- Email: [email protected]
HIATUS HERNIA
211 Under the
experimental conditions used, voluntary
reduction of physical activity taken
place
as an
adaptation
to a minimal level will have to reduced levels of energy
Thus the estimate of maintenance needs can be regarded as appropriate to a very sedentary mode of existence. For an adult 65 kg. man, for example, the estimated maintenance requirement of 11 MJ (2600 C.) 11 may be compared with the requirements given in table n ranging from light activity 11-3 MJ (2700 C.) to 15.1 MJ (3600 C.) for the very active " reference " man.
intake.
Growth Requirements The energy cost of growth can be estimated from the effect on N balance of increasing energy intakes under conditions when energy is the factor limiting N gain. Values ranging from 5-4 to 6’8 mg. of N stored in new tissue per additional C. for young and adult rats and for adult men can be calculated from reported data.8-10,12,13 If one assumes 18% for the protein content of tissue gain, these values correspond to 4-3-5-4 C. per g. of weight gain. Independent estimates by Kielanowski,6 of the energy costs of deposition of protein and of fat are 15-9 and 12-9 C. per g. deposited. Assuming that normal tissue gained during growth contains 16% fat, these figures would imply a cost of 5-0 C. per g. of tissue. The different estimates are thus in reasonably close agreement, and the value of 5 C. per g. has been used for the calculations which follow. Ashworth 14 and Ashworth et al.,15 from measurements on infants recovering from malnutrition, obtained a value of 10 C. pe’ g. for the excess energy required above basal for each gramme of tissue formed, equivalent to a cost above maintenance (1-5 x basal) of 8-3 C. per g. of tissue gain. This figure is, however, likely to be an over-estimate since it will include the cost of physical activity, which under the conditions of measurement was probably not inconsider-
able.
Requirements for Maintenance
and Growth Compared with Observed Intakes Table 11 shows the energy needs for maintenance and growth of boys at different ages. The weights and weight gains have been derived from the Harvard standards. The difference between maintenance plus growth needs and the recommended intakes represents the amounts of energy potentially available to the average individual for activity. There are few direct estimates of the energy cost of activities in children, and none in infants. However, in the adult the energy available for activity calculated by this method is in reasonable agreement with direct estimates of energy expenditure involved in different types of occupation. Department of Human Nutrition, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT.
P. R. PAYNE J. C. WATERLOW.
IMMUNOLOGICAL ASPECTS OF THE GUILLAIN-BARRÉ SYNDROME SiR,-Your editorial of June 26 (p. 1340) suggests that it is surprising not to find clinical evidence of centralnervous-system damage in the Guillain-Barré syndrome, even though the patients’ lymphocytes seem to be sensitised to
central-nervous-system antigen (encephalitogenic factor).
10. Miller, D. S., Payne, P. R. J. theoret. Biol. 1963, 5, 1398. 11. Recommended Intakes of Nutrients for the United Kingdom: Report of the Panel on Recommended Allowances of Nutrients. Rep. publ. Hlth med. Subj. Lond. 1969, no. 120. 12. Benditt, E. P., Humphreys, E. M., Wissler, R. W., Steffee, C. H., Frazier, L. E., Cannon, P. R. J. Lab. clin. Med. 1948, 33, 257. 13. Calloway, D. H., Spector, A. J. Nutrition, 1955, 56, 533. 14. Ashworth, A. Br. J. Nutr. 1969, 23, 835. 15. Ashworth, A., Bell, R., James, W. P. T., Waterlow, J. C. Lancet, 1968, ii, 600.
In fact, the necropsy study by Asbury et al.l cited in your presents convincing evidence of widespread centralnervous-system involvement in the Guillain-Barre syndrome. This fits in well with the presence of encephalitotext
genic-factor-sensitised lymphocytes. The question then has to be restated: is it surprising not to find clinical evidence of central-nervous-system damage in the presence of anatomical lesions ? I think it is not: in the presence of severe peripheral motor (and sensory) disturbance the classic signs of central involvement (Babinski’s sign, reflex anomalies, ataxia, &c.) do not help, and mental symptoms may be difficult to evaluate in a critically ill patient. Clinique Universitaire de Médecine, 1200 Geneva, Switzerland.
