52 CLOSTRIDIUM BUTYRICUM AND NECROTISING ENTEROCOLITIS Howard and her colleagues’ describe an outbreak SIR,—Dr of necrotising enterocolitis (N.E.C.) with ten cases in 29 days. This cluster, and the fact that few of the babies had any predisposing condition such as prematurity, hypoxia, umbilical catheterisation, and hyperosmolar feeds, stresses the point that N.E.C. is an epidemic illness and that the causative agent must be looked for intensively. Stringent measures to reduce crossinfection have been effective when trying to reduce the number of babies with N.E.C. in a special-care unit.2 Among organisms which have been related to N.E.C. are Klebsiella sp., Escherichia coli, Clostridium perfringens, and Coxsackie viruses.3-6 According to Howard et al. we should now add Cl. butyricum, a species not previously considered to cause disease in man or animals and which does not produce a toxin, so typical and essential for other clostridia causing intestinal symptoms. The evidence that Cl. butyricum caused N.E.C. was the fact that this organism was found in fxces and blood from most cases. It was cultured in stools from the two infants in whom symptoms arose a long time after the main outbreak. The stool specimens from the remaining babies were all collected on one day towards the end of the outbreak, which involved, in many cases, a considerable delay between the appearance of symptoms and the collection of specimens for anaerobic analysis. As the gut flora might have changed during this period,’ the failure to isolate Cl. butyricum has little bearing on the claim of Howard et al. We find it surprising that anaerobic examination of stool specimens did not reveal the presence of a greater variety of organisms and also a higher incidence of mixed anaerobes. In our experience (see table) most pre-term babies 2 weeks after birth have established a varied flora, although not always of the same composition as one would see in healthy full-term infants or adults. The table shows that of the first four fully investigated infants (in a trial comparing gut flora in pre-term infants fed fresh human milk or cow’s milk) all were colonised with Cl. butyricum: however, none had any signs of N.E.C. although predisposing conditions were present in some. Since many of the unaffected babies in the Royal Free study are likely to have been much younger than 2 weeks on the day of sampling, we would not expect them to have a stabilised gut flora and the absence of Cl. butyricum in this control group is not
surprising. The gas-liquid chromatographic (G.L.C.) pattern of the stools is said to have been compatible with the presence of Cl. butyricum in four of the cases where the organism was not cultured. Cl. butyricum in vitro produces a G.L.C. tracing similar to that of many other clostridial species and indeed to some other anaerobic general We cannot see how any organism can be characterised by the in-vivo detection of volatile fatty acids unless the material examined has been shown to contain only a single species. More relevant to the pathogenesis was the finding that Cl. butyricum was isolated from seven of eleven blood cultures and that a G.L.c. tracing characteristic of the organism was found in another
done,
one was
two
negative,
blood cultures. One culture was not and one grew Klebsiella sp. Referring
Howard, F., Flynn, D. M., Bradley, J., Noone, P., Szawatkowshi, M. Lancet, 1977, ii, 1099. 2. Book, L. S., Overall, J. L., Herbst, J. J., Britt, M. R., Epstein, B., Jung, A. L. New Engl. J. Med. 1977, 297, 984. 3. Reid, W. D., Shannon, M. P. Can med. Ass. J. 1973, 108, 573. 4. Virnig, N. L., Reynolds, J. W. Am. J. Dis. Child. 1974, 128, 186. 5. Pedersen, P. V., Hansen, F. H., Halveg, A. B., Christiansen, E. D., Justesen, T., Høgh, P. Lancet, 1976, ii, 715. 6. Johnson, F. E., Crnic, D. M., Simmons, M. A., Lilly, J. R. Archs Dis. Childh. 1977, 52, 802. 7. Willis, A. T., Bullen, C. L., Williams, K., Fagg, C. G., Bourne, A., Vignon, M. Br. med J. 1973, iv, 67. 8. Holdeman, L. V., Moore, W. E. C. (editors) Anaerobe Laboratory Manual. Anaerobe Laboratory, Virginia Polytechnic Institute and State University, 1.
