- Email: [email protected]
ST-SEGMENT DISPLACEMENT AFTER ACUTE MYOCARDIAL INFARCTION
665
Suizzested ferric-reductase shunt.
the mitochondrial level. Normally, the addition of a substrate for the Krebs cycle to an intact mitochondrial preparation leads to a very slow rate of oxygen uptake, reflecting the minimal movement of electrons down the electron-transport chain. When adenosine diphosphate is added in addition to the Krebs-cycle substrate, oxygen uptake is very rapid. These mitochondria are said to exhibit respiratory control. As early as three hours after the ingestion of a toxic quantity of iron, Ganote and Nahara were able to demonstrate an increased rate of oxygen uptake in the presence of a Krebs-cycle substrate alone, and a decreased rate of oxygen uptake after the additional provision of adenosine diphosphate. The rates of oxygen uptake in both these situations were nearly the same in iron-poisoned animals. Thus, in iron-poisoned mitochondria, the addition of a substrate produces electron transport and oxygen uptake, while the additional provision of adenosine diphosphate does not lead to a further increase in oxygen uptake. These poisoned mitochondria can be said to lack respiratory control. The basis of these in-vitro perturbations in mitochondrial function might be explained, at least in part, by a report of Barnes et al. on mitochondrial iron metabolism.l3 These workers described a previously unknown enzymatic activity, which we shall refer to as ferric reductase, associated with the inner surface of the inner mitochondrial membrane and catalysing the reduction of ferric iron to ferrous iron. Iron in the ferrous state is the substrate for ferrochelatase, which inserts iron into protoporphyrin ix to form heme. It seems reasonable that, in the presence of excess iron, the ferric reductase could serve as a shunt for electrons, removing them from their usual pathway and donating them to the ferric iron. The ferrous iron produced might then be oxidised by oxygen, setting up a cycle as illustrated in the accompanying figure. Such a shunt is suggested by the experimentally demonstrated oxygen uptake by mitochondria provided with ferric ions in the presence of rotenone, which blocks electron flow between a flavoprotein and co-enzyme Q. Oxygen is then taken up when the ferrous iron generated via the ferric-reductase shunt is auto-oxidised back to ferric iron within the mitochondrial matrix. Although not initially recognised, ferric reductase may thus have pivotal importance in the clinical, morphological, and biochemical consequences of iron intoxication. Given unlimited supplies of the ferric ion, the enzyme could preferentially catalyse the shunting of electrons away from the electron-transport chain. This would be feasible since the reduction of ferric iron is thermodynamically favoured over the channelling of electrons through the conventional cytochrome system. This surmise is consistent with the demonstrated loss of respiratory control in liver mitochondria from iron-poisoned animals and would explain at
13.
Barnes, R., Connelly, J. L., Jones, O. T. G. Biochem. J. 1972, 128, 1043.
the changes observed in the rates of oxygen uptake in the presence and absence of adenosine diphosphate. An active ferric-reductase shunt would result directly in immediate cessation of aerobic adenosine-triphosphate synthesis, precipitating a cellular energy crisis. This could be correlated with the elevated lactic and citric acid levels and the depletion of glycogen stores observed in iron poisoning. Ultimately, failure to synthesise sufficient adenosine triphosphate could lead to cell death. Obviously the ferric-reductase shunt need not be localised exclusively to liver mitochondria, and a similar explanation might be applicable to the cardiovascular, neurological, and gastrointestinal manifestations associated with iron intoxication. The existence of the ferric-reductase shunt may provide a point of departure for further investigation of the biochemical mechanism of acute iron toxicity and may have a
bearing
on
treatment.
Boston University School of
Medicine, City Hospital, Boston, Massachusetts, U.S.A. Boston University School of Boston
JAMES L. ROBOTHAM. ROBERT F. TROXLER.
Medicine.
Johns Hopkins University School Medicine, Baltimore, Maryland.
o
PAUL S. LIETMAN.