L. FIERZ.
HIATUS HERNIA
SiR,-In your editorial Hiatus Hernia: Reddest of Herrings (July 10, p. 83) you discuss a paper by Cohen and Harris2 and draw attention to the importance of the lower oesophageal sphincter mechanism in preventing gastro-oesophageal reflux and to the occurrence of reflux and of cesophagitis in the absence of a hiatus hernia. That troublesome reflux may occur in the absence of a hernia has, of course, become widely accepted, though few, I think, have found that this occurs anything like as frequently as would seem to be suggested by Cohen and Harris. You confess to some difficulty in explaining how success is achieved by surgical repair of hiatus hernia because of evidence that sphincter competence is the main factor in preventing reflux and the findings of Cohen and Harris that the lower oesophageal sphincter could be equally weak and incompetent whether a hiatus hernia is present or not. But are the results of conventional repair operations that are designed merely to restore normal anatomy so good as to be at variance with these findings ? I think not. My own experience, and that of many others, is that such repair operations give rather disappointing results. Apart from hernia recurrence being some 25%, I have found that even in the 75% of cases without demonstrable recurrence complete relief of reflux symptoms is obtained in only 33% and that there is little or no improvement in symptoms in some 25%. Indeed, in about a third of the patients without hernia recurrence gastric reflux can be demonstrated on
X-ray screening. Such results would seem to me to be not altogether incompatible with the findings of Cohen and Harris, in so far as they demonstrate that in many individuals, though apparently not in all, a lower oesophageal sphincter or other anti-reflux mechanism which is inefficient when the sphincter is located above the hiatus remains inefficient even when this is fixed in its normal position. It has been suggested that the explanation for the muchimproved results that may be obtained by using one of the plication types of operation for hiatus hernia or for gastrooesophageal reflux without herniation, such as those described by Nissen and by Belsey, is that these operations ensure that the lower oesophageal sphincter in its new overreduced position has its function constantly enhanced by the support of the surrounding intra-abdominal pressure. The findings of Cohen and Harris would seem to throw some doubt on this explanation; and I am particularly interested in this since I have held for some time that these plication arrangements work so well because they produce a completely new anti-reflux mechanism-a valve mechanism. In the particular plication operation I carry out, the lower end of the oesophagus is not over-reduced, but fixed 1. 2.
Asbury, A. K., Arnason, B. G., Adams, R. D. Medicine, Baltimore, 1969, 48, 173. Cohen, S., Harris, L. D. New Engl. J. Med. 1971, 284, 1053.
212 in its normal position, as with a conventional anatomical type of repair-this may have some advantages-and an anti-reflux valve mechanism is constructed beyond the cardia. To date, this arrangement appears to succeed completely in preventing gastro-cesophageal reflux. That an efficient anti-reflux valve mechanism is, in fact, achieved in this way can readily be demonstrated by carrying out the plication procedure on cadaveric stomachs and testing them at the laboratory bench. Passage of fluid from the stomach into the oesophagus is prevented. There can be no question of any part being played in this by surrounding intra-abdominal pressure, by pressure differential between thorax and abdomen, or by muscle action in the lower oesophagus or elsewhere. It would seem justifiable to conclude that the new anatomical arrangement prevents reflux by producing a new anti-reflux mechanism-a valve mechanism-rather than by enabling normal anti-reflux mechanisms to work more
efficiently. Department of Thoracic Surgery, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA.