Blacksburg, Virginia, 1975.
GUT FLORA IN FOUR LOW-BIRTHWEIGHT INFANTS
to our comments on the anaerobic examination of stool, we would like to question the efficiency of the anaerobic methodology in blood-culturing. We are surprised that two blood cultures after 4 and 16 weeks incubation showed chromatographic evidence of only the relatively fast growing Cl. butyricum. There remains the fact that Cl. butyricum was grown in seven of twelve cases, four of these after 4 month’s incubation. It is difficult to evaluate these findings. Since Cl. butyricum seems to be a common organism in pre-term infants, a quantitative analysis of stool might often have shown that Cl. butyricum was predominant, in which case one would expect it, more frequently than other organisms, to invade the inflamed areas of the intestine and then enter the bloodstream. Howard et al. do not comment on the finding of spore-forming gram-positive bacilli in the histological preparations. N.E.C. has been attributed to both non-infectious and infectious causes. Although Cl. butyricum may be involved in the pathogenesis of N.E.C., we, in agreement with Virnig and Reynolds,’* believe that many organisms of the gut flora can contribute to this disease, when the mucosa and its defence
53 mechanisms factors.
are
altered
by
one or
several of the
predisposing
search of
a
gested that
Departments of Pædiatrics and Neonatal Medicine (Institute of Child Health) and Department of Bacteriology, Royal Postgraduate Medical School, London W12
L. GOTHEFORS I. BLENKHARN
MIXED B.C.G. AND IRRADIATED-CELL IMMUNOTHERAPY IN ACUTE LEUKÆMIA
SIR,-Dr Powles and his colleagues’ suggest that cells mixed B.C.G. may be effective in prolonging remission in acute myelogenous leukxmia (A.M.L.) and be superior to "standard" immunotherapy (i.e., cells and s.c.c. given separately). Our own experience of 7 years has been with standard immunotherapy and we have recently introduced the crucial control arm involving patients who receive no maintenance treatment during remission.2.3 We have already demonstrated that early intensive induction and consolidation chemotherapy is an
with
PROLONGED REMISSIONS
(IN WEEKS)
my then mentor, Dr J. W. Keyser, sugthromboplastin. As a result I described in entirely unexpected nor epoch-making finding thromboplastins gave different prothrombin
paper",
I look at
1957’ the not that different ratios, and described
some aspects of the behaviour of the reagents on storage. Instead of being pleased that I had backed a winner, I have in recent years become mystified by the national and international importance attached to the behaviour of an emulsion of brain. It ill becomes a laboratory worker to minimise the need for precision, but -is not the emphasis placed upon this test disproportionate to its significance? Before this heresy is hounded by the purists, might I add insult to injury by claiming that, provided our patients do not bleed, variations in the "therapeutic range" are of little clinical significance-after all the therapeutic benefit itself for the largest use of anticoagulants in ischoemic heart-disease has yet to be established. Finally, despite the plethora of agencies to "control" the prothrombin-time, I would question whether we have made any fundamental advance since Quick described his test in 19352 and the state of the art was summarised by Biggs and Macfarlane in 19493 and you in 1957.4
Bridgend General Hospital, Bridgend, Mid Glamorgan CF31 1JP
D. E. B. POWELL
DEAFNESS AFTER PERFORATION OF ROUND-WINDOW MEMBRANE
SiR,-Mr Knight (Nov. 12, p. 1003) has described
cases
of
sensorineural deafness resulting from perforation of the round-window membrane. I suggest that such deafness results not from any interference with the mechanics or hydrodynamics of the cochlea (the cochlea is very resistant to such disturbancesS) but from the specific ototoxic effects of blood, which have already been shown in the guineapig.6 If this is generally true there are obvious implications for otology. severe
+=still in remission.