ST-SEGMENT DISPLACEMENT AFTER ACUTE MYOCARDIAL INFARCTION
SIR,-The article by Dr Morris and his colleagues (Aug. 17, p. 372) requires comment. They state that STsegment displacement at 48 hours provides no additional information for predicting those patients in whom complications subsequently develop over a six-week period. This statement may be misconstrued. Certainly no statistician will believe that Morris et al. have proved the absence of a relationship between the ST-segment shift and the development of late ventricular dysrhythmias. On the other hand, our data clearly indicate the presence of such a relationship. In the past seven years ST-segment displacement has been used in the assessment of the duration of monitoring in the Belfast coronary-care units. 1-3 In a detailed prospective study, 187 of 466 patients were 48 hours free from risk factors evident on clinical examination.4 31 of the 187 had ST-segment displacement greater than 2 mm., and among these the incidence of late ventricular dysrhythmias was 23%. The ST segment had fallen below 2 mm. in 156 of the 187, and among these the incidence of late ventricular dysrhythmias was 1% (p < 0-001). Morris et al. do not report the incidence of late ventricular dysrhythmias among patients whose ST segment had fallen below 2 mm. at the end of 48 hours. It is, therefore, difficult to understand how they conclude that ST-segment displacement would not provide any information additional to simple clinical examination. The conclusions of Morris et al. are at variance not only with those reached in Belfast but also with the conclusions of workers in Denmark and at Harvard. Nielsen,5 in a study of 404 patients, found that the magnitude of STsegment elevation gave valuable prognostic information useful in the selection of patients for prolonged monitoring. Madias et al.6 also found that the magnitude of the ST shift correlated with the clinical course and prognosis.
at
1. 2.
3. 4. 5. 6.
Pantridge, J. F. Unpublished. Boyle, D. McC., Barber, J. M., Walsh, M. J., Shivalingappa, G., Chaturvedi, N. C. Lancet, 1972, ii, 57. Chaturvedi, N. C., Walsh, M. J., Evans, A., Munro, P., Boyle, D. McC., Barber, J. M. Br. Heart J. 1974, 36, 533. Wilson, C., Pantridge, J. F. Lancet, 1973, ii, 1284. Nielsen, B. L. Circulation, 1973, 48, 338. Madias, J. E., Venkataraman, K., Vokonas, P. S., Hood, W. B., Jr. ibid. 1973, suppl. IV, p. 195.
666 The explanation of the anomalous conclusions of Morris al. may lie in large part in the difficulties inherent in the retrospective study of inadequate data. C. WILSON Royal Victoria Hospital, A. J. ADGEY A. Grosvenor Road, D. McC. BOYLE. Belfast BT12 6BA. et
BABES -
----T j-
_
__
_
-____
Stefan S. Nicolau Institute of Virology, 285 Sos. Mihai Bravu, Bucharest, Romania.
SIR,-Dr Frizzera and his associates
BABEŞ.
6
described
an
interesting disorder in which immunoblastic proliferation is accompanied by proliferation of small venules and hypertrophy and hyperplasia of endothelial cells within such vessels. They believe this process to be non-neoplastic, and comment on its histopathological resemblance to a graft-v. -host reaction. That immunoblastic and endothelial proliferation occur together in this disorder is of considerable theoretical interest. Frizzera et al. speculate that the disorder may actually represent a graft-v.-host reaction, presumably autoimmune in origin. Allograft rejection is accompanied by endothelial hypertrophy,’-1° and in rejecting ovine renal allografts endothelial mitosis has been observed.10 These endothelial changes have been considered a consequence of attack by donor lymphoid cells on host endothelium. We have observed striking endothelial proliferation in venules which were the site of lymphocytic and immunoblastic emigration in the course of experimental immune synovitis in rabbits. 11 Here, of course, both lymphoid and endothelial cells were of host origin. It appears, therefore, that stimulated lymphoid cells somehow cause endothelial cells to proliferate. It is possible that this is effected through release of a soluble mediator substance or lymphokine ". In this regard, it is perhaps relevant that Folkman et al.12 "
have described a soluble substance in tumours which stimulates vascular proliferation. On the other hand, it is
9. 10. 11. 12.