J. A. W. BINGHAM.
SERUM-INSULIN LEVELS IN PATIENTS ON INSULIN
SIR,-Patients receiving exogenous insulin tend rapidly to develop insulin antibodies. These invalidate measurements of insulin by immunoassay, so there is little informa-
tion on insulin levels in patients receiving insulin therapy. Reavan and Salans,l using the rat epididymal-fat-pad bioassay for insulin, indicated that during the late afternoon diabetics receiving insulin have plasma insulin levels nine times higher than non-diabetic individuals not receiving insulin (971 uu per ml. vs 100 !lU per ml.). These workers speculated that such hyperinsulinism might play a role in the chronic vascular complications of diabetes. We have measured immunoassayable insulin in four diabetic patients in whom insulin therapy was being initiated-i.e., before the development of antibodies. The four women (age-range 48-61) had failed to achieve good diabetic control on oral hypoglycasmic agents. The oral agents were discontinued, and four days later the patients were admitted to the hospital where they received three meals a day (8 A.M., 12 noon, and 6 P.M.). During a control day the patients received no insulin and blood-samples were drawn at times indicated in the table. On the subsequent two days, the patients received subcutaneous injections of 30 u of N.P.H. porkinsulin after the 8 A.M. blood specimen was drawn. Immunoassayable plasma-insulinand plasma-glucose 3 were
relation to the blood-glucose levels before insulin therapy. 30 u of N.P.H. insulin resulted in a modest increase in insulin levels throughout the day, tending to return to the preinjection levels by the following morning. There was only a modest decrease in plasma-glucose levels in the first two days of insulin therapy. However, after two weeks of this insulin schedule, three of the four patients achieved good diabetic control while the fourth achieved fair control. Thus, immunoassayable-insulin levels during insulin therapy are closer to physiological levels than the bioassay measurements of insulin would suggest. Division of Endocrinology, Duke University Medical Center, KENNETH E. QUICKEL, JEROME M. FELDMAN. Durham, N.C. 27706.
JR.
CAFFEINE AND BLADDER CANCER SiR,-Dr. Cole, in his interesting papershowing an apparent association between coffee-drinking and bladder This cancer, suggests that caffeine may be involved. seems a priori unlikely if only because his non-coffeedrinking controls-unless they restrict themselves to water, selected soft drinks, and alcohol-will have at least some caffeine intake, since caffeine is present not only in coffee but also in tea, cocoa, and Coca-Cola’. While caffeine is at lower concentrations in these beverages, there must be considerable overlap in the total caffeine intake of coffee-drinkers and non-coffee-drinkers. In addition, although it is true that caffeine has been shown to be mutagenic in lower organisms, in recent reviews there was no definite evidence for caffeine mutagenicity in mice2 or man.3 Indeed, caffeine is probably the most intensively investigated potential human mutagen for which at present no clear mutagenic activity in mammals has been established.44 An interesting feature of Dr. Cole’s data is the difference in the relative risks of bladder cancer between males and females among coffee-drinkers when controlled for age, cigarette-smoking, and occupation. Relative to a risk of 1-00 among non-coffee-drinkers he found the risk to men coffee-drinkers to be 1-24 and to women coffee-drinkers 2-58. It has been shown5 that caffeine at a concentration of 10-4M (equivalent to 8 cups of coffee or 11 cups of tea) stimulates the rate of mitosis of human lymphocytes from female donors in vitro, while at the same concentration it decreases the mitotic rate of lymphocytes from male donors when compared with control cultures from the same individuals containing no caffeine. If caffeine has the same effect on the mitotic rate of bladder-cancer cells, then this might explain the difference found by Dr. Cole between the sexes.
determined.
The table shows that insulin values
were
quite
low in
1. Reaven, G., Salans, L. Ann. intern. Med. 1964, 61, 680. Feldman, J. M., Lebovitz, H. E. Endocrinology, 1970, 86, 313, Saifer, A., Gerstenfeld, B. J. Lab. clin. Med. 1958, 51, 448.
2. 3.
1. Cole, P. Lancet, 1971, i, 1335. 2. Epstein, S. in Chemical Mutagenesis in Mammals and Man by F. Vogel and G. Röhrborn); p. 404. Berlin, 1970. 3. Vogel, F. ibid. p. 433. 4. Adler, I. D. ibid. p. 383. 5. Timson, J. Br. J. Pharmac. 1970, 38, 731.
PLASMA INSULIN AND GLUCOSE
*
Numbers
are
LEVELS*
mean±S.B.M. of 4 observations.