important factor in the determination of prolonged remission in those patients who enter remission. We have also described genetic factors which influence survival in A.M.L., notably HLA and probably ABO and Rh phenotypes, regardless of maintenance treatment. We have two patients in the "no maintenance" control arm who are still in their first remissions at 115 and 87 weeks, while others receiving standard immunotherapy have had first remissions ranging from 101+ to 250 weeks with individual second and subsequent remissions of 4 to 5 years, and who are haematologically and clinically well (see table). There are "atypical" patients whose long survival gives rise to "tails" in life tables and complicates the evaluation of treatment in this disease, making it very difficult to assess the significance of reports such as that of Powles et al. Department of Medical Genetics, St Mary’s Hospital, Manchester M13 0JH
S. R. ZUHRIE R. HARRIS
Department of Clinical Hæmatology, Manchester Royal Infirmary
C. GEARY
THROMBOPLASTIN GENERATION
SIR,-The correspondence, articles, and heat generated by thromboplastin threaten to rival that of the classification of lymphoma. Many years ago when I was a junior lecturer "in 1. Powles, R. L., and others Lancet, 1977, ii, 1107. 2. Freeman, C. B., Harris, R., Geary, C. G., Leyland, M. J., MacIver, J. E., Delamore, I. W. Br. med. J. 1973, iv, 571. 3. Harris, R., and others Br. J. Cancer (in the press). 4. Harris, R., Zuhrie, S. R., Taylor, G. M., Freeman, C. B., Wentzel, J., Geary, C., Maclver, J. E. Lancet, 1977, ii, 653.
Department of Physiology, University of Western Australia, Nedlands, Western Australia
J. R. JOHNSTONE
SPOONS FOR MAKING GLUCOSE-SALT SOLUTION
SIR,-Oral rehydration, if done properly, reduces infant deaths from malnutrition and diarrhcea.s These are the first or second causes of death in most developing countries. Our first priority must be to teach mothers to give a home-made rehydration fluid to children with diarrhoea. They can make this fluid either from salt and ordinary sugar ("salt and sugar water") or, if they are fortunate, from a packet of glucose and electrolytes ("glucose-salt solution"). Each litre usually contains glucose (20 g) sodium chloride (3-5g), sodium bicarbonate (2.5 g) and potassium chloride (1.5 g). Health posts need some easy and sufficiently accurate way of measuring the constituents of this mixture so that if packets are not commercially available they can be made in the health post and given to mothers, or the fluid can be made in the health post and given to mothers, or the fluid can be made and used in the health post itself. For this purpose, we have devised the set of measuring spoons (see figure). They are intended for use by 1. Powell, D. E. B. J. clin. Path. 1957, 10, 262. 2. Quick, A. J. J. biol. Chem. 1935, 109, 73. 3. Biggs, R., Macfarlane, R. G. J. clin. Path. 1949, 2, 33. 4. Lancet, 1957, ii, 679. 5. Wilson, J. R., Johnstone, J. R. J. acoust. Soc. Am. 1975, 57, 705. 6. Johnstone, J. R., Johnstone, B. M., Alder, V. A., Yates, G. K. Proc. Aust. Physiol. Soc. 1975, 6, 149 7. Whitehead, R. Proc. R. Soc. B, 1977, 199, 49. 8. Lancet, 1975, i, 79.