SMOKING AND LUNG CANCER
SIR,-Professor Burch has convincingly advocated 1-3 reconsideration of the genotypic explanation (put forward by R. A. Fisher 4) for the smoking/lung-cancer correlation. In addition, Burch has called for hypotheses to be advanced " that are consistent .with the epidemiological evidence". This letter attempts such a hypothesis, open (at least in
a
experimental investigation. following appear to militate against Fisher’s hypo(1) it seems strange that a gene(s) will increase the probability of lung cancer and smoking; (2) there has been a secular change in lung-cancer incidence, as the recorded
part)
to
The thesis :
of increase differs between the sexes.4 Considering (1), genes related to the incidence of certain diseases (including some cancers) are found in the immune response (Ir), histocompatibility (HL-A), and mixed lymphocyte culture (M.L.C.) chromosome segment.’ These genes control both humoral and cellular specific immune reactions on an all-or-almost-none basis. There is reason to believe that such supergene segments consist of coadapted alleles, the success of which depends upon the consistent association of a number of alleles 6,7 (in this case certain immune-react or non-react alleles associating with certain other react or non-react alleles). The genotypes produced are characterised by particular patterns of immune reactions. Furthermore, cross-over evidence indicates hundreds of other unidentified loci in this supergene,8 with a distinct possibility that many of these loci control specific immune reactions. With regard to smoking, the lungs provide a major antigen entry point into the body.9 I suggest: (a) smoke droplets stimulate a range of immune reactions; (b) the pattern of reactions to the droplet compounds will differ according to the Ir, HL-A, M.L.C. specificities of the individual; (c) stress-relieving effects of nicotine have been emphasised as the reason for the smoking habit," but the presence or lack of immune reactions may negate these effects (e.g., unpleasant hypersensitivity in " reactors" or toxicity in " non-reactors) ", influencing smoking rate
VINCENT T.
DYSPROTEINÆMIA
8.
GRAHAM, JR.
-_____
PATHOGENESIS OF VASCULAR PROLIFERATION IN ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY WITH
2. 3. 4. 5. 6. 7.
Department of Medicine, Cape Western Reserve University, University Hospitals, Cleveland, Ohio 44106, U.S.A. RICHARD C.
OR PETRI DISH?
SIR,-In his first treatise on bacteriology, published in May, 1885,1 Victor Babes described the use of a low-walled jar for bacteria isolations. In the same year Nicati and Rietsch also mentioned these jars, which they used for the isolation of the cholera vibrio.2 In 1887 Petri3 described his use, on a large scale, of this type of low-walled jar, which became known as the Petri-Schalen or Petri dish. Later, Frdnkel4 supported Babe’s assertionthat the credit for the conception and application of this idea should go to Babes and not to Petri. Is it now too late to try to claim this discovery for Romania ?
1.
also possible that endothelial proliferation is a consequence of direct cellular interaction between stimulated lymphoid cells and endothelium. Further investigation is needed to distinguish between these possibilities.
Cornil, A. V., Babes, V. Les bactéries et leur rôle dans l’éthiologie, l’anatomie et l’histologie pathologique des maladies infectieuses. Paris, 1885. Nicati, W., Rietsch, S. Arch. physiol. norm. path. 1885, 6, 72. Petri, R. J. Zentbl. Bakt. ParasitKde, 1887, 1, 279. Quoted in Victor Babeş, Opere alese. Bucharest, 1954. Babeş, V., Vico, H. Rom. med. 1898, 6, 433. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. Williams, P. L., Williams, M. A., Kountz, S. L., Dempster, W. J. J. Anat. 1964, 98, 545. Porter, K. A., Joseph, N. H., Rendall, J. M., Stolinski, C., Hoehn, R. J., Calne, R. Y. Lab. Invest. 1964, 13, 1080. Feldman, J. D., Lee, S. J. exp. Med. 1967, 126, 783. Pedersen, N. C., Morris, B. ibid. 1970, 131, 936. Graham, R. C., Jr., Shannon, S. L. Am. J. Path. 1972, 69, 7. Folkman, J., Merler, E., Abernathy, C., Williams, G. J. exp. Med. 1971, 133, 275.
