- Email: [email protected]
REGULATION OF GRANULOPOIESIS
924 double-think
can
be
overcome
by
a
single-mindedness
in
achieving it. Medical School, 43 Woodstock Road,
Oxford.
JOHN M. POTTER, Director of Postgraduate Medical Education and Training.
REGULATION OF GRANULOPOIESIS
SiR,—Dr. Robinson and Dr. Mangalik (Oct. 7, p. 742) suggested that granulopoiesis is controlled by a positive feedback. While I agree with their arguments for the evidence of positive stimulation of granulopoiesis being of prime importance, I should like to draw attention to the behaviour of pure positive and negative feedback systems. In a positive system, control of production is mediated by the product itself, stimulation provoking further manufacture of the stimulating product-in fact a vicious circle. Similarly, production in a pure negative feedback system would be totally inflexible, as they rightly suggest, if the product negatively influenced its own manufacture. Neither of these situations applies to granulopoiesis, which is both controlled and flexible. I would therefore propose that in some form a negative balance must exist for granulopoiesis to be controlled-just as, for example, in a typical negative feedback system illustrated by corticotrophin and cortisol production there exists a positive stimulatory limb. This is a perfectly flexible system, and capable of rapid increases in cortisol levels despite the damping-down effect anticipated in a pure system, and functionally it behaves in the same way as the positive feedback that Dr. Robinson and Dr. Mangalik describe for
granulopoiesis. In other words, there is a confusion in distinction between a positive feedback system and a control system where positive stimulation predominates. I would therefore be wary of applying the term " positive feedback " to the control of granulopoiesis; but I would suggest that the uniqueness of the system is rather in the fact that control is mediated by end-cells stimulating their own precursors, rather than the stimulus being applied by hormones from a different organ. Department of Hæmatology, Westminster Hospital Medical School, London S.W.1.
A.
J. BARRETT.
SIR,-Dr. Robinson and Dr. Mangalik’s speculative of the regulation of granulopoiesis by positive
proposal
feedback is unacceptable in its present form. The proposed loop would either be unstable, or exhibit " neutral stability ", akin to that of the undamped harmonic In neither case could the system respond oscillator.1 homceostatically to the full range of perturbations from which the granulopoietic system is known to recover. The difficulties of the scheme may be exemplified as follows: (a) The suggested loop compensates only for increased death mature granulocytes. It fails to account for marrow rein advance of generation from drug-induced damage occurring depression of the blood neutrophil number.2 (b) Recovery from granulocyte depletion due to leukapheresis 3.4 rather than granulocyte killing is unexplained. (c) Any episode of granulocytosis would be rendered permanent by the positive feedback from the increased numbers of granulocytes experiencing death from senescence in any
of
1. 2.
N. Nonlinear Oscillations. Princeton, 1962. Boggs, D. R., Athens, J. W., Haab, O. P., Cancilla, P. A., Raab, S. O., Cartwright, G. E., Wintrobe, M. M. Blood, 1964, 23, 53. 3. Bierman, H. R., Kelly, K. H., Byron, R. L., Marshall, G. J. Br. J. Hœmat. 1961, 7, 51. 4. Thomas, E. D., Plain, G. L., Thomas, D. J. Lab. clin. Med. 1965, 66, 64.
Minorsky,
time-interval. No mechanism for restoring a normal granulocyte number following granulocytosis is provided by the scheme.
Incidental granulocytosis unrelated to infection-for example, during sustained oscillatory granulopoiesis 5 or damped oscillatory granulopoiesis subsequent to drug or radiation-induced damage 6-9-would de-stabilise the control system. These objections do
exclude the possibility that the coexists with others capable of proposed loop maintaining stability. For example, if immature granulocytes produced an inhibitor and mature granulocytes a stimulator, then a relationship between the two loop gains could be chosen which would result in a stable system, capable of responding homoeostatically to each of the perturbations mentioned, while preserving the advantages of the scheme proposed by Robinson and Mangalik. Control systems theory can sometimes be useful in assessing models of physiological regulation. We have previously presented mathematical models of the control of erythropoiesis 10-12 with this objective. Our current studies of models of the control of granulopoiesis will be not
control
reported shortly. Western Regional Hospital Board, Department of Clinical Physics and Bio-engineering, 11 West Graham Street, Glasgow G4 9LF.
