- Email: [email protected]
ANUS OR STOMA?
805
of menstruation’ and
usually well tolerated. Patients should start with a low dose, such as 1.25 mg, taken late in the day
Menstruation usually returns within four weeks of the start of treatment but occasionally the response takes several months. In patients with gonadotrophin deficiency or ovarian failure bromocrip-
with food and then gradually increased. For the treatment of hyperprolactinaemia the usual full dose is 7.5 mg per day (2-5 mg with breakfast, lunch, and supper). Side-effects at the start of treatment include postural hypotension and nausea and vomiting; and in the long term, constipation may be troublesome. Of greater concern is the fact that rats treated with bromocriptine for 100 weeks acquired malignant endometrial tumours. However, no such changes have been found in women on long-term bromocriptine,3O and prolactin has very different roles in rat and man. Bromocriptine is now being used in several diseases and not simply for hyperprolactinaemia. The drug is expensive, is unlikely to become much cheaper, and no satisfactory alternative dopamine agonist is available. Acromegaly and parkinsonism are not so common that the expense of long-term bromocriptine would be crushing; menstrual disorders, however, are
tine results in
rapid
return
ovulation. 1,19-21
tine is not effective.
Surprisingly, bromocriptine gonadal function in some amenorrhœic or oligomenorrhoeic patients who have normal serum-prolactin levels. 12,22-24 The highest response-rate in normoprolactineemic women with anovulation has been in patients with post-pill amenorrhcea or oligomenorrhoea. The mechanism by which bromocriptine restores normal gonadal function in patients with hyperprorestores
normal
lactinaemia is not well understood. Evidence both in vitro and in vivo suggests that prolactin in high concentration antagonises the action of gonadotrophins on the ovary. 12,25 There is little evidence that bromocriptine directly alters gonadotrophin secretion in man. Whether bromocriptine itself has a direct effect on the ovary is unknown. In addition, preliminary results suggest that hyperprolactinæmia is associated with increased adrenal androgen secretion and that the androgen levels are returned to normal by bromocriptine. 26,21 The physician might therefore be tempted to view bromocriptine as the drug of choice for the treatment of secondary amenorrhoea. This temptation, however, must be resisted until the patient has been properly investigated. If bromocriptine is given to a patient with a pituitary tumour and she becomes pregnant, the tumour may swell and produce a visual-field defect. When such a patient wants a baby she should have her pituitary tumour assessed and, if necessary, treated by surgery or radiotherapy.28 These treatments are aimed at preventing tumour growth during pregnancy, and after operation or irradiation the patient almost invariably requires bromocriptine therapy. In patients with prolactinomas who do not wish to become pregnant bromocriptine therapy alone may inhibit tumour growth.29 Obviously these patients should not be given oestrogen-containing oral contraceptives. Bromocriptine when properly prescribed is
’
19.
Lutterbeck, P. M., Pryor, J. S., Varga, L., Wenner, R. Br. med. J. 1971, iii, 228.
20 del
Pozo, E., Varga, L., Wyss, H., Tolis, G., Friesen, H., Wenner, R., Vetter, L., Uettweiller, A. J. clin. Endocr.Metab. 1974, 39, 18. 21 Thomer, M. O., Besser, G. M., Hagen, C. McNeilly, A. S.Br. med. J. 1974, ii, 419. 22 Seppälä, M., Hirvonen, E., Ranta, T. Lancet, 1976, i, 1154. 23 Tolis, G., Naftolin, F., Am. J. Obstet. Gynec. 1976, 126, 426. 24 Van der Steeg, H. J., Coelingh Bennink, H. J. T. Lancet, 1977, i, 502. 25. McNatty, K. P., Sawers, R. S., McNeilly, A. S. Nature, 1974, 250, 653. 26 Edwards, C. R. W., Jeffcoate, W. J. in Pharmacological and Clinical Aspects of Bromocriptine (Proc. Symp. R. Coll. Physns); p43. London, 1977. 27 Giusti, G., Bassi, F., Borsi, L., Cattaneo, S., Giannotti, P., Lanza, L., Pazzagli, M., Vigiani, C., Serio, M. in Prolactin and Human Reproduction edited by P. G. Crosignani and C. Robyn). London, 1977. 28 Thorner, M. O., Besser, G. M., Jones, A., Dacie, J., Jones, A. E. Br. med. 29
J. 1975, iv, 694. Wass, J. A. H., Thorner, M. O., Morris, D. V., Rees, Lesley, H., Mason, A. S., Jones, A. E., Besser, G. M. ibid. 1977, i, 875.