surprising. The gas-liquid chromatographic (G.L.C.) pattern of the stools is said to have been compatible with the presence of Cl. butyricum in four of the cases where the organism was not cultured. Cl. butyricum in vitro produces a G.L.C. tracing similar to that of many other clostridial species and indeed to some other anaerobic general We cannot see how any organism can be characterised by the in-vivo detection of volatile fatty acids unless the material examined has been shown to contain only a single species. More relevant to the pathogenesis was the finding that Cl. butyricum was isolated from seven of eleven blood cultures and that a G.L.c. tracing characteristic of the organism was found in another
done,
one was
two
negative,
blood cultures. One culture was not and one grew Klebsiella sp. Referring
Howard, F., Flynn, D. M., Bradley, J., Noone, P., Szawatkowshi, M. Lancet, 1977, ii, 1099. 2. Book, L. S., Overall, J. L., Herbst, J. J., Britt, M. R., Epstein, B., Jung, A. L. New Engl. J. Med. 1977, 297, 984. 3. Reid, W. D., Shannon, M. P. Can med. Ass. J. 1973, 108, 573. 4. Virnig, N. L., Reynolds, J. W. Am. J. Dis. Child. 1974, 128, 186. 5. Pedersen, P. V., Hansen, F. H., Halveg, A. B., Christiansen, E. D., Justesen, T., Høgh, P. Lancet, 1976, ii, 715. 6. Johnson, F. E., Crnic, D. M., Simmons, M. A., Lilly, J. R. Archs Dis. Childh. 1977, 52, 802. 7. Willis, A. T., Bullen, C. L., Williams, K., Fagg, C. G., Bourne, A., Vignon, M. Br. med J. 1973, iv, 67. 8. Holdeman, L. V., Moore, W. E. C. (editors) Anaerobe Laboratory Manual. Anaerobe Laboratory, Virginia Polytechnic Institute and State University, 1.
Blacksburg, Virginia, 1975.
GUT FLORA IN FOUR LOW-BIRTHWEIGHT INFANTS
to our comments on the anaerobic examination of stool, we would like to question the efficiency of the anaerobic methodology in blood-culturing. We are surprised that two blood cultures after 4 and 16 weeks incubation showed chromatographic evidence of only the relatively fast growing Cl. butyricum. There remains the fact that Cl. butyricum was grown in seven of twelve cases, four of these after 4 month’s incubation. It is difficult to evaluate these findings. Since Cl. butyricum seems to be a common organism in pre-term infants, a quantitative analysis of stool might often have shown that Cl. butyricum was predominant, in which case one would expect it, more frequently than other organisms, to invade the inflamed areas of the intestine and then enter the bloodstream. Howard et al. do not comment on the finding of spore-forming gram-positive bacilli in the histological preparations. N.E.C. has been attributed to both non-infectious and infectious causes. Although Cl. butyricum may be involved in the pathogenesis of N.E.C., we, in agreement with Virnig and Reynolds,’* believe that many organisms of the gut flora can contribute to this disease, when the mucosa and its defence
53 mechanisms factors.
are
altered
by
one or
several of the
predisposing
search of
a
gested that
Departments of Pædiatrics and Neonatal Medicine (Institute of Child Health) and Department of Bacteriology, Royal Postgraduate Medical School, London W12
L. GOTHEFORS I. BLENKHARN
MIXED B.C.G. AND IRRADIATED-CELL IMMUNOTHERAPY IN ACUTE LEUKÆMIA
SIR,-Dr Powles and his colleagues’ suggest that cells mixed B.C.G. may be effective in prolonging remission in acute myelogenous leukxmia (A.M.L.) and be superior to "standard" immunotherapy (i.e., cells and s.c.c. given separately). Our own experience of 7 years has been with standard immunotherapy and we have recently introduced the crucial control arm involving patients who receive no maintenance treatment during remission.2.3 We have already demonstrated that early intensive induction and consolidation chemotherapy is an
with
PROLONGED REMISSIONS
(IN WEEKS)
my then mentor, Dr J. W. Keyser, sugthromboplastin. As a result I described in entirely unexpected nor epoch-making finding thromboplastins gave different prothrombin
paper",
I look at
1957’ the not that different ratios, and described
some aspects of the behaviour of the reagents on storage. Instead of being pleased that I had backed a winner, I have in recent years become mystified by the national and international importance attached to the behaviour of an emulsion of brain. It ill becomes a laboratory worker to minimise the need for precision, but -is not the emphasis placed upon this test disproportionate to its significance? Before this heresy is hounded by the purists, might I add insult to injury by claiming that, provided our patients do not bleed, variations in the "therapeutic range" are of little clinical significance-after all the therapeutic benefit itself for the largest use of anticoagulants in ischoemic heart-disease has yet to be established. Finally, despite the plethora of agencies to "control" the prothrombin-time, I would question whether we have made any fundamental advance since Quick described his test in 19352 and the state of the art was summarised by Biggs and Macfarlane in 19493 and you in 1957.4
Bridgend General Hospital, Bridgend, Mid Glamorgan CF31 1JP
D. E. B. POWELL
DEAFNESS AFTER PERFORATION OF ROUND-WINDOW MEMBRANE
SiR,-Mr Knight (Nov. 12, p. 1003) has described
cases
of
sensorineural deafness resulting from perforation of the round-window membrane. I suggest that such deafness results not from any interference with the mechanics or hydrodynamics of the cochlea (the cochlea is very resistant to such disturbancesS) but from the specific ototoxic effects of blood, which have already been shown in the guineapig.6 If this is generally true there are obvious implications for otology. severe
+=still in remission.
