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FETAL-MATERNAL RELATIONS
1056
treated group of 9 patients had a shorter course of influenza than the 9 placebo-treated patients, as judged by overall impression and by analysis of duration of fever and of duration and severity of signs and symptoms. That the infection was of the influenza A2 type was suggested by the development of high titres of complement-fixation antibodies against soluble influenza-A antigens in some patients and staff. In another inquiry, in the Virginia State Penitentiary,18 amantadine, rimantadine, and placebo were given at random to inmates who had developed influenzal symptoms within the previous twenty-four hours during an outbreak of influenza A2. Again, statistically significant increases in the rates of overall clinical improvement, defervescence, and disappearance of signs and symptoms were observed in patients receiving amantadine or rimantadine; but no appreciable difference was found between the two drugs. In neither trial did the antiviral agents interfere with the development of antibody formation, probably because, by the time treatment was started, sufficient cells had been affected for antibody production to be inhibited. These trials suggest that amantadine and rimantadine may be of value in the treatment of established influenza A2 if given within forty-eight hours of onset. A significant increase in rate of recovery alone, however, is not necessarily important in practice, and Rabinovich et a1.l? emphasise that one point that could not be measured in these patients was their ability to return to work. If, in fact, these drugs hastened return to work in patients infected with this virus, the cost of treatment might be justified.
FETAL-MATERNAL RELATIONS
THE proceedings of two international symposia on fetal-maternal relations have recently been published. One was a Ciba symposium,19 held in London in December, 1968, and the other 20 took place in Milan in September, 1968, under the auspices of the International Society for Biochemical Pharmacology. Although the title of the former emphasises the independence of the fetus as a living organism whereas the latter emphasises its intimate relationship with the placenta and hence the mother, the two books have much in common. In particular, they give a clear indication of the growing-points of research in both clinical and laboratory investigation into fetal phy-
siology. Many of the questions asked by research-workers are of the common-sense sort often raised by students, yet often they are difficult to answer. For example, R. V. Short 21 asks how a pregnant animal first becomes " aware of the presence of a fertilised egg in its uterus. It is generally accepted that human
physiologically "
W. L., Pollack, D., Grunert, R. R. New Engl. J. Med. 1969, 281, 579. 19. Foetal Autonomy. Edited by G. E. W. WOLSTENHOLME and MAEVE
18.
as the mare, pregnancy may be recognised while the embryo is still in the Fallopian tube, though the complex hormonal relationships are not well understood. Some of the most intriguing problems discussed in the two books are concerned with the immunological relation between mother and fetus. Why, for instance, does the pregnant mother tolerate her baby which, being an allograft, should be incompatible with her and so be rejected ? C. A. Currie,22 discussing the current hypotheses, suggests that at about the time of implantation the mother’s immune mechanisms are confronted by blastocyst antigens and react to them. As the trophoblast continues to form, it produces a continual low dose of fetal antigens, and the mother probably responds by synthesising antibodies which localise on any fetal structure they can reach. Generally, this will be the trophoblast, since this is the only tissue in continuous and direct contact with maternal cells, but since trophoblast is of low antigenicity it is not killed by the antibody. Thus, the antibodies produced by the mother may adsorb to the surface of the trophoblast and inhibit cellular immune reactions in both directions-i.e., maternal-to-fetal and fetal-tomaternal. In this way the trophoblast may act as a site for antibody enhancement; in addition it acts as a physical barrier by severely limiting the number of cells which are able to pass from one circulation to the other. A similar view is put forward by Lanman.23 Another interesting and related topic is the question of the structural relation between fetal and maternal tissues at the placental area, especially under pathological conditions. U. M. Lister,24 who examined dysmature placentas by electron microscopy, reports destruction of both syncytium and stroma by the deposition of fibrinoid material, and severe damage to stromal capillaries. Other placental abnormalities are
animals, such
analysed by Wigglesworth.25 Several reports are concerned with blood-flow in the Our understanding of the way in which maternal blood circulates in the placenta owes much to the work of Ramsey.26 She has envisaged a system in which blood spurts in jets from openings in spiral arteries into the intervillous spaces, after which it drains away through venous channels. This idea has not been confirmed, however, in an experimental analysis carried out by H. G. Lemtis.2’His results are based mainly on X-ray cinematography of human placentas maintained in vitro in an artificial uterus and injected with radio-opaque materials. He concludes that the maternal blood in the placenta flows in circles along special tracks. Panigel ’28 who has examined by electron microsconv the ultrastructure of Derfused
placenta.