extremely common.... ANUS OR STOMA? IRONICALLY it was the advent of an efficient ileostomy thirty years ago which led to ileo-rectal anastomosis, for this paved the way for safe ablation of the large bowel severely damaged by ulcerative colitis. Previously, oper-
ation had been an occasional and very much a last resort, with disabling consequences if an ileostomy was needed; sometimes staged resections were associated with ileo-rectal or ileo-sigmoid anastomosis but the concept of excision and anastomosis as a deliberate policy had not been pursued during an era before the ileostomy became manageable with an adherent bag. When the benefits of bowel excision became evident, thoughts naturally turned to excision with preservation of anal function. In the 1950s the relative merits of the two procedures .were hotly contested, and the debate continues, albeit somewhat muted. The arguments for and against ileorectal anastomosis are paraded again in a review of 36 patients (4 with Crohn’s disease) so treated between 1958 and 1976 by Jones and his colleagues.’ These have altered little, if at all: advantage, the avoidance of a stoma ; disadvantage, failure to eliminate the disease and a change in bowel function. They reiterate the fact that inflammation of the rectum may become so severe as to warrant its excision and conversion to an ileostomy-as in 3 of their series. Moreover, if the disease persists because the rectum is retained, the patient is still at risk from the remote complications; so they found that ankylosing spondylitis persisted in 1 patient while arthritis of hands and knees developed after operation in another as did erythema nodosum and chronic active hepatitis in 2 others. As regards bowel function, none was incontinent but frequency of stool varied between three and six loose motions
a
day; they make
no
mention of precipitancy
or
30. Besser, G. M., Doniach, I., Canti, G., Curling, M, Setchell, M. E., Thorner, M. O., Wass, J. A. H., Grudziniskas, J. G. ibid. 1977, ii, 868. 1. Jones, P. F., Munro, A., Evan, S. W. B. Br. J. Surg. 1977, 64, 615.
806 urgency which is sometimes sufficient to cause disability in these patients. After 2 postoperative deaths there were 5 late deaths, 1 each from anorexia nervosa, chronic active hepatitis, "natural causes", carcinoma of the oesophagus, and hepatic metastasis from colonic carcinoma. They record no case of cancer in the retained rectum but emphasise this risk (which they judge to be 3%) as a major concern in the continued management of these patients. Indeed this hazard alone demands annual review of patients with an anastomosis: it must be borne in mind that some patients are irked by this and eventually default. During the same period Jones and coworkers treated 41 patients by panproctocolectomy and they make the point that such patients can be discharged after a year or two. In addition there was an interesting small group of 5 patients with ileostomy and colectomy in whom the rectum was not removed, all of whom died, no causes being given. Did cancer develop in any of these? What we do not know is what happened to the 41 ileostomy patients treated by the same workers in the same period, and this is a pity. For anastomosis needs to be compared with the only alternative, the stoma; fundamentally, those who argue for ileo-rectal anastomosis assume that, because an anus is more natural than a stoma, life must be better with an anus. But is it, if it
entails persistent diarrhoea, repeated hospital visits, and the continued hazards of the disease? On the other hand, how often in a lifetime does a patient with an ileostomy have to return to hospital or seek advice from the Ileostomy Association or a stoma therapist? These are important matters, requiring almost a social study, which could now be answered. There is a sizeable cohort of patients now reaching their seventh decade-their natural term-who have had either excision with ileostomy or ileo-rectal anastomosis twenty-five or more years ago. Its members can still be traced through centres such as Birmingham, Leeds, and London. What has life been like for them? Maybe its quality has differed little between the two groups, but we ought to find out. There is good reason to undertake this study now. The incidence of Crohn’s disease in Britain increased threefold between 1958 and 1971,2 and doubtless with it Crohn’s colitis, but that of ulcerative colitis rose only slightly. In Maimo over the same period the incidence rose from 3.5 to 6 - 0 per 100000.3 If a proper judgment is to be made it would best be made when most of the operations were for ulcerative colitis, for though no doubt some cases of Crohn’s disease were unwittingly included in colitis series of twenty-five years ago--since the condition was seldom recognised then-most of the patients did have ulcerative colitis. Now the pattern has changed; with the propensity of Crohn’s disease for recurrence and its ability to affect any part of the gut, an assessment of the results of the two operations per se will become more difficult to achieve. For ulcerative colitis, the disease and its symptoms can be eliminated by surgery; there can be no certainty of this when the operations are performed for Crohn’s disease. Moreover, the observation of Lockhart-Mummery4 that recurrence is longer delayed after panproctocolectomy than after colectomy and ileo-rectal anastomosis would be a strong 2.
