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TETRACYCLINES AND THE LIVER IN PREGNANCY
357 The definition of an initial illness and an active phase important advances and confirmation of these findings other areas is clearly needed. The epidemiological clues in must be followed up. The curious tribal distribution of the disease noted in Uganda 14 needs explanation. But if a seasonal febrile illness is the start of endomyocardial fibrosis in other areas, then it seems we must seek the cause in an infection or toxin rather than in some nutritional insult.l5 Parry and Abrahams may thus have given us the key. are
GROUPS
of small groups by Miss Margaret unusual social document which cocks a mild Phillips snook at the sophisticated discipline of 20th18th-century research .century techniques. She wanted to discover something about the formation and development of small groups-of any collection of people, that is, who felt themselves to be a group and who were not too many to know each other at least by sight. Studies in the United States had been made on group models under laboratory conditions, but the results seemed hardly relevant to spontaneous groups in their natural environments, and were of little help to those struggling with group manage" ment in real life." A group, Miss Phillips felt, was a product of its setting and must be studied as such. She therefore asked her friends to report on any groups of which they were themselves members. In their replies she sought common factors and recurrent patterns, and her analysis gives an entertaining series of vignettes of life in this country and the germs of one or two testable hypotheses. The stories were collected between 1940 and 1960. Many were wartime groups-interned aliens, evacuees, an ENSA team, infantry in training. Some had sprung up spontaneously for a specific purpose-for example, professional men who wished to draw up a statement of political policy. Others were dependent on a larger, containing institution and had been assembled arbitrarily by its authority. These included room-mates in a teachers’ training college, teachers on a school staff, and nurses in hospital. Whatever the nature of the group, however, the reporter’s account showed how unity flourished where the environment was friendly, where there were common aims and ideals, and where common effort met with some success. In the fire-fighting team, for example, there was friction between regular and auxiliary members until the team proved itself during the London blitz, and earned public acclamation. Once the emergency was over, bickering reappeared. The internees’ camp committee lost cohesion and support in the face of persistent failure to induce the authorities to improve camp conditions. A group of young people pursuing common intellectual interests was virtually destroyed by one egocentric and uncooperative member and by the pairing-off of its members. The religious groups studied (Roman Catholic nuns, a Protestant community, and a Friends’ meeting) seemed to have the most effective methods of controlling disruptive members and influences. Among the nuns, for instance, personal friendships were discouraged, and nuns were moved from house to house to counter the growth of THE
analysis 16 is
an
14. Shaper, A. G., Coles, R. M. ibid. 1965, 27, 121. 15. McKinney, B., Crawford, M. A. Lancet, 1965, ii, 880. 16. Small Social Groups in England. By MARGARET PHILLIPS. London: Methuen. 1965. Pp. 318. 15s.