T. E. WHELDON J. KIRK.
SIR,-The clonal theory of the pathogenesis of acute states that the bone-marrow is replaced by the progeny of a malignant cell. The cell-kill rationale of therapy is an outgrowth of this theory. However, an alternative hypothesis views the disease as due to the effect of environmental factors on intrinsically normal cells. This hypothesis implies a rationale of therapy directed at reversing these effects rather than the quantitative destruction of the altered cells. The recent report of development of leukxmia in donor cells after marrow engraftment 13 provides evidence for the environmental-agent hypothesis. If the leukxmic process were due to a change in inherently normal cells or their environment rendering them unable to mature normally, one might ask whether this change leukxmia
results from the presence of an abnormal factor or the deletion of a normal factor in the microenvironment. The Robinson-Mangalik hypothesis on the regulation of granulopoiesis provides some very interesting evidence in acute granulocytic leukaemia (A.G.L.) which favours the latter. Patients with A.G.L. have low or absent urinary excretion of the substance present in normal urine which promotes the development of clones of mature granulocytes from marrow cultured in agar. 14 The excretion of this granulocyte colony-stimulating factor (c.s.F.) rises in remission. Mature granulocytes, but not blasts, actively secrete c.s.F.15 When A.G.L. peripheral blood is cultured over a feeder layer of normal granulocytes,16 colonies of mature granulocytes arise. Since the leukaemic cell is responsive to c.s.F. in vitro, we suggest that the induction 5. Morley, A. A. Lancet, 1966, ii, 1220. 6. Host, H. Rad. Res. 1966, 27, 638. 7. Host, H. Acta radiol. 1966, 4, 337. 8. Lawrence, J. W., Craddock, C. G., Jr., Campbell, T. N. J. Lab. clin. Med. 1967, 69, 88. 9. Breivik, H. J. cell. Physiol. 1972, 79, 171. 10. Orr, J. S., Kirk, J., Gray, K. G., Anderson, J. Br. J. Hœmat. 1968, 15, 23. 11. Kirk, J., Orr, J. S., Hope. C. S. ibid. p. 35. 12. Kirk, J., Orr, J. S., Wheldon, T. E., Gray, W. M. J. theoret. Biol. 1970, 26, 265. 13. Fialkow, P. J., Thomas, E. D., Bryant, J. I., Neiman, P. E. Lancet, 1971, i, 251. 14. Robinson, W. A., Pike, B. L. New Engl. J. Med. 1970, 282, 1291. 15. Otsuka, A., Robinson, W. A., Entringer, M. A. Proceedings of the Sixth Leucocyte Culture Conference; p. 37. New York, 1972. 16. Robinson, W. A., Kurnick, J. E., Pike, B. L. Blood, 1971, 38, 500.
925 of A.G.L. may be due to interference with this stimulating factor rather than an attack of the blastogenic cell itself.
other hand, appeared only in hypovolaemia of over 30%. and even at this stage the B.P. still averaged over 100 mm,
A vicious cycle then ensues: destruction or impaired secretion of C.S.F. results in failure of granulocyte maturation and leads to decreased C.S.F. production. Interference with C.S.F. as a mechanism of leukaemogenesis is also consistent with the observed reduction in blast numbers produced transitorily by massive granulocyte infusions.17 Whereas the cell-kill hypothesis has led to considerable therapeutic achievement, the mechanism of action of chemotherapeutic agents may not be simply via quantitative destruction of abnormal cells. Further therapeutic achievement may be accomplished by efforts to alter the environmental effects of leukocmogenic agents, including replacement of humoral substances destroyed by the leuksemic
Hg.
process. Department of Medicine, U.S. Army General Hospital, Fort Gordon, Georgia 30905, U.S.A.
JOHN E. KURNICK.
Thomson Road General Hospital, Toa Payoh Rise, Singapore 11.