Miller, D. S., Keighley, A. C., Langman, M. J. S. Lancet, 1974, ii, 691. 3. Brahme, F., Lindstrom, C., Wenckert, A. Gastroenterology, 1975, 69, 342. 4. Lockhart-Mummery, H. E. Br. J. Surg. 1972, 59, 823.
argument for the stoma-if the observation is
con-
firmed. Reviewing their series in Birmingham, Steinberg et a1.s were unable to confirm it. And, to cap it all, there are those happier mortals who consider much of the controversy about the relative courses after operation in ulcerative and Crohn’s colitis to be futile,6and longterm results to be much the same. Surely yet another reason for comparing the long-term results in ulcerative colitis before it is too late is to provide a baseline from which to determine whether that bald statement is true.
BLOOD IN THE ALCOHOL STREAM THE effects of high alcohol intake on the cells of the blood have been investigated largely in normal volunteers or ill alcoholics; we know little about the effects on blood-cells of "heavy regular drinking". What diagnostic difficulties might arise when a regular drinker is being investigated for other conditions? Chronic alcoholism depresses red-cell production.7 This happens even in well-nourished, non-anæmic alcoholics without evidence of cirrhosis,8 and typically the serum-iron is high, bone-marrow uptake of iron is low,’ erythroblast cytoplasm is vacuolated, and the bone-marrow contains abnormal sideroblasts. On withdrawal of alcohol these abnormalities disappear. In malnourished alcoholics who are folate-deficient the depression of erythropoiesismay be accompanied by macrocytosis in the peripheral blood and megaloblastic change in the bone-marrow.1O When such individuals are admitted to hospital, the reticulocytosis after withdrawal of alcohol and return to a normal diet may give rise to mistaken suspicions of haemolysis or bleeding. Haemoglobin often falls in the early days after drying-out, as the diuretic effect of alcohol is lost, but this fall tends to be succeeded by a gradual rise as red-cell production is freed from the suppressant effects of alcohol and of folate deficiency. The bone-marrow granulocyte reserve, and hence granulocyte production, may also be reduced in severe alcoholism."Cytoplasmic vacuolation, similar to that in erythroblasts, occurs in promyelocytes in the bone-marrow of alcoholics" and their ability to respond to infection with increased production of granulocytes is often subnormal. Bacterial infection may indeed cause leucopenia rather than leucocytosis, and alcoholics are unable to sustain high levels of granulocyte production from the bone-marrow when given repeated doses of endotoxin. This defect can be found in alcoholics without evidence of cirrhosis, portal hypertension, or hypersplenism. In patients with splenomegaly, splenic sequestration of red cells, white cells, and platelets may give rise to the more typical picture of hypersplenism due to portal hypertension. Platelet-counts tend to be low in alcoholics, even when folic-acid status is normal. When alcohol intake ceases the count usually rises and may become higher 5.
D. M., Allan, R. H., Thompson, H., Brooke, B. N., AlexanderWilliams, J., Cooke, W. J. Gut, 1974, 15, 845. 6. Fawaz, K. A., Glotzer, D. J., Goldman, H., Dickersin, G. R., Gross, W., Patterson, J. F. Gastroenterology, 1976, 71, 372. 7. Jandl, J. H. J. clin Invest. 1955, 34, 390. 8. Hourihane, D. O. B., Weir, D. G. Br. med. J. 1970, i, 86. 9. Waters, A. H., Morely, A. A., Rankm, J. G. ibid. 1966, ii, 1565. 10. Hines, J. D. Br. J. Hœmat. 1969, 16, 87. 11. McFarland, W., Libre, E. P. Ann. intern. Med. 1963, 59, 865. 12. Lindenbaum, J., Lieber, D. S. New Engl. J. Med. 1969, 281, 333.
