caused striking xanthoderma and xanthotrichia.11 In another patient, sudden death was caused by immunological interaction between monoclonal IgM and an intravenous divalent X-ray contrast medium.12 Further work on the nature and role of previous stimulation may provide insight into the cell proliferation of myeloma and other B-cell disorders. response. Lustermans and Klein urge
unusually high A.s.O
MECILLINAM
antibiotic
newly released in the penicillins but has certain novel properties. Other penicillins are synthesised from aminopenicillanic acid, and its antibacterial spectrum is different.’ Whereas most penicillins have considerable activity against gram-positive organisms and are generally less active against the gram-negative, the reverse is true of mecillinam. There is no useful activity against staphylococci or streptococci but Escherichia coli (including many ampicillin-resistant strains) and Klebsiella spp. are susceptible to as little as 0.01to 0.1 mg/l.’ Proteus spp. are less uniform in their sensitivity and Pseudomonas aeruginosa and Bacteroides are resistant. In-vitro testing of this antibiotic is difficult since the activity seems to be influenced by inoculum size and the nature of the medium. This leads to the next major difference between mecillinam and the penicillins. Usually MECILLINAM, U.K., is related
an
to
the
7. Salmon, S. E., Seligmann, M. Lancet, 1974, ii, 1230. 8. Potter, M. Semin. Hemat. 1973, 10, 19. 9. Seligmann, M., Sassy, C., Chevalier, A. J. Immun. 1973, 110, 85. 10. Sullivan, P. W., Salmon, S. E. J. clin. Invest. 1972, 51, 1697. 11. Farhangi, M., Osserman, E. F. New Engl. J. Med. 1976, 294, 177. 12. Harboe, M., Følling, I., Haugen, O. A., Bauer, K. Lancet, 1976, ii, 285. 1. Reeves, D. S. J. Antimicrob. Chemother. 1977, 3, suppl. B, p. 5.