P. H. FENG DANIEL CHUA.
MECHANISMS OF REACTION IN LEPROSY SIR,-In commenting on your editorial (Sept. 16, 1 p. 580) it is important to reconsider Hansen’s and Looft’s original classification of leprosy, because it is based on the natural history of the disease at a time when the signs were not influenced by modern therapy. They described two groups. Firstly, one with nodules and infiltration of the skin accompanied by abundant bacilli. The disease was slowly progressive and rarely arrested, but nerve damage was late in appearance and slight. In the other group cutaneous patches appeared, followed shortly by signs The patches then faded or of serious nerve damage. the patient irreversibly crippled. Bacilli were present, but only initially and in small numbers, and thus the disease was arrested at an early stage. Relapse was uncommon. Hansen and Looft called this the maculo-anaesthetic group, the anaesthesia referring to the sensory loss in the extremities and not to anaesthesia in the patches. They emphasised the distinction between the two syndromes, mixed forms being rare. In the current classification the natural history is neglected, the differences between the two syndromes are obscured, and vital changes in the peripheral nervous system in the early phase of the disease are not appreciated. Furthermore, it is based on criteria which have not been independently verified. Hansen and Looft described in the maculo-ansesthetic syndrome symmetrical swellings in the distal part of the limbs. These are probably similar to the acute oedema of the hands and feet described by Davison3 and are accompanied by acute loss of superficial sensory modalities of glove-and-stocking distribution. Biopsy of the dermis in this area in one patient showed a perivascular mononuclear infiltrate also invading the fine nerve-fibres.4 The nerve damage was thus cell-mediated, similar to that in experimental allergic neuritis5 and Guillain-Barré polyneuritis. Acute cell-mediated nerve damage has also been produced experimentally by injection of syngenic lymphocytes in thymectomised mice with lepromatous leprosy7,8 and without ingestion of sulphones, so that the syndrome seems to be part of the natural history of the
disappeared, leaving BLOOD-VOLUMES IN GASTROINTESTINAL HÆMORRHAGE SIR,-May I endorse the views of Mr. Irvin and his colleagues (Sept. 2, p. 446) who suggested that a raised pulse-rate is a more sensitive index than blood-pressure in the assessment of oligaemia ? During the past six months the medical unit of this hospital has been measuring blood-volumes in patients with gastrointestinal haemorrhage and attempting to correlate this with the pulse-rate and blood-pressure taken at the same time. Methodology consists of the ’Volemetron’ and 1251, and two blood samples were taken 10 and 20 minutes after injection. This was extrapolated to 0, and total blood-volume was calculated from the plasma-volume and haematocrit, utilising the F cell ratio.1S This was compared with normal values obtained from the local population. These values have been published elsewhere.19 The results were:
No. 1 2 3 4
Predicted Measured % bloodbloodDif- Pulserate volume volume ference 108 4200 3250 23 2900 40 110 4320 4200 3250 23 115 4500
3200
16
120
Bloodpressure
(mm. Hg) 100/70 130/80 110/80 100/60
Diagnosis Bleeding varices Bleeding varices ?
Gastritis G.I.
?
120 140
110/70 120/70 100/60 80/60 110/60
Bleeding ulcer Bleeding ulcer Mild G.i. bleeding Bleeding ulcer Severe bleeding
36 9 10 25
100 96 120 110
90/60 120/80 120/80 160/80
Bleeding ulcer
7
64
140/90
Bleeding peptic
6 7 8 9
3150 3860 2700 4000 4000
2800 2900
11 25
2650 2400 2200
2 40 45
10 11 12 13
4100 4080 3450 4200
2600 3700 3100 3150
14
3900
3600
5
bleeding,
cause
100 96 100
ulcer Gastric erosion Gastric erosion
Bleeding duodenal ulcer ulcer
Although no statistical analysis is attempted, since the project is still continuing, an examination of the above data confirms Mr. Irvin’s findings. This result has also support in the work of a German group 20 who found that the pulse-rate rises at blood-volume reduction of 5-10%. A reduction in systolic blood-pressure, on the some
Robinson, W. A., Entringer, M. A., Otsuka, A. The Nature of Leukaemia; p. 151. Sydney, 1972. 18. Albert, S. N., Gravel, Y., Turmel, Y., Albert, C. A. Anesth. Analg. 1965, 44, 805. 19. Feng, P. H., Cheah, P. S., Singh, B., Lee, Y. K. Asian J. Med. 1972, 8, 237. 20. Bohmig, H. J. Wien. klin. Wschr. 1964, 76, 356. English summary in Blood Volume: Excerpra Medica, special edition no. 1, J 1969, p. 6.