(cigarettes, cigar, pipe, non-smoking) choices; (d)
an
immune reaction is not without its drawbacks (e.g., general 11 and specific 12 immune depression may result). Such depression has been implicated in a predisposition to at least one human neoplasm. 12 If we assume smokers are generally " reactors " to smoke droplets and that reaction predisposes to lung cancer we may expect to observe a genetic correlation and (with increased cigarette consumption) a certain amount of causal effect. We can also expect non-react individuals to possess react genes not found in the smoker supergene (s) and can predict that non-smokers will be predisposed to 1. 2. 3. 4.
Burch, P. R. J. Lancet, 1972, ii, 132. Burch, P. R. J. ibid. 1973, i, 939. Burch, P. R. J. ibid. 1973, ii, 1315. Fisher, R. A. Smoking: the Cancer Controversy. Edinburgh, 1959, 5. McDevitt, H. O., Bodmer, W. F. Am. J. Med. 1972, 52, 1. 6. Fisher, R. A. The Genetical Theory of Natural Selection. Oxford, 1930.
7. 8. 9. 10. 11. 12.
Ford, E. B. Ecological Genetics. London, 1970. Bodmer, W. F. Nature, 1972, 237, 139. Thomas, W., Holt, P. G., Keast, D. Nature, 1973, 243, 241. Hall, G. H., Morrison, C. F. ibid. p. 199. Salaman, M. H. Proc. R. Soc. Med. 1970, 63, 11. Bomford, R., Wedderburn, N. Nature, 1973, 242, 471.
Suizzested ferric-reductase shunt.
the mitochondrial level. Normally, the addition of a substrate for the Krebs cycle to an intact mitochondrial preparation leads to a very slow rate of oxygen uptake, reflecting the minimal movement of electrons down the electron-transport chain. When adenosine diphosphate is added in addition to the Krebs-cycle substrate, oxygen uptake is very rapid. These mitochondria are said to exhibit respiratory control. As early as three hours after the ingestion of a toxic quantity of iron, Ganote and Nahara were able to demonstrate an increased rate of oxygen uptake in the presence of a Krebs-cycle substrate alone, and a decreased rate of oxygen uptake after the additional provision of adenosine diphosphate. The rates of oxygen uptake in both these situations were nearly the same in iron-poisoned animals. Thus, in iron-poisoned mitochondria, the addition of a substrate produces electron transport and oxygen uptake, while the additional provision of adenosine diphosphate does not lead to a further increase in oxygen uptake. These poisoned mitochondria can be said to lack respiratory control. The basis of these in-vitro perturbations in mitochondrial function might be explained, at least in part, by a report of Barnes et al. on mitochondrial iron metabolism.l3 These workers described a previously unknown enzymatic activity, which we shall refer to as ferric reductase, associated with the inner surface of the inner mitochondrial membrane and catalysing the reduction of ferric iron to ferrous iron. Iron in the ferrous state is the substrate for ferrochelatase, which inserts iron into protoporphyrin ix to form heme. It seems reasonable that, in the presence of excess iron, the ferric reductase could serve as a shunt for electrons, removing them from their usual pathway and donating them to the ferric iron. The ferrous iron produced might then be oxidised by oxygen, setting up a cycle as illustrated in the accompanying figure. Such a shunt is suggested by the experimentally demonstrated oxygen uptake by mitochondria provided with ferric ions in the presence of rotenone, which blocks electron flow between a flavoprotein and co-enzyme Q. Oxygen is then taken up when the ferrous iron generated via the ferric-reductase shunt is auto-oxidised back to ferric iron within the mitochondrial matrix. Although not initially recognised, ferric reductase may thus have pivotal importance in the clinical, morphological, and biochemical consequences of iron intoxication. Given unlimited supplies of the ferric ion, the enzyme could preferentially catalyse the shunting of electrons away from the electron-transport chain. This would be feasible since the reduction of ferric iron is thermodynamically favoured over the channelling of electrons through the conventional cytochrome system. This surmise is consistent with the demonstrated loss of respiratory control in liver mitochondria from iron-poisoned animals and would explain at
13.