natural affection. All three groups made use of silence as an aid to harmony. Every group, Miss Phillips confirmed, had a working together " (or instrumental), and a " living together " (or expressive) phase. In the latter its integrity was most vulnerable. Leadership had to provide coordination and organisation in the first phase and a little " mothering " of members in the second. These two sides to the leader’s role were not necessarily found in the same person. In general the larger the containing organisation the less satisfactory the expressive side of group life. In the Armed Forces, for instance, harmony and satisfaction were found only where work was absorbing and to the liking of those detailed to do it. Reports from the nursing profession rivalled those from the Forces in unhappiness, with complaints of isolation and the cold and uncaring attitude of authority. Nursing, Miss Phillips contends, is still suffering from the relics of conventual and military discipline imposed by Florence Nightingale. The 1960 reports were happier by far than those of 1940, but still provided evidence of a rigid hierarchy, the anxiety this possibly encourages among superiors, and the consequent harshness visited upon juniors. Miss Phillips suggests that nurses should work throughout their training in small compact groups, that social intercourse should be encouraged regardless of rank and seniority, and that a home sister should be at hand as confidante and " mother". Many of the reports from teachers showed signs of poor leadership. They told of staff-rooms unused, teachers arriving at or leaving the school without hail or farewell, and conflicting aims and intentions. Lack of cohesion was especially evident in State secondary schools. The staff tended to have widely differing trainings and backgrounds ; and they were subject to many outside pressures-the Ministry of Education, the public, parents, and the Press. Outside influence was also obvious in accounts of Women’s Institute meetings. Middle-class members, for instance, sat in the front, labourers’ wives at the back. Miss Phillips advises administrators, when examining an unsatisfactory group, to consider not only its make-up but also its social setting. And she insists that the design of buildings should take account of the group’s expressive as well as its instrumental side. She might have added that looking at things as they are is still a good wayof discovering how they work. "
TETRACYCLINES AND THE LIVER IN PREGNANCY
IN the 1950s, when the tetracyclines were introduced clinical medicine, they were recognised to be general inhibitors of cell metabolism, and this effect was particularly apparent in the liver. More specifically, tetracyclines apparently interfere with the incorporation of glutamate into protein, inhibit acetate metabolism, and impair oxidative phosphorylation. This depression of cell anabolism is so clearcut that tetracyclines were even used in cancer chemotherapy. Bateman and co-workers1 gave 1-2 g. of oxyterracycline daily by the arterial route to 23 patients with cancer; but, in several patients, jaundice and renal damage developed and this treatment of malignant disease was abandoned. When the tetracyclines were introduced for the chemotherapy of infections, liver to
1.
Bateman, J. C., Barberio, J. R., Grice, P., Klopp, C. T., Pierpoint, H. Archs intern. Med. 1952, 90, 763.
358
Lepper and his group2 gave 2 g. of chlortetracycline daily by mouth or intravenously to 7 patients, and, in all 7, enlargement of the liver and jaundice developed, and the 5 of these who died (chiefly of the disease for which antibiotic therapy was given) had fatty livers. damage
was
also noted.
An association has now been established between tetracycline and the acute fatty liver of pregnancy-a condition described in 1940 by Sheehan.3 During the last trimester of pregnancy, these mothers had jaundice,
and vomiting, haematemesis, abdominal pain, was the usual outcome, several days after delivery. In many ways, the course was similar to acute fulminant viral hepatitis, but of the liver revealed no hepatoexamination histological cellular necrosis, little or no inflammatory reaction, and many small intracytoplasmic lipid-laden vacuoles arranged around a centrally placed, normal nucleus. Sheehan termed the condition " obstetric acute yellow atrophy ", but others prefer the term " acute fatty liver of pregnancy ". Schultz et al. reported the deaths of 6 women who had had acute pyelonephritis associated with pregnancy and who had received tetracycline intravenously. They had nausea, vomiting, wide fluctuations in temperature, jaundice, hxmatemesis, melasna, and azotxmia. All these patients had had tetracycline in doses greater than those usually recommended, the maximum daily dose varying from 3-5 to 6 g. intravenously. The chief necropsy finding in each case was fine drops of fat in liver cells throughout the lobules. In addition, acute pyelonephritis was found in 4 patients, 3 of whom also had small abscesses in the kidneys. 2 others had fatty deposits in the renal tubular epithelium. In 1964, Whalley et al. reported 4 cases of fatty liver of pregnancy following tetracycline treatment for acute pyelonephritis; 3 of these 4 patients survived. Kahil et al.also reported 2 pregnant patients who died with acute fatty liver, both of whom had received tetracycline, one for pyelonephritis and the other for