17.
disease. If leprosy is approached in this way then a basis can be provided for its rational management. Nerve damage due to the disease itself can then be distinguished from that due to drugs such as dapsone and thalidomide. It will also be possible to avoid the term reaction. " Lepra reaction " is used in your editorial to define changes occurring in pre-existing skin lesions, but it has been used to include erythema nodosum leprosum (E.N.L.) 9 as well, and also as a synonym for E.N.L. alone.1o 1. 2. 3. 4. 5. 6.
7.
Hansen, G. A., Looft, G. Leprosy in its Clinical and Pathological Aspects. Bristol, 1895. Hansen, G. A. Lepra, 1900, 1, 3. Davison, A. R. Lep. Rev. 1961, 29, 29. Crawford, C. L. ibid. 1968, 39, 9. Waksman, B. H., Adams, R. D. J. exp. Med. 1955, 102, 213. Asbury, A. K., Arnason, B. G., Adams, R. D. Medicine, Baltimore, 1969, 48, 173. Rees, R. J. W., Weddell, A. G. M. Ann. N. Y. Acad. Sci. 1968, 154,
214. 8. Rees, R. J. W., Weddell, A. G. M. Int. J. Lep. 1968, 36, 629. 9. VIIth International Congress of Leprology, Tokyo, November, 1958. Int. J. Lep. 1958, 26, 380. 10. Iyer, C. C. S., Languillon, J., Ramanujan, K., Tarabini-Castellani, G., Terencio De Las Aquas, J., Bechelli, L. M., Uemura, K., Martinez Domingues, V., Sundaresan, T. Bull. Wld Hlth Org. 1971, 45, 719.
can
be
overcome
by
a
single-mindedness
in
achieving it. Medical School, 43 Woodstock Road,
Oxford.
JOHN M. POTTER, Director of Postgraduate Medical Education and Training.
REGULATION OF GRANULOPOIESIS
SiR,—Dr. Robinson and Dr. Mangalik (Oct. 7, p. 742) suggested that granulopoiesis is controlled by a positive feedback. While I agree with their arguments for the evidence of positive stimulation of granulopoiesis being of prime importance, I should like to draw attention to the behaviour of pure positive and negative feedback systems. In a positive system, control of production is mediated by the product itself, stimulation provoking further manufacture of the stimulating product-in fact a vicious circle. Similarly, production in a pure negative feedback system would be totally inflexible, as they rightly suggest, if the product negatively influenced its own manufacture. Neither of these situations applies to granulopoiesis, which is both controlled and flexible. I would therefore propose that in some form a negative balance must exist for granulopoiesis to be controlled-just as, for example, in a typical negative feedback system illustrated by corticotrophin and cortisol production there exists a positive stimulatory limb. This is a perfectly flexible system, and capable of rapid increases in cortisol levels despite the damping-down effect anticipated in a pure system, and functionally it behaves in the same way as the positive feedback that Dr. Robinson and Dr. Mangalik describe for
granulopoiesis. In other words, there is a confusion in distinction between a positive feedback system and a control system where positive stimulation predominates. I would therefore be wary of applying the term " positive feedback " to the control of granulopoiesis; but I would suggest that the uniqueness of the system is rather in the fact that control is mediated by end-cells stimulating their own precursors, rather than the stimulus being applied by hormones from a different organ. Department of Hæmatology, Westminster Hospital Medical School, London S.W.1.
A.