Barnes, R., Connelly, J. L., Jones, O. T. G. Biochem. J. 1972, 128, 1043.
the changes observed in the rates of oxygen uptake in the presence and absence of adenosine diphosphate. An active ferric-reductase shunt would result directly in immediate cessation of aerobic adenosine-triphosphate synthesis, precipitating a cellular energy crisis. This could be correlated with the elevated lactic and citric acid levels and the depletion of glycogen stores observed in iron poisoning. Ultimately, failure to synthesise sufficient adenosine triphosphate could lead to cell death. Obviously the ferric-reductase shunt need not be localised exclusively to liver mitochondria, and a similar explanation might be applicable to the cardiovascular, neurological, and gastrointestinal manifestations associated with iron intoxication. The existence of the ferric-reductase shunt may provide a point of departure for further investigation of the biochemical mechanism of acute iron toxicity and may have a
bearing
on
treatment.
Boston University School of
Medicine, City Hospital, Boston, Massachusetts, U.S.A. Boston University School of Boston
JAMES L. ROBOTHAM. ROBERT F. TROXLER.
Medicine.
Johns Hopkins University School Medicine, Baltimore, Maryland.
o
PAUL S. LIETMAN.
ST-SEGMENT DISPLACEMENT AFTER ACUTE MYOCARDIAL INFARCTION
SIR,-The article by Dr Morris and his colleagues (Aug. 17, p. 372) requires comment. They state that STsegment displacement at 48 hours provides no additional information for predicting those patients in whom complications subsequently develop over a six-week period. This statement may be misconstrued. Certainly no statistician will believe that Morris et al. have proved the absence of a relationship between the ST-segment shift and the development of late ventricular dysrhythmias. On the other hand, our data clearly indicate the presence of such a relationship. In the past seven years ST-segment displacement has been used in the assessment of the duration of monitoring in the Belfast coronary-care units. 1-3 In a detailed prospective study, 187 of 466 patients were 48 hours free from risk factors evident on clinical examination.4 31 of the 187 had ST-segment displacement greater than 2 mm., and among these the incidence of late ventricular dysrhythmias was 23%. The ST segment had fallen below 2 mm. in 156 of the 187, and among these the incidence of late ventricular dysrhythmias was 1% (p < 0-001). Morris et al. do not report the incidence of late ventricular dysrhythmias among patients whose ST segment had fallen below 2 mm. at the end of 48 hours. It is, therefore, difficult to understand how they conclude that ST-segment displacement would not provide any information additional to simple clinical examination. The conclusions of Morris et al. are at variance not only with those reached in Belfast but also with the conclusions of workers in Denmark and at Harvard. Nielsen,5 in a study of 404 patients, found that the magnitude of STsegment elevation gave valuable prognostic information useful in the selection of patients for prolonged monitoring. Madias et al.6 also found that the magnitude of the ST shift correlated with the clinical course and prognosis.
at
1. 2.
3. 4. 5. 6.