severe nausea
headaches, and stupor. Death
bronchopneumonia. In a review of the subject, Kunelis and his group7 have described 16 patients with fatty liver of pregnancy. 12 had acute pyelonephritis and were being treated with large doses of tetracycline intravenously. 4, who had not received tetracycline, had hepatic lesions that were indistinguishable from those seen in fatty liver of pregnancy. 6 non-pregnant women who were treated with tetracycline intravenously had similar fatty changes of the liver. There was a high incidence of pathological or functional involvement of the pancreas, kidneys, and brain. The central nervous system changes were so severe that they could have been responsible for the stupor and coma. The liver in pregnancy, with its increased demands for protein anabolism, may be more sensitive than the non-pregnant one to agents that depress this function, such as the tetracyclines. The similarity between the fatty liver of pregnancy and that seen in experimental lesions produced by other substances which depress protein anabolism, such as Lepper, M. H., Wolfe, C. K., Zimmerman, H. A., Cladwell, E. R., Spies, H. W., Dowling, H. F. ibid. 1951, 88, 271. 3. Sheehan, H. L. J. Obstet. Gynœc. Brit. Emp. 1940, 47, 49. 4 Schultz, J. C., Adamson, J. S. Jr., Workman, W. W., Norman, T. D. New Engl. J. Med. 1963, 269, 999. 5. Whalley, P. J., Adams, R. H., Combes, B. Gastroenterology, 1964, 46, 308. 6. Kahil, M. E., Fred, H. L., Brown, H., Davis, J. S. Archs intern. Med. 1964, 113, 63. 7. Kunelis, C. T., Peters, J. L., Edmondson, H. A. Am. J. Med. 1965, 38, 359. 2.
diets deficient in essential aminoacids, is striking. Coexisting pyelonephritis could also predispose to fatty liver of pregnancy. The acute fatty liver of pregnancy is certainly not only due to tetracycline. A patient with this condition who was studied by serial light and electron microscopy of liver biopsy specimens had never received tetracycline.a She was in a very poor nutritional state, and this is believed to have been the prime factor. Nevertheless, it is advisable to avoid the use of the tetracyclines, especially intravenously, during the last trimester of pregnancy. The risk of liver damage may be greatest when the patient has pyelonephritis or is undernourished.
ethionine
or
SCOTLAND’S HOSPITAL PLAN
THE latest review of the 1962 ten-year hospital programme for Scotland9 covers only the next five years. The Scottish Home and Health Department now makes it clear that this shorter period is more realistic for firm planning than a ten-year period, and it hopes to lessen the planning-time of individual schemes in order to reduce the need for long advance notice of starting-dates. To do this it proposes to cut the number of stages at which detailed design work will be examined and approved, using cost limits as the main control mechanism. If this spares some of the duplicated efforts of scarce technical staff, it will be welcomed. The review includes tentative (some may say far too tentative) asides on future hospital policy. The interdependence and integration of the health services are mentioned without any suggestion of how they are to be promoted in building terms, except in an oblique reference to the possible development of health centres in relation to some rural hospitals. The programme assumes a capital expenditure of about E60 million in the quinquennium 1966-67 to 1970-71. Though at first the list of schemes seems impressive, it makes very poor reading against the list which regional boards would like to see: the statement " that it has not been possible to include in the programme a number of schemes which regional boards would naturally have wished to start in this period" must surely rank as one of the major understatements of 1966. The yawning and widening gap between the programme and the real need merits far greater illumination so that the task of bridging it can be squarely faced. There seem to be two solutions: firstly, a large increase in the capital available and hence an acceleration in the programme; and, secondly, a major simplification and standardisation in design, in accordance with the concept of the utility hospital. The case for the second of these two solutions has been forcefully stated by a pseudonymous contributor. to A cheap hospital to build is not necessarily a cheap hospital to run; nor is it necessarily economical in staff. Nevertheless, this approach merits more attention than the brief note under the heading " Industrialist Building Methods " in the Scottish review. Neither solution will suffice alone. The answer lies in a combination of the two-more money and greater readiness to accept the good at the expense of the theoretical ideal. R. J., Dowling, E. A., Alexander, H. C., Sibrans, D., H. Ann. intern. Med. 1965, 63, 851. 9. Review of the Hospital Plan for Scotland. Cmnd. 2877. H.M. Office, 1966. 10. Lancet, Feb. 5, 1966, p. 308. 8.