J. BARRETT.
SIR,-Dr. Robinson and Dr. Mangalik’s speculative of the regulation of granulopoiesis by positive
proposal
feedback is unacceptable in its present form. The proposed loop would either be unstable, or exhibit " neutral stability ", akin to that of the undamped harmonic In neither case could the system respond oscillator.1 homceostatically to the full range of perturbations from which the granulopoietic system is known to recover. The difficulties of the scheme may be exemplified as follows: (a) The suggested loop compensates only for increased death mature granulocytes. It fails to account for marrow rein advance of generation from drug-induced damage occurring depression of the blood neutrophil number.2 (b) Recovery from granulocyte depletion due to leukapheresis 3.4 rather than granulocyte killing is unexplained. (c) Any episode of granulocytosis would be rendered permanent by the positive feedback from the increased numbers of granulocytes experiencing death from senescence in any
of
1. 2.
N. Nonlinear Oscillations. Princeton, 1962. Boggs, D. R., Athens, J. W., Haab, O. P., Cancilla, P. A., Raab, S. O., Cartwright, G. E., Wintrobe, M. M. Blood, 1964, 23, 53. 3. Bierman, H. R., Kelly, K. H., Byron, R. L., Marshall, G. J. Br. J. Hœmat. 1961, 7, 51. 4. Thomas, E. D., Plain, G. L., Thomas, D. J. Lab. clin. Med. 1965, 66, 64.
Minorsky,
time-interval. No mechanism for restoring a normal granulocyte number following granulocytosis is provided by the scheme.
Incidental granulocytosis unrelated to infection-for example, during sustained oscillatory granulopoiesis 5 or damped oscillatory granulopoiesis subsequent to drug or radiation-induced damage 6-9-would de-stabilise the control system. These objections do
exclude the possibility that the coexists with others capable of proposed loop maintaining stability. For example, if immature granulocytes produced an inhibitor and mature granulocytes a stimulator, then a relationship between the two loop gains could be chosen which would result in a stable system, capable of responding homoeostatically to each of the perturbations mentioned, while preserving the advantages of the scheme proposed by Robinson and Mangalik. Control systems theory can sometimes be useful in assessing models of physiological regulation. We have previously presented mathematical models of the control of erythropoiesis 10-12 with this objective. Our current studies of models of the control of granulopoiesis will be not
control
reported shortly. Western Regional Hospital Board, Department of Clinical Physics and Bio-engineering, 11 West Graham Street, Glasgow G4 9LF.
T. E. WHELDON J. KIRK.
SIR,-The clonal theory of the pathogenesis of acute states that the bone-marrow is replaced by the progeny of a malignant cell. The cell-kill rationale of therapy is an outgrowth of this theory. However, an alternative hypothesis views the disease as due to the effect of environmental factors on intrinsically normal cells. This hypothesis implies a rationale of therapy directed at reversing these effects rather than the quantitative destruction of the altered cells. The recent report of development of leukxmia in donor cells after marrow engraftment 13 provides evidence for the environmental-agent hypothesis. If the leukxmic process were due to a change in inherently normal cells or their environment rendering them unable to mature normally, one might ask whether this change leukxmia
results from the presence of an abnormal factor or the deletion of a normal factor in the microenvironment. The Robinson-Mangalik hypothesis on the regulation of granulopoiesis provides some very interesting evidence in acute granulocytic leukaemia (A.G.L.) which favours the latter. Patients with A.G.L. have low or absent urinary excretion of the substance present in normal urine which promotes the development of clones of mature granulocytes from marrow cultured in agar. 14 The excretion of this granulocyte colony-stimulating factor (c.s.F.) rises in remission. Mature granulocytes, but not blasts, actively secrete c.s.F.15 When A.G.L. peripheral blood is cultured over a feeder layer of normal granulocytes,16 colonies of mature granulocytes arise. Since the leukaemic cell is responsive to c.s.F. in vitro, we suggest that the induction 5. Morley, A. A. Lancet, 1966, ii, 1220. 6. Host, H. Rad. Res. 1966, 27, 638. 7. Host, H. Acta radiol. 1966, 4, 337. 8. Lawrence, J. W., Craddock, C. G., Jr., Campbell, T. N. J. Lab. clin. Med. 1967, 69, 88. 9. Breivik, H. J. cell. Physiol. 1972, 79, 171. 10. Orr, J. S., Kirk, J., Gray, K. G., Anderson, J. Br. J. Hœmat. 1968, 15, 23. 11. Kirk, J., Orr, J. S., Hope. C. S. ibid. p. 35. 12. Kirk, J., Orr, J. S., Wheldon, T. E., Gray, W. M. J. theoret. Biol. 1970, 26, 265. 13. Fialkow, P. J., Thomas, E. D., Bryant, J. I., Neiman, P. E. Lancet, 1971, i, 251. 14. Robinson, W. A., Pike, B. L. New Engl. J. Med. 1970, 282, 1291. 15. Otsuka, A., Robinson, W. A., Entringer, M. A. Proceedings of the Sixth Leucocyte Culture Conference; p. 37. New York, 1972. 16. Robinson, W. A., Kurnick, J. E., Pike, B. L. Blood, 1971, 38, 500.