Pantridge, J. F. Unpublished. Boyle, D. McC., Barber, J. M., Walsh, M. J., Shivalingappa, G., Chaturvedi, N. C. Lancet, 1972, ii, 57. Chaturvedi, N. C., Walsh, M. J., Evans, A., Munro, P., Boyle, D. McC., Barber, J. M. Br. Heart J. 1974, 36, 533. Wilson, C., Pantridge, J. F. Lancet, 1973, ii, 1284. Nielsen, B. L. Circulation, 1973, 48, 338. Madias, J. E., Venkataraman, K., Vokonas, P. S., Hood, W. B., Jr. ibid. 1973, suppl. IV, p. 195.
666 The explanation of the anomalous conclusions of Morris al. may lie in large part in the difficulties inherent in the retrospective study of inadequate data. C. WILSON Royal Victoria Hospital, A. J. ADGEY A. Grosvenor Road, D. McC. BOYLE. Belfast BT12 6BA. et
BABES -
----T j-
_
__
_
-____
Stefan S. Nicolau Institute of Virology, 285 Sos. Mihai Bravu, Bucharest, Romania.
SIR,-Dr Frizzera and his associates
BABEŞ.
6
described
an
interesting disorder in which immunoblastic proliferation is accompanied by proliferation of small venules and hypertrophy and hyperplasia of endothelial cells within such vessels. They believe this process to be non-neoplastic, and comment on its histopathological resemblance to a graft-v. -host reaction. That immunoblastic and endothelial proliferation occur together in this disorder is of considerable theoretical interest. Frizzera et al. speculate that the disorder may actually represent a graft-v.-host reaction, presumably autoimmune in origin. Allograft rejection is accompanied by endothelial hypertrophy,’-1° and in rejecting ovine renal allografts endothelial mitosis has been observed.10 These endothelial changes have been considered a consequence of attack by donor lymphoid cells on host endothelium. We have observed striking endothelial proliferation in venules which were the site of lymphocytic and immunoblastic emigration in the course of experimental immune synovitis in rabbits. 11 Here, of course, both lymphoid and endothelial cells were of host origin. It appears, therefore, that stimulated lymphoid cells somehow cause endothelial cells to proliferate. It is possible that this is effected through release of a soluble mediator substance or lymphokine ". In this regard, it is perhaps relevant that Folkman et al.12 "
have described a soluble substance in tumours which stimulates vascular proliferation. On the other hand, it is
9. 10. 11. 12.
SMOKING AND LUNG CANCER
SIR,-Professor Burch has convincingly advocated 1-3 reconsideration of the genotypic explanation (put forward by R. A. Fisher 4) for the smoking/lung-cancer correlation. In addition, Burch has called for hypotheses to be advanced " that are consistent .with the epidemiological evidence". This letter attempts such a hypothesis, open (at least in
a
experimental investigation. following appear to militate against Fisher’s hypo(1) it seems strange that a gene(s) will increase the probability of lung cancer and smoking; (2) there has been a secular change in lung-cancer incidence, as the recorded
part)
to
The thesis :
of increase differs between the sexes.4 Considering (1), genes related to the incidence of certain diseases (including some cancers) are found in the immune response (Ir), histocompatibility (HL-A), and mixed lymphocyte culture (M.L.C.) chromosome segment.’ These genes control both humoral and cellular specific immune reactions on an all-or-almost-none basis. There is reason to believe that such supergene segments consist of coadapted alleles, the success of which depends upon the consistent association of a number of alleles 6,7 (in this case certain immune-react or non-react alleles associating with certain other react or non-react alleles). The genotypes produced are characterised by particular patterns of immune reactions. Furthermore, cross-over evidence indicates hundreds of other unidentified loci in this supergene,8 with a distinct possibility that many of these loci control specific immune reactions. With regard to smoking, the lungs provide a major antigen entry point into the body.9 I suggest: (a) smoke droplets stimulate a range of immune reactions; (b) the pattern of reactions to the droplet compounds will differ according to the Ir, HL-A, M.L.C. specificities of the individual; (c) stress-relieving effects of nicotine have been emphasised as the reason for the smoking habit," but the presence or lack of immune reactions may negate these effects (e.g., unpleasant hypersensitivity in " reactors" or toxicity in " non-reactors) ", influencing smoking rate
VINCENT T.