Steinberg,
of menstruation’ and
usually well tolerated. Patients should start with a low dose, such as 1.25 mg, taken late in the day
Menstruation usually returns within four weeks of the start of treatment but occasionally the response takes several months. In patients with gonadotrophin deficiency or ovarian failure bromocrip-
with food and then gradually increased. For the treatment of hyperprolactinaemia the usual full dose is 7.5 mg per day (2-5 mg with breakfast, lunch, and supper). Side-effects at the start of treatment include postural hypotension and nausea and vomiting; and in the long term, constipation may be troublesome. Of greater concern is the fact that rats treated with bromocriptine for 100 weeks acquired malignant endometrial tumours. However, no such changes have been found in women on long-term bromocriptine,3O and prolactin has very different roles in rat and man. Bromocriptine is now being used in several diseases and not simply for hyperprolactinaemia. The drug is expensive, is unlikely to become much cheaper, and no satisfactory alternative dopamine agonist is available. Acromegaly and parkinsonism are not so common that the expense of long-term bromocriptine would be crushing; menstrual disorders, however, are
tine results in
rapid
return
ovulation. 1,19-21
tine is not effective.
Surprisingly, bromocriptine gonadal function in some amenorrhœic or oligomenorrhoeic patients who have normal serum-prolactin levels. 12,22-24 The highest response-rate in normoprolactineemic women with anovulation has been in patients with post-pill amenorrhcea or oligomenorrhoea. The mechanism by which bromocriptine restores normal gonadal function in patients with hyperprorestores
normal
lactinaemia is not well understood. Evidence both in vitro and in vivo suggests that prolactin in high concentration antagonises the action of gonadotrophins on the ovary. 12,25 There is little evidence that bromocriptine directly alters gonadotrophin secretion in man. Whether bromocriptine itself has a direct effect on the ovary is unknown. In addition, preliminary results suggest that hyperprolactinæmia is associated with increased adrenal androgen secretion and that the androgen levels are returned to normal by bromocriptine. 26,21 The physician might therefore be tempted to view bromocriptine as the drug of choice for the treatment of secondary amenorrhoea. This temptation, however, must be resisted until the patient has been properly investigated. If bromocriptine is given to a patient with a pituitary tumour and she becomes pregnant, the tumour may swell and produce a visual-field defect. When such a patient wants a baby she should have her pituitary tumour assessed and, if necessary, treated by surgery or radiotherapy.28 These treatments are aimed at preventing tumour growth during pregnancy, and after operation or irradiation the patient almost invariably requires bromocriptine therapy. In patients with prolactinomas who do not wish to become pregnant bromocriptine therapy alone may inhibit tumour growth.29 Obviously these patients should not be given oestrogen-containing oral contraceptives. Bromocriptine when properly prescribed is
’
19.
Lutterbeck, P. M., Pryor, J. S., Varga, L., Wenner, R. Br. med. J. 1971, iii, 228.
20 del
Pozo, E., Varga, L., Wyss, H., Tolis, G., Friesen, H., Wenner, R., Vetter, L., Uettweiller, A. J. clin. Endocr.Metab. 1974, 39, 18. 21 Thomer, M. O., Besser, G. M., Hagen, C. McNeilly, A. S.Br. med. J. 1974, ii, 419. 22 Seppälä, M., Hirvonen, E., Ranta, T. Lancet, 1976, i, 1154. 23 Tolis, G., Naftolin, F., Am. J. Obstet. Gynec. 1976, 126, 426. 24 Van der Steeg, H. J., Coelingh Bennink, H. J. T. Lancet, 1977, i, 502. 25. McNatty, K. P., Sawers, R. S., McNeilly, A. S. Nature, 1974, 250, 653. 26 Edwards, C. R. W., Jeffcoate, W. J. in Pharmacological and Clinical Aspects of Bromocriptine (Proc. Symp. R. Coll. Physns); p43. London, 1977. 27 Giusti, G., Bassi, F., Borsi, L., Cattaneo, S., Giannotti, P., Lanza, L., Pazzagli, M., Vigiani, C., Serio, M. in Prolactin and Human Reproduction edited by P. G. Crosignani and C. Robyn). London, 1977. 28 Thorner, M. O., Besser, G. M., Jones, A., Dacie, J., Jones, A. E. Br. med. 29
J. 1975, iv, 694. Wass, J. A. H., Thorner, M. O., Morris, D. V., Rees, Lesley, H., Mason, A. S., Jones, A. E., Besser, G. M. ibid. 1977, i, 875.