925 of A.G.L. may be due to interference with this stimulating factor rather than an attack of the blastogenic cell itself.
other hand, appeared only in hypovolaemia of over 30%. and even at this stage the B.P. still averaged over 100 mm,
A vicious cycle then ensues: destruction or impaired secretion of C.S.F. results in failure of granulocyte maturation and leads to decreased C.S.F. production. Interference with C.S.F. as a mechanism of leukaemogenesis is also consistent with the observed reduction in blast numbers produced transitorily by massive granulocyte infusions.17 Whereas the cell-kill hypothesis has led to considerable therapeutic achievement, the mechanism of action of chemotherapeutic agents may not be simply via quantitative destruction of abnormal cells. Further therapeutic achievement may be accomplished by efforts to alter the environmental effects of leukocmogenic agents, including replacement of humoral substances destroyed by the leuksemic
Hg.
process. Department of Medicine, U.S. Army General Hospital, Fort Gordon, Georgia 30905, U.S.A.
JOHN E. KURNICK.
Thomson Road General Hospital, Toa Payoh Rise, Singapore 11.
P. H. FENG DANIEL CHUA.
MECHANISMS OF REACTION IN LEPROSY SIR,-In commenting on your editorial (Sept. 16, 1 p. 580) it is important to reconsider Hansen’s and Looft’s original classification of leprosy, because it is based on the natural history of the disease at a time when the signs were not influenced by modern therapy. They described two groups. Firstly, one with nodules and infiltration of the skin accompanied by abundant bacilli. The disease was slowly progressive and rarely arrested, but nerve damage was late in appearance and slight. In the other group cutaneous patches appeared, followed shortly by signs The patches then faded or of serious nerve damage. the patient irreversibly crippled. Bacilli were present, but only initially and in small numbers, and thus the disease was arrested at an early stage. Relapse was uncommon. Hansen and Looft called this the maculo-anaesthetic group, the anaesthesia referring to the sensory loss in the extremities and not to anaesthesia in the patches. They emphasised the distinction between the two syndromes, mixed forms being rare. In the current classification the natural history is neglected, the differences between the two syndromes are obscured, and vital changes in the peripheral nervous system in the early phase of the disease are not appreciated. Furthermore, it is based on criteria which have not been independently verified. Hansen and Looft described in the maculo-ansesthetic syndrome symmetrical swellings in the distal part of the limbs. These are probably similar to the acute oedema of the hands and feet described by Davison3 and are accompanied by acute loss of superficial sensory modalities of glove-and-stocking distribution. Biopsy of the dermis in this area in one patient showed a perivascular mononuclear infiltrate also invading the fine nerve-fibres.4 The nerve damage was thus cell-mediated, similar to that in experimental allergic neuritis5 and Guillain-Barré polyneuritis. Acute cell-mediated nerve damage has also been produced experimentally by injection of syngenic lymphocytes in thymectomised mice with lepromatous leprosy7,8 and without ingestion of sulphones, so that the syndrome seems to be part of the natural history of the
disappeared, leaving BLOOD-VOLUMES IN GASTROINTESTINAL HÆMORRHAGE SIR,-May I endorse the views of Mr. Irvin and his colleagues (Sept. 2, p. 446) who suggested that a raised pulse-rate is a more sensitive index than blood-pressure in the assessment of oligaemia ? During the past six months the medical unit of this hospital has been measuring blood-volumes in patients with gastrointestinal haemorrhage and attempting to correlate this with the pulse-rate and blood-pressure taken at the same time. Methodology consists of the ’Volemetron’ and 1251, and two blood samples were taken 10 and 20 minutes after injection. This was extrapolated to 0, and total blood-volume was calculated from the plasma-volume and haematocrit, utilising the F cell ratio.1S This was compared with normal values obtained from the local population. These values have been published elsewhere.19 The results were:
No. 1 2 3 4
Predicted Measured % bloodbloodDif- Pulserate volume volume ference 108 4200 3250 23 2900 40 110 4320 4200 3250 23 115 4500
3200
16
120
Bloodpressure
(mm. Hg) 100/70 130/80 110/80 100/60
Diagnosis Bleeding varices Bleeding varices ?