DYSPROTEINÆMIA
8.
GRAHAM, JR.
-_____
PATHOGENESIS OF VASCULAR PROLIFERATION IN ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY WITH
2. 3. 4. 5. 6. 7.
Department of Medicine, Cape Western Reserve University, University Hospitals, Cleveland, Ohio 44106, U.S.A. RICHARD C.
OR PETRI DISH?
SIR,-In his first treatise on bacteriology, published in May, 1885,1 Victor Babes described the use of a low-walled jar for bacteria isolations. In the same year Nicati and Rietsch also mentioned these jars, which they used for the isolation of the cholera vibrio.2 In 1887 Petri3 described his use, on a large scale, of this type of low-walled jar, which became known as the Petri-Schalen or Petri dish. Later, Frdnkel4 supported Babe’s assertionthat the credit for the conception and application of this idea should go to Babes and not to Petri. Is it now too late to try to claim this discovery for Romania ?
1.
also possible that endothelial proliferation is a consequence of direct cellular interaction between stimulated lymphoid cells and endothelium. Further investigation is needed to distinguish between these possibilities.
Cornil, A. V., Babes, V. Les bactéries et leur rôle dans l’éthiologie, l’anatomie et l’histologie pathologique des maladies infectieuses. Paris, 1885. Nicati, W., Rietsch, S. Arch. physiol. norm. path. 1885, 6, 72. Petri, R. J. Zentbl. Bakt. ParasitKde, 1887, 1, 279. Quoted in Victor Babeş, Opere alese. Bucharest, 1954. Babeş, V., Vico, H. Rom. med. 1898, 6, 433. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. Williams, P. L., Williams, M. A., Kountz, S. L., Dempster, W. J. J. Anat. 1964, 98, 545. Porter, K. A., Joseph, N. H., Rendall, J. M., Stolinski, C., Hoehn, R. J., Calne, R. Y. Lab. Invest. 1964, 13, 1080. Feldman, J. D., Lee, S. J. exp. Med. 1967, 126, 783. Pedersen, N. C., Morris, B. ibid. 1970, 131, 936. Graham, R. C., Jr., Shannon, S. L. Am. J. Path. 1972, 69, 7. Folkman, J., Merler, E., Abernathy, C., Williams, G. J. exp. Med. 1971, 133, 275.
(cigarettes, cigar, pipe, non-smoking) choices; (d)
an
immune reaction is not without its drawbacks (e.g., general 11 and specific 12 immune depression may result). Such depression has been implicated in a predisposition to at least one human neoplasm. 12 If we assume smokers are generally " reactors " to smoke droplets and that reaction predisposes to lung cancer we may expect to observe a genetic correlation and (with increased cigarette consumption) a certain amount of causal effect. We can also expect non-react individuals to possess react genes not found in the smoker supergene (s) and can predict that non-smokers will be predisposed to 1. 2. 3. 4.
Burch, P. R. J. Lancet, 1972, ii, 132. Burch, P. R. J. ibid. 1973, i, 939. Burch, P. R. J. ibid. 1973, ii, 1315. Fisher, R. A. Smoking: the Cancer Controversy. Edinburgh, 1959, 5. McDevitt, H. O., Bodmer, W. F. Am. J. Med. 1972, 52, 1. 6. Fisher, R. A. The Genetical Theory of Natural Selection. Oxford, 1930.
7. 8. 9. 10. 11. 12.
Ford, E. B. Ecological Genetics. London, 1970. Bodmer, W. F. Nature, 1972, 237, 139. Thomas, W., Holt, P. G., Keast, D. Nature, 1973, 243, 241. Hall, G. H., Morrison, C. F. ibid. p. 199. Salaman, M. H. Proc. R. Soc. Med. 1970, 63, 11. Bomford, R., Wedderburn, N. Nature, 1973, 242, 471.