(edited
experimental conditions used, voluntary
reduction of physical activity taken
place
as an
adaptation
to a minimal level will have to reduced levels of energy
Thus the estimate of maintenance needs can be regarded as appropriate to a very sedentary mode of existence. For an adult 65 kg. man, for example, the estimated maintenance requirement of 11 MJ (2600 C.) 11 may be compared with the requirements given in table n ranging from light activity 11-3 MJ (2700 C.) to 15.1 MJ (3600 C.) for the very active " reference " man.
intake.
Growth Requirements The energy cost of growth can be estimated from the effect on N balance of increasing energy intakes under conditions when energy is the factor limiting N gain. Values ranging from 5-4 to 6’8 mg. of N stored in new tissue per additional C. for young and adult rats and for adult men can be calculated from reported data.8-10,12,13 If one assumes 18% for the protein content of tissue gain, these values correspond to 4-3-5-4 C. per g. of weight gain. Independent estimates by Kielanowski,6 of the energy costs of deposition of protein and of fat are 15-9 and 12-9 C. per g. deposited. Assuming that normal tissue gained during growth contains 16% fat, these figures would imply a cost of 5-0 C. per g. of tissue. The different estimates are thus in reasonably close agreement, and the value of 5 C. per g. has been used for the calculations which follow. Ashworth 14 and Ashworth et al.,15 from measurements on infants recovering from malnutrition, obtained a value of 10 C. pe’ g. for the excess energy required above basal for each gramme of tissue formed, equivalent to a cost above maintenance (1-5 x basal) of 8-3 C. per g. of tissue gain. This figure is, however, likely to be an over-estimate since it will include the cost of physical activity, which under the conditions of measurement was probably not inconsider-
able.
Requirements for Maintenance
and Growth Compared with Observed Intakes Table 11 shows the energy needs for maintenance and growth of boys at different ages. The weights and weight gains have been derived from the Harvard standards. The difference between maintenance plus growth needs and the recommended intakes represents the amounts of energy potentially available to the average individual for activity. There are few direct estimates of the energy cost of activities in children, and none in infants. However, in the adult the energy available for activity calculated by this method is in reasonable agreement with direct estimates of energy expenditure involved in different types of occupation. Department of Human Nutrition, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT.
P. R. PAYNE J. C. WATERLOW.
IMMUNOLOGICAL ASPECTS OF THE GUILLAIN-BARRÉ SYNDROME SiR,-Your editorial of June 26 (p. 1340) suggests that it is surprising not to find clinical evidence of centralnervous-system damage in the Guillain-Barré syndrome, even though the patients’ lymphocytes seem to be sensitised to
central-nervous-system antigen (encephalitogenic factor).
10. Miller, D. S., Payne, P. R. J. theoret. Biol. 1963, 5, 1398. 11. Recommended Intakes of Nutrients for the United Kingdom: Report of the Panel on Recommended Allowances of Nutrients. Rep. publ. Hlth med. Subj. Lond. 1969, no. 120. 12. Benditt, E. P., Humphreys, E. M., Wissler, R. W., Steffee, C. H., Frazier, L. E., Cannon, P. R. J. Lab. clin. Med. 1948, 33, 257. 13. Calloway, D. H., Spector, A. J. Nutrition, 1955, 56, 533. 14. Ashworth, A. Br. J. Nutr. 1969, 23, 835. 15. Ashworth, A., Bell, R., James, W. P. T., Waterlow, J. C. Lancet, 1968, ii, 600.
In fact, the necropsy study by Asbury et al.l cited in your presents convincing evidence of widespread centralnervous-system involvement in the Guillain-Barre syndrome. This fits in well with the presence of encephalitotext
genic-factor-sensitised lymphocytes. The question then has to be restated: is it surprising not to find clinical evidence of central-nervous-system damage in the presence of anatomical lesions ? I think it is not: in the presence of severe peripheral motor (and sensory) disturbance the classic signs of central involvement (Babinski’s sign, reflex anomalies, ataxia, &c.) do not help, and mental symptoms may be difficult to evaluate in a critically ill patient. Clinique Universitaire de Médecine, 1200 Geneva, Switzerland.