Duma,
Dempsey, Stationery
GROUPS
of small groups by Miss Margaret unusual social document which cocks a mild Phillips snook at the sophisticated discipline of 20th18th-century research .century techniques. She wanted to discover something about the formation and development of small groups-of any collection of people, that is, who felt themselves to be a group and who were not too many to know each other at least by sight. Studies in the United States had been made on group models under laboratory conditions, but the results seemed hardly relevant to spontaneous groups in their natural environments, and were of little help to those struggling with group manage" ment in real life." A group, Miss Phillips felt, was a product of its setting and must be studied as such. She therefore asked her friends to report on any groups of which they were themselves members. In their replies she sought common factors and recurrent patterns, and her analysis gives an entertaining series of vignettes of life in this country and the germs of one or two testable hypotheses. The stories were collected between 1940 and 1960. Many were wartime groups-interned aliens, evacuees, an ENSA team, infantry in training. Some had sprung up spontaneously for a specific purpose-for example, professional men who wished to draw up a statement of political policy. Others were dependent on a larger, containing institution and had been assembled arbitrarily by its authority. These included room-mates in a teachers’ training college, teachers on a school staff, and nurses in hospital. Whatever the nature of the group, however, the reporter’s account showed how unity flourished where the environment was friendly, where there were common aims and ideals, and where common effort met with some success. In the fire-fighting team, for example, there was friction between regular and auxiliary members until the team proved itself during the London blitz, and earned public acclamation. Once the emergency was over, bickering reappeared. The internees’ camp committee lost cohesion and support in the face of persistent failure to induce the authorities to improve camp conditions. A group of young people pursuing common intellectual interests was virtually destroyed by one egocentric and uncooperative member and by the pairing-off of its members. The religious groups studied (Roman Catholic nuns, a Protestant community, and a Friends’ meeting) seemed to have the most effective methods of controlling disruptive members and influences. Among the nuns, for instance, personal friendships were discouraged, and nuns were moved from house to house to counter the growth of THE
analysis 16 is
an
14. Shaper, A. G., Coles, R. M. ibid. 1965, 27, 121. 15. McKinney, B., Crawford, M. A. Lancet, 1965, ii, 880. 16. Small Social Groups in England. By MARGARET PHILLIPS. London: Methuen. 1965. Pp. 318. 15s.
natural affection. All three groups made use of silence as an aid to harmony. Every group, Miss Phillips confirmed, had a working together " (or instrumental), and a " living together " (or expressive) phase. In the latter its integrity was most vulnerable. Leadership had to provide coordination and organisation in the first phase and a little " mothering " of members in the second. These two sides to the leader’s role were not necessarily found in the same person. In general the larger the containing organisation the less satisfactory the expressive side of group life. In the Armed Forces, for instance, harmony and satisfaction were found only where work was absorbing and to the liking of those detailed to do it. Reports from the nursing profession rivalled those from the Forces in unhappiness, with complaints of isolation and the cold and uncaring attitude of authority. Nursing, Miss Phillips contends, is still suffering from the relics of conventual and military discipline imposed by Florence Nightingale. The 1960 reports were happier by far than those of 1940, but still provided evidence of a rigid hierarchy, the anxiety this possibly encourages among superiors, and the consequent harshness visited upon juniors. Miss Phillips suggests that nurses should work throughout their training in small compact groups, that social intercourse should be encouraged regardless of rank and seniority, and that a home sister should be at hand as confidante and " mother". Many of the reports from teachers showed signs of poor leadership. They told of staff-rooms unused, teachers arriving at or leaving the school without hail or farewell, and conflicting aims and intentions. Lack of cohesion was especially evident in State secondary schools. The staff tended to have widely differing trainings and backgrounds ; and they were subject to many outside pressures-the Ministry of Education, the public, parents, and the Press. Outside influence was also obvious in accounts of Women’s Institute meetings. Middle-class members, for instance, sat in the front, labourers’ wives at the back. Miss Phillips advises administrators, when examining an unsatisfactory group, to consider not only its make-up but also its social setting. And she insists that the design of buildings should take account of the group’s expressive as well as its instrumental side. She might have added that looking at things as they are is still a good wayof discovering how they work. "