Gastritis G.I.
?
120 140
110/70 120/70 100/60 80/60 110/60
Bleeding ulcer Bleeding ulcer Mild G.i. bleeding Bleeding ulcer Severe bleeding
36 9 10 25
100 96 120 110
90/60 120/80 120/80 160/80
Bleeding ulcer
7
64
140/90
Bleeding peptic
6 7 8 9
3150 3860 2700 4000 4000
2800 2900
11 25
2650 2400 2200
2 40 45
10 11 12 13
4100 4080 3450 4200
2600 3700 3100 3150
14
3900
3600
5
bleeding,
cause
100 96 100
ulcer Gastric erosion Gastric erosion
Bleeding duodenal ulcer ulcer
Although no statistical analysis is attempted, since the project is still continuing, an examination of the above data confirms Mr. Irvin’s findings. This result has also support in the work of a German group 20 who found that the pulse-rate rises at blood-volume reduction of 5-10%. A reduction in systolic blood-pressure, on the some
Robinson, W. A., Entringer, M. A., Otsuka, A. The Nature of Leukaemia; p. 151. Sydney, 1972. 18. Albert, S. N., Gravel, Y., Turmel, Y., Albert, C. A. Anesth. Analg. 1965, 44, 805. 19. Feng, P. H., Cheah, P. S., Singh, B., Lee, Y. K. Asian J. Med. 1972, 8, 237. 20. Bohmig, H. J. Wien. klin. Wschr. 1964, 76, 356. English summary in Blood Volume: Excerpra Medica, special edition no. 1, J 1969, p. 6.
17.
disease. If leprosy is approached in this way then a basis can be provided for its rational management. Nerve damage due to the disease itself can then be distinguished from that due to drugs such as dapsone and thalidomide. It will also be possible to avoid the term reaction. " Lepra reaction " is used in your editorial to define changes occurring in pre-existing skin lesions, but it has been used to include erythema nodosum leprosum (E.N.L.) 9 as well, and also as a synonym for E.N.L. alone.1o 1. 2. 3. 4. 5. 6.
7.
Hansen, G. A., Looft, G. Leprosy in its Clinical and Pathological Aspects. Bristol, 1895. Hansen, G. A. Lepra, 1900, 1, 3. Davison, A. R. Lep. Rev. 1961, 29, 29. Crawford, C. L. ibid. 1968, 39, 9. Waksman, B. H., Adams, R. D. J. exp. Med. 1955, 102, 213. Asbury, A. K., Arnason, B. G., Adams, R. D. Medicine, Baltimore, 1969, 48, 173. Rees, R. J. W., Weddell, A. G. M. Ann. N. Y. Acad. Sci. 1968, 154,
214. 8. Rees, R. J. W., Weddell, A. G. M. Int. J. Lep. 1968, 36, 629. 9. VIIth International Congress of Leprology, Tokyo, November, 1958. Int. J. Lep. 1958, 26, 380. 10. Iyer, C. C. S., Languillon, J., Ramanujan, K., Tarabini-Castellani, G., Terencio De Las Aquas, J., Bechelli, L. M., Uemura, K., Martinez Domingues, V., Sundaresan, T. Bull. Wld Hlth Org. 1971, 45, 719.