L. FIERZ.
HIATUS HERNIA
SiR,-In your editorial Hiatus Hernia: Reddest of Herrings (July 10, p. 83) you discuss a paper by Cohen and Harris2 and draw attention to the importance of the lower oesophageal sphincter mechanism in preventing gastro-oesophageal reflux and to the occurrence of reflux and of cesophagitis in the absence of a hiatus hernia. That troublesome reflux may occur in the absence of a hernia has, of course, become widely accepted, though few, I think, have found that this occurs anything like as frequently as would seem to be suggested by Cohen and Harris. You confess to some difficulty in explaining how success is achieved by surgical repair of hiatus hernia because of evidence that sphincter competence is the main factor in preventing reflux and the findings of Cohen and Harris that the lower oesophageal sphincter could be equally weak and incompetent whether a hiatus hernia is present or not. But are the results of conventional repair operations that are designed merely to restore normal anatomy so good as to be at variance with these findings ? I think not. My own experience, and that of many others, is that such repair operations give rather disappointing results. Apart from hernia recurrence being some 25%, I have found that even in the 75% of cases without demonstrable recurrence complete relief of reflux symptoms is obtained in only 33% and that there is little or no improvement in symptoms in some 25%. Indeed, in about a third of the patients without hernia recurrence gastric reflux can be demonstrated on
X-ray screening. Such results would seem to me to be not altogether incompatible with the findings of Cohen and Harris, in so far as they demonstrate that in many individuals, though apparently not in all, a lower oesophageal sphincter or other anti-reflux mechanism which is inefficient when the sphincter is located above the hiatus remains inefficient even when this is fixed in its normal position. It has been suggested that the explanation for the muchimproved results that may be obtained by using one of the plication types of operation for hiatus hernia or for gastrooesophageal reflux without herniation, such as those described by Nissen and by Belsey, is that these operations ensure that the lower oesophageal sphincter in its new overreduced position has its function constantly enhanced by the support of the surrounding intra-abdominal pressure. The findings of Cohen and Harris would seem to throw some doubt on this explanation; and I am particularly interested in this since I have held for some time that these plication arrangements work so well because they produce a completely new anti-reflux mechanism-a valve mechanism. In the particular plication operation I carry out, the lower end of the oesophagus is not over-reduced, but fixed 1. 2.
Asbury, A. K., Arnason, B. G., Adams, R. D. Medicine, Baltimore, 1969, 48, 173. Cohen, S., Harris, L. D. New Engl. J. Med. 1971, 284, 1053.
212 in its normal position, as with a conventional anatomical type of repair-this may have some advantages-and an anti-reflux valve mechanism is constructed beyond the cardia. To date, this arrangement appears to succeed completely in preventing gastro-cesophageal reflux. That an efficient anti-reflux valve mechanism is, in fact, achieved in this way can readily be demonstrated by carrying out the plication procedure on cadaveric stomachs and testing them at the laboratory bench. Passage of fluid from the stomach into the oesophagus is prevented. There can be no question of any part being played in this by surrounding intra-abdominal pressure, by pressure differential between thorax and abdomen, or by muscle action in the lower oesophagus or elsewhere. It would seem justifiable to conclude that the new anatomical arrangement prevents reflux by producing a new anti-reflux mechanism-a valve mechanism-rather than by enabling normal anti-reflux mechanisms to work more
efficiently. Department of Thoracic Surgery, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA.