extremely common.... ANUS OR STOMA? IRONICALLY it was the advent of an efficient ileostomy thirty years ago which led to ileo-rectal anastomosis, for this paved the way for safe ablation of the large bowel severely damaged by ulcerative colitis. Previously, oper-
ation had been an occasional and very much a last resort, with disabling consequences if an ileostomy was needed; sometimes staged resections were associated with ileo-rectal or ileo-sigmoid anastomosis but the concept of excision and anastomosis as a deliberate policy had not been pursued during an era before the ileostomy became manageable with an adherent bag. When the benefits of bowel excision became evident, thoughts naturally turned to excision with preservation of anal function. In the 1950s the relative merits of the two procedures .were hotly contested, and the debate continues, albeit somewhat muted. The arguments for and against ileorectal anastomosis are paraded again in a review of 36 patients (4 with Crohn’s disease) so treated between 1958 and 1976 by Jones and his colleagues.’ These have altered little, if at all: advantage, the avoidance of a stoma ; disadvantage, failure to eliminate the disease and a change in bowel function. They reiterate the fact that inflammation of the rectum may become so severe as to warrant its excision and conversion to an ileostomy-as in 3 of their series. Moreover, if the disease persists because the rectum is retained, the patient is still at risk from the remote complications; so they found that ankylosing spondylitis persisted in 1 patient while arthritis of hands and knees developed after operation in another as did erythema nodosum and chronic active hepatitis in 2 others. As regards bowel function, none was incontinent but frequency of stool varied between three and six loose motions
a
day; they make
no
mention of precipitancy
or
30. Besser, G. M., Doniach, I., Canti, G., Curling, M, Setchell, M. E., Thorner, M. O., Wass, J. A. H., Grudziniskas, J. G. ibid. 1977, ii, 868. 1. Jones, P. F., Munro, A., Evan, S. W. B. Br. J. Surg. 1977, 64, 615.
806 urgency which is sometimes sufficient to cause disability in these patients. After 2 postoperative deaths there were 5 late deaths, 1 each from anorexia nervosa, chronic active hepatitis, "natural causes", carcinoma of the oesophagus, and hepatic metastasis from colonic carcinoma. They record no case of cancer in the retained rectum but emphasise this risk (which they judge to be 3%) as a major concern in the continued management of these patients. Indeed this hazard alone demands annual review of patients with an anastomosis: it must be borne in mind that some patients are irked by this and eventually default. During the same period Jones and coworkers treated 41 patients by panproctocolectomy and they make the point that such patients can be discharged after a year or two. In addition there was an interesting small group of 5 patients with ileostomy and colectomy in whom the rectum was not removed, all of whom died, no causes being given. Did cancer develop in any of these? What we do not know is what happened to the 41 ileostomy patients treated by the same workers in the same period, and this is a pity. For anastomosis needs to be compared with the only alternative, the stoma; fundamentally, those who argue for ileo-rectal anastomosis assume that, because an anus is more natural than a stoma, life must be better with an anus. But is it, if it
entails persistent diarrhoea, repeated hospital visits, and the continued hazards of the disease? On the other hand, how often in a lifetime does a patient with an ileostomy have to return to hospital or seek advice from the Ileostomy Association or a stoma therapist? These are important matters, requiring almost a social study, which could now be answered. There is a sizeable cohort of patients now reaching their seventh decade-their natural term-who have had either excision with ileostomy or ileo-rectal anastomosis twenty-five or more years ago. Its members can still be traced through centres such as Birmingham, Leeds, and London. What has life been like for them? Maybe its quality has differed little between the two groups, but we ought to find out. There is good reason to undertake this study now. The incidence of Crohn’s disease in Britain increased threefold between 1958 and 1971,2 and doubtless with it Crohn’s colitis, but that of ulcerative colitis rose only slightly. In Maimo over the same period the incidence rose from 3.5 to 6 - 0 per 100000.3 If a proper judgment is to be made it would best be made when most of the operations were for ulcerative colitis, for though no doubt some cases of Crohn’s disease were unwittingly included in colitis series of twenty-five years ago--since the condition was seldom recognised then-most of the patients did have ulcerative colitis. Now the pattern has changed; with the propensity of Crohn’s disease for recurrence and its ability to affect any part of the gut, an assessment of the results of the two operations per se will become more difficult to achieve. For ulcerative colitis, the disease and its symptoms can be eliminated by surgery; there can be no certainty of this when the operations are performed for Crohn’s disease. Moreover, the observation of Lockhart-Mummery4 that recurrence is longer delayed after panproctocolectomy than after colectomy and ileo-rectal anastomosis would be a strong 2.