Wingfield,
O’CONNOR. Ciba Foundation Symposium. London: Churchill. 1969. Pp. 326. 70s. 20. Pœto-Placental Unit. Edited by A. PECILE and C. FINZI. Amsterdam: Excerpta Medica Foundation. 1969. Pp. 436. £11 19s.
or $28.50. 21.
beings and rhesus monkeys probably recognise that they are pregnant because of the luteotrophic activity of the implanted conceptus. Short, however, points out that this is not a universal mechanism, and in some
Short, R. V. in Foetal Autonomy; p. 2.
22. 23. 24. 25. 26.
Currie, C. A. ibid. p. 132. Lanman, J. T. in Fœto-Placental Unit; p. 43. Lister, U. M. ibid. p. 8. Wigglesworth, J. S. ibid. p. 34. Ramsey, E. M. in Obstetrics (edited by J. P. Greenhill); p. 101,
27. 28.
Philadelphia, 1965. Lemtis, H. G. in Fœto-Placental Unit; p. 23. Panigel, M. ibid. p. 279.
1057
human placental cotyledons, concludes that perfusion need cause little damage to the metabolic activity of the trophoblast. The importance of the hormone balance in the fetal and maternal tissues is emphasised by the fact that 13 papers are devoted to the subject in the Italian symposium and 3 in the British one. K. J. Ryan 29 considers the hormonal control of gestation from a comparative point of view. There is evidence that as gestation progresses the progesterone/cestrogen ratio
declines, and there is
some possibility that proand inhibits oestrogen promotes the congesterone traction of uterine muscle. Ryan has produced a scheme to show how the relative levels of oestrogen and progesterone produced by the placenta may be controlled by the growth of the fetus. The fetus would be the major source of oestrogen precursors, and, as pregnancy progresses, the increasing feto-placental weight ratio would favour the lowering of the progesterone relative to the oestrogen. G. C. Liggins 30 describes some experiments designed to test the factors responsible for parturition in the ewe. By stimulating the fetal adrenals with corticotrophin, premature parturition was provoked. Conversely, fetal adrenalectomy retarded parturition. A number of papers are concerned with steroid metabolism in the placenta and fetus, the considerable literature on the subject being reviewed in an important contribution by Diczfalusy. 31 The activity of the endocrines in the fetus itself is considered by J ost, 32 who concludes that most endocrine organs exert some physiological function before birth. Alexander et al. 33 analyse the metabolism of the sheep fetus in some detail. They conclude that glucose can be the only major metabolite and that, although fructose is present in high concentration, its oxidation is small. Tuchmann-Duplessis 34 reviews some of the ways in which teratological influences may act, and Fabro and Sieber 36 show how in the rabbit, at least, a number of drugs injected into the mother can penetrate even into the unimplanted blastocyst.
WORKING-HOURS OF JUNIOR HOSPITAL DOCTORS
THE work of junior hospital staff is much under debate following the report 36 of the Royal Commission and the report on responsibilities of the consultant
grades The charter of the Junior Hospital Doctors’ Association (seep. 1082) mentions " the principle of eight hours work, eight hours study and recreation, and eight hours for sleep ". When arguing for shorter working hours, however, it is not enough to produce in evidence 29. Ryan, K. J. ibid. p. 120. 30. Liggins, G. C. in Foetal Autonomy; p. 218. 31. Diczfalusy, E. in Fœtal-Placental Unit; p. 65. 32. Jost, A. in Foetal Autonomy; p. 79. 33. Alexander, D. P. ibid. p. 95. 34. Tuchmann-Duplessis, H. ibid. p. 245. 35. Fabro, S., Sieber, S. M. in Fœto-Placental Unit; p. 313. 36. Report of the Royal Commission on Medical Education. H.M. Stationery Office, 1968. See Lancet, 1968, i, 809. 37. The Responsibilities of the Consultant Grade. H.M. Stationery Office, 1969. See Lancet, 1969, i, 1134.
image of the bleary-eyed, sleepless house-officer, coping gallantly with continual emergencies throughout the night. Facts are badly needed if sensible working patterns for hospital staffs are to be designed for the 1970s. Few work studies have been done in depth, but a report 38from Scotland exemplifies
the
how useful information can be obtained. For a fortnight the work done by the juniors in a modern 450-bed district hospital in Kirkcaldy was carefully recorded. A return was completed by the doctor for every call he received outside " office hours ", and as a check the nursing staff logged all the calls they made.