J. A. W. BINGHAM.
SERUM-INSULIN LEVELS IN PATIENTS ON INSULIN
SIR,-Patients receiving exogenous insulin tend rapidly to develop insulin antibodies. These invalidate measurements of insulin by immunoassay, so there is little informa-
tion on insulin levels in patients receiving insulin therapy. Reavan and Salans,l using the rat epididymal-fat-pad bioassay for insulin, indicated that during the late afternoon diabetics receiving insulin have plasma insulin levels nine times higher than non-diabetic individuals not receiving insulin (971 uu per ml. vs 100 !lU per ml.). These workers speculated that such hyperinsulinism might play a role in the chronic vascular complications of diabetes. We have measured immunoassayable insulin in four diabetic patients in whom insulin therapy was being initiated-i.e., before the development of antibodies. The four women (age-range 48-61) had failed to achieve good diabetic control on oral hypoglycasmic agents. The oral agents were discontinued, and four days later the patients were admitted to the hospital where they received three meals a day (8 A.M., 12 noon, and 6 P.M.). During a control day the patients received no insulin and blood-samples were drawn at times indicated in the table. On the subsequent two days, the patients received subcutaneous injections of 30 u of N.P.H. porkinsulin after the 8 A.M. blood specimen was drawn. Immunoassayable plasma-insulinand plasma-glucose 3 were
relation to the blood-glucose levels before insulin therapy. 30 u of N.P.H. insulin resulted in a modest increase in insulin levels throughout the day, tending to return to the preinjection levels by the following morning. There was only a modest decrease in plasma-glucose levels in the first two days of insulin therapy. However, after two weeks of this insulin schedule, three of the four patients achieved good diabetic control while the fourth achieved fair control. Thus, immunoassayable-insulin levels during insulin therapy are closer to physiological levels than the bioassay measurements of insulin would suggest. Division of Endocrinology, Duke University Medical Center, KENNETH E. QUICKEL, JEROME M. FELDMAN. Durham, N.C. 27706.
JR.
CAFFEINE AND BLADDER CANCER SiR,-Dr. Cole, in his interesting papershowing an apparent association between coffee-drinking and bladder This cancer, suggests that caffeine may be involved. seems a priori unlikely if only because his non-coffeedrinking controls-unless they restrict themselves to water, selected soft drinks, and alcohol-will have at least some caffeine intake, since caffeine is present not only in coffee but also in tea, cocoa, and Coca-Cola’. While caffeine is at lower concentrations in these beverages, there must be considerable overlap in the total caffeine intake of coffee-drinkers and non-coffee-drinkers. In addition, although it is true that caffeine has been shown to be mutagenic in lower organisms, in recent reviews there was no definite evidence for caffeine mutagenicity in mice2 or man.3 Indeed, caffeine is probably the most intensively investigated potential human mutagen for which at present no clear mutagenic activity in mammals has been established.44 An interesting feature of Dr. Cole’s data is the difference in the relative risks of bladder cancer between males and females among coffee-drinkers when controlled for age, cigarette-smoking, and occupation. Relative to a risk of 1-00 among non-coffee-drinkers he found the risk to men coffee-drinkers to be 1-24 and to women coffee-drinkers 2-58. It has been shown5 that caffeine at a concentration of 10-4M (equivalent to 8 cups of coffee or 11 cups of tea) stimulates the rate of mitosis of human lymphocytes from female donors in vitro, while at the same concentration it decreases the mitotic rate of lymphocytes from male donors when compared with control cultures from the same individuals containing no caffeine. If caffeine has the same effect on the mitotic rate of bladder-cancer cells, then this might explain the difference found by Dr. Cole between the sexes.
determined.
The table shows that insulin values
were
quite
low in
1. Reaven, G., Salans, L. Ann. intern. Med. 1964, 61, 680. Feldman, J. M., Lebovitz, H. E. Endocrinology, 1970, 86, 313, Saifer, A., Gerstenfeld, B. J. Lab. clin. Med. 1958, 51, 448.
2. 3.
1. Cole, P. Lancet, 1971, i, 1335. 2. Epstein, S. in Chemical Mutagenesis in Mammals and Man by F. Vogel and G. Röhrborn); p. 404. Berlin, 1970. 3. Vogel, F. ibid. p. 433. 4. Adler, I. D. ibid. p. 383. 5. Timson, J. Br. J. Pharmac. 1970, 38, 731.
PLASMA INSULIN AND GLUCOSE
*
Numbers
are
LEVELS*
mean±S.B.M. of 4 observations.
(edited