Miller, D. S., Keighley, A. C., Langman, M. J. S. Lancet, 1974, ii, 691. 3. Brahme, F., Lindstrom, C., Wenckert, A. Gastroenterology, 1975, 69, 342. 4. Lockhart-Mummery, H. E. Br. J. Surg. 1972, 59, 823.
argument for the stoma-if the observation is
con-
firmed. Reviewing their series in Birmingham, Steinberg et a1.s were unable to confirm it. And, to cap it all, there are those happier mortals who consider much of the controversy about the relative courses after operation in ulcerative and Crohn’s colitis to be futile,6and longterm results to be much the same. Surely yet another reason for comparing the long-term results in ulcerative colitis before it is too late is to provide a baseline from which to determine whether that bald statement is true.
BLOOD IN THE ALCOHOL STREAM THE effects of high alcohol intake on the cells of the blood have been investigated largely in normal volunteers or ill alcoholics; we know little about the effects on blood-cells of "heavy regular drinking". What diagnostic difficulties might arise when a regular drinker is being investigated for other conditions? Chronic alcoholism depresses red-cell production.7 This happens even in well-nourished, non-anæmic alcoholics without evidence of cirrhosis,8 and typically the serum-iron is high, bone-marrow uptake of iron is low,’ erythroblast cytoplasm is vacuolated, and the bone-marrow contains abnormal sideroblasts. On withdrawal of alcohol these abnormalities disappear. In malnourished alcoholics who are folate-deficient the depression of erythropoiesismay be accompanied by macrocytosis in the peripheral blood and megaloblastic change in the bone-marrow.1O When such individuals are admitted to hospital, the reticulocytosis after withdrawal of alcohol and return to a normal diet may give rise to mistaken suspicions of haemolysis or bleeding. Haemoglobin often falls in the early days after drying-out, as the diuretic effect of alcohol is lost, but this fall tends to be succeeded by a gradual rise as red-cell production is freed from the suppressant effects of alcohol and of folate deficiency. The bone-marrow granulocyte reserve, and hence granulocyte production, may also be reduced in severe alcoholism."Cytoplasmic vacuolation, similar to that in erythroblasts, occurs in promyelocytes in the bone-marrow of alcoholics" and their ability to respond to infection with increased production of granulocytes is often subnormal. Bacterial infection may indeed cause leucopenia rather than leucocytosis, and alcoholics are unable to sustain high levels of granulocyte production from the bone-marrow when given repeated doses of endotoxin. This defect can be found in alcoholics without evidence of cirrhosis, portal hypertension, or hypersplenism. In patients with splenomegaly, splenic sequestration of red cells, white cells, and platelets may give rise to the more typical picture of hypersplenism due to portal hypertension. Platelet-counts tend to be low in alcoholics, even when folic-acid status is normal. When alcohol intake ceases the count usually rises and may become higher 5.
D. M., Allan, R. H., Thompson, H., Brooke, B. N., AlexanderWilliams, J., Cooke, W. J. Gut, 1974, 15, 845. 6. Fawaz, K. A., Glotzer, D. J., Goldman, H., Dickersin, G. R., Gross, W., Patterson, J. F. Gastroenterology, 1976, 71, 372. 7. Jandl, J. H. J. clin Invest. 1955, 34, 390. 8. Hourihane, D. O. B., Weir, D. G. Br. med. J. 1970, i, 86. 9. Waters, A. H., Morely, A. A., Rankm, J. G. ibid. 1966, ii, 1565. 10. Hines, J. D. Br. J. Hœmat. 1969, 16, 87. 11. McFarland, W., Libre, E. P. Ann. intern. Med. 1963, 59, 865. 12. Lindenbaum, J., Lieber, D. S. New Engl. J. Med. 1969, 281, 333.
Steinberg,