important factor in the determination of prolonged remission in those patients who enter remission. We have also described genetic factors which influence survival in A.M.L., notably HLA and probably ABO and Rh phenotypes, regardless of maintenance treatment. We have two patients in the "no maintenance" control arm who are still in their first remissions at 115 and 87 weeks, while others receiving standard immunotherapy have had first remissions ranging from 101+ to 250 weeks with individual second and subsequent remissions of 4 to 5 years, and who are haematologically and clinically well (see table). There are "atypical" patients whose long survival gives rise to "tails" in life tables and complicates the evaluation of treatment in this disease, making it very difficult to assess the significance of reports such as that of Powles et al. Department of Medical Genetics, St Mary’s Hospital, Manchester M13 0JH
S. R. ZUHRIE R. HARRIS
Department of Clinical Hæmatology, Manchester Royal Infirmary
C. GEARY
THROMBOPLASTIN GENERATION
SIR,-The correspondence, articles, and heat generated by thromboplastin threaten to rival that of the classification of lymphoma. Many years ago when I was a junior lecturer "in 1. Powles, R. L., and others Lancet, 1977, ii, 1107. 2. Freeman, C. B., Harris, R., Geary, C. G., Leyland, M. J., MacIver, J. E., Delamore, I. W. Br. med. J. 1973, iv, 571. 3. Harris, R., and others Br. J. Cancer (in the press). 4. Harris, R., Zuhrie, S. R., Taylor, G. M., Freeman, C. B., Wentzel, J., Geary, C., Maclver, J. E. Lancet, 1977, ii, 653.
Department of Physiology, University of Western Australia, Nedlands, Western Australia
J. R. JOHNSTONE
SPOONS FOR MAKING GLUCOSE-SALT SOLUTION
SIR,-Oral rehydration, if done properly, reduces infant deaths from malnutrition and diarrhcea.s These are the first or second causes of death in most developing countries. Our first priority must be to teach mothers to give a home-made rehydration fluid to children with diarrhoea. They can make this fluid either from salt and ordinary sugar ("salt and sugar water") or, if they are fortunate, from a packet of glucose and electrolytes ("glucose-salt solution"). Each litre usually contains glucose (20 g) sodium chloride (3-5g), sodium bicarbonate (2.5 g) and potassium chloride (1.5 g). Health posts need some easy and sufficiently accurate way of measuring the constituents of this mixture so that if packets are not commercially available they can be made in the health post and given to mothers, or the fluid can be made in the health post and given to mothers, or the fluid can be made and used in the health post itself. For this purpose, we have devised the set of measuring spoons (see figure). They are intended for use by 1. Powell, D. E. B. J. clin. Path. 1957, 10, 262. 2. Quick, A. J. J. biol. Chem. 1935, 109, 73. 3. Biggs, R., Macfarlane, R. G. J. clin. Path. 1949, 2, 33. 4. Lancet, 1957, ii, 679. 5. Wilson, J. R., Johnstone, J. R. J. acoust. Soc. Am. 1975, 57, 705. 6. Johnstone, J. R., Johnstone, B. M., Alder, V. A., Yates, G. K. Proc. Aust. Physiol. Soc. 1975, 6, 149 7. Whitehead, R. Proc. R. Soc. B, 1977, 199, 49. 8. Lancet, 1975, i, 79.