TETRACYCLINES AND THE LIVER IN PREGNANCY
IN the 1950s, when the tetracyclines were introduced clinical medicine, they were recognised to be general inhibitors of cell metabolism, and this effect was particularly apparent in the liver. More specifically, tetracyclines apparently interfere with the incorporation of glutamate into protein, inhibit acetate metabolism, and impair oxidative phosphorylation. This depression of cell anabolism is so clearcut that tetracyclines were even used in cancer chemotherapy. Bateman and co-workers1 gave 1-2 g. of oxyterracycline daily by the arterial route to 23 patients with cancer; but, in several patients, jaundice and renal damage developed and this treatment of malignant disease was abandoned. When the tetracyclines were introduced for the chemotherapy of infections, liver to
1.
Bateman, J. C., Barberio, J. R., Grice, P., Klopp, C. T., Pierpoint, H. Archs intern. Med. 1952, 90, 763.
358
Lepper and his group2 gave 2 g. of chlortetracycline daily by mouth or intravenously to 7 patients, and, in all 7, enlargement of the liver and jaundice developed, and the 5 of these who died (chiefly of the disease for which antibiotic therapy was given) had fatty livers. damage
was
also noted.
An association has now been established between tetracycline and the acute fatty liver of pregnancy-a condition described in 1940 by Sheehan.3 During the last trimester of pregnancy, these mothers had jaundice,
and vomiting, haematemesis, abdominal pain, was the usual outcome, several days after delivery. In many ways, the course was similar to acute fulminant viral hepatitis, but of the liver revealed no hepatoexamination histological cellular necrosis, little or no inflammatory reaction, and many small intracytoplasmic lipid-laden vacuoles arranged around a centrally placed, normal nucleus. Sheehan termed the condition " obstetric acute yellow atrophy ", but others prefer the term " acute fatty liver of pregnancy ". Schultz et al. reported the deaths of 6 women who had had acute pyelonephritis associated with pregnancy and who had received tetracycline intravenously. They had nausea, vomiting, wide fluctuations in temperature, jaundice, hxmatemesis, melasna, and azotxmia. All these patients had had tetracycline in doses greater than those usually recommended, the maximum daily dose varying from 3-5 to 6 g. intravenously. The chief necropsy finding in each case was fine drops of fat in liver cells throughout the lobules. In addition, acute pyelonephritis was found in 4 patients, 3 of whom also had small abscesses in the kidneys. 2 others had fatty deposits in the renal tubular epithelium. In 1964, Whalley et al. reported 4 cases of fatty liver of pregnancy following tetracycline treatment for acute pyelonephritis; 3 of these 4 patients survived. Kahil et al.also reported 2 pregnant patients who died with acute fatty liver, both of whom had received tetracycline, one for pyelonephritis and the other for
severe nausea
headaches, and stupor. Death
bronchopneumonia. In a review of the subject, Kunelis and his group7 have described 16 patients with fatty liver of pregnancy. 12 had acute pyelonephritis and were being treated with large doses of tetracycline intravenously. 4, who had not received tetracycline, had hepatic lesions that were indistinguishable from those seen in fatty liver of pregnancy. 6 non-pregnant women who were treated with tetracycline intravenously had similar fatty changes of the liver. There was a high incidence of pathological or functional involvement of the pancreas, kidneys, and brain. The central nervous system changes were so severe that they could have been responsible for the stupor and coma. The liver in pregnancy, with its increased demands for protein anabolism, may be more sensitive than the non-pregnant one to agents that depress this function, such as the tetracyclines. The similarity between the fatty liver of pregnancy and that seen in experimental lesions produced by other substances which depress protein anabolism, such as Lepper, M. H., Wolfe, C. K., Zimmerman, H. A., Cladwell, E. R., Spies, H. W., Dowling, H. F. ibid. 1951, 88, 271. 3. Sheehan, H. L. J. Obstet. Gynœc. Brit. Emp. 1940, 47, 49. 4 Schultz, J. C., Adamson, J. S. Jr., Workman, W. W., Norman, T. D. New Engl. J. Med. 1963, 269, 999. 5. Whalley, P. J., Adams, R. H., Combes, B. Gastroenterology, 1964, 46, 308. 6. Kahil, M. E., Fred, H. L., Brown, H., Davis, J. S. Archs intern. Med. 1964, 113, 63. 7. Kunelis, C. T., Peters, J. L., Edmondson, H. A. Am. J. Med. 1965, 38, 359. 2.