The three-man
study team observed the experiment satisfied that the returns accurately reflected the work done (except for a technical hitch with the anaesthetists, who had to be exluded). Basic figures showed house-officers (including senior houseofficers) working an average 52 1/2 hours a week plus 47 hours on call, with only 68 hours off-duty, though there were wide variations. Registrars averaged 49 closely and
were
hours’ clinical work and 45 hours
on
call.
One of the aims
was to discover whether the hoswork could be done as well with pital’s emergency fewer doctors available at a time, providing them all with more off-duty. The answer to this question is difficult, depending as it does on value judgments, such as the degree of urgency of the calls. It seems that only 13-2% of calls both to house-officers and to registrars required a doctor within five minutes, though this assessment was made by the doctors themselves after dealing with the situation, and the urgency might have seemed greater to the nurse at the time the calls were made. House-officers felt that as many as 59% of the calls could have been dealt with by any house-officer, of any specialty, and the study team suggest that even this figure is low. Nevertheless, however trivial the need may seem, there is no-one as well fitted to deal with a situation as a doctor who knows the patient. The study team analysed nearly 1000 occasions at 15-minute intervals during the night and weekends, when a minimum of six house-officers were on duty, to see how many were actually working. Three doctors had urgent business simultaneously on only 30 occasions, and four were in action together a mere six times, though one doctor was usually doing some non-urgent work at the same time. On 78% of the occasions at least four houseofficers were not engaged in hospital work, and on only two occasions was every doctor actually working. If the team’s belief in the interchangeability of houseofficer work is accepted, these figures indicate that in Kirkcaldy fewer doctors need be on duty " out of hours ".
importance of this report lies not so much in interesting facts, which are open to a variety of interpretations, as in the demonstration that doctors’ work is not so mysterious as to be impenetrable by work-study techniques. Far more of these inquiries The
its
needed if we doctors the have. are
extra
38.
are not to waste
the time of the
Royal Commission
urges
us
to
Walker, R. G., Miller, W. R., McLean, I. G. A Study of the Work of Hospital Junior Medical Staff, 1969. Scottish Health Service Studies no. 10. Scottish Home and Health Department, Edinburgh.
treated group of 9 patients had a shorter course of influenza than the 9 placebo-treated patients, as judged by overall impression and by analysis of duration of fever and of duration and severity of signs and symptoms. That the infection was of the influenza A2 type was suggested by the development of high titres of complement-fixation antibodies against soluble influenza-A antigens in some patients and staff. In another inquiry, in the Virginia State Penitentiary,18 amantadine, rimantadine, and placebo were given at random to inmates who had developed influenzal symptoms within the previous twenty-four hours during an outbreak of influenza A2. Again, statistically significant increases in the rates of overall clinical improvement, defervescence, and disappearance of signs and symptoms were observed in patients receiving amantadine or rimantadine; but no appreciable difference was found between the two drugs. In neither trial did the antiviral agents interfere with the development of antibody formation, probably because, by the time treatment was started, sufficient cells had been affected for antibody production to be inhibited. These trials suggest that amantadine and rimantadine may be of value in the treatment of established influenza A2 if given within forty-eight hours of onset. A significant increase in rate of recovery alone, however, is not necessarily important in practice, and Rabinovich et a1.l? emphasise that one point that could not be measured in these patients was their ability to return to work. If, in fact, these drugs hastened return to work in patients infected with this virus, the cost of treatment might be justified.
FETAL-MATERNAL RELATIONS
THE proceedings of two international symposia on fetal-maternal relations have recently been published. One was a Ciba symposium,19 held in London in December, 1968, and the other 20 took place in Milan in September, 1968, under the auspices of the International Society for Biochemical Pharmacology. Although the title of the former emphasises the independence of the fetus as a living organism whereas the latter emphasises its intimate relationship with the placenta and hence the mother, the two books have much in common. In particular, they give a clear indication of the growing-points of research in both clinical and laboratory investigation into fetal phy-
siology. Many of the questions asked by research-workers are of the common-sense sort often raised by students, yet often they are difficult to answer. For example, R. V. Short 21 asks how a pregnant animal first becomes " aware of the presence of a fertilised egg in its uterus. It is generally accepted that human
physiologically "
W. L., Pollack, D., Grunert, R. R. New Engl. J. Med. 1969, 281, 579. 19. Foetal Autonomy. Edited by G. E. W. WOLSTENHOLME and MAEVE
18.
as the mare, pregnancy may be recognised while the embryo is still in the Fallopian tube, though the complex hormonal relationships are not well understood. Some of the most intriguing problems discussed in