diets deficient in essential aminoacids, is striking. Coexisting pyelonephritis could also predispose to fatty liver of pregnancy. The acute fatty liver of pregnancy is certainly not only due to tetracycline. A patient with this condition who was studied by serial light and electron microscopy of liver biopsy specimens had never received tetracycline.a She was in a very poor nutritional state, and this is believed to have been the prime factor. Nevertheless, it is advisable to avoid the use of the tetracyclines, especially intravenously, during the last trimester of pregnancy. The risk of liver damage may be greatest when the patient has pyelonephritis or is undernourished.
ethionine
or
SCOTLAND’S HOSPITAL PLAN
THE latest review of the 1962 ten-year hospital programme for Scotland9 covers only the next five years. The Scottish Home and Health Department now makes it clear that this shorter period is more realistic for firm planning than a ten-year period, and it hopes to lessen the planning-time of individual schemes in order to reduce the need for long advance notice of starting-dates. To do this it proposes to cut the number of stages at which detailed design work will be examined and approved, using cost limits as the main control mechanism. If this spares some of the duplicated efforts of scarce technical staff, it will be welcomed. The review includes tentative (some may say far too tentative) asides on future hospital policy. The interdependence and integration of the health services are mentioned without any suggestion of how they are to be promoted in building terms, except in an oblique reference to the possible development of health centres in relation to some rural hospitals. The programme assumes a capital expenditure of about E60 million in the quinquennium 1966-67 to 1970-71. Though at first the list of schemes seems impressive, it makes very poor reading against the list which regional boards would like to see: the statement " that it has not been possible to include in the programme a number of schemes which regional boards would naturally have wished to start in this period" must surely rank as one of the major understatements of 1966. The yawning and widening gap between the programme and the real need merits far greater illumination so that the task of bridging it can be squarely faced. There seem to be two solutions: firstly, a large increase in the capital available and hence an acceleration in the programme; and, secondly, a major simplification and standardisation in design, in accordance with the concept of the utility hospital. The case for the second of these two solutions has been forcefully stated by a pseudonymous contributor. to A cheap hospital to build is not necessarily a cheap hospital to run; nor is it necessarily economical in staff. Nevertheless, this approach merits more attention than the brief note under the heading " Industrialist Building Methods " in the Scottish review. Neither solution will suffice alone. The answer lies in a combination of the two-more money and greater readiness to accept the good at the expense of the theoretical ideal. R. J., Dowling, E. A., Alexander, H. C., Sibrans, D., H. Ann. intern. Med. 1965, 63, 851. 9. Review of the Hospital Plan for Scotland. Cmnd. 2877. H.M. Office, 1966. 10. Lancet, Feb. 5, 1966, p. 308. 8.
Duma,
Dempsey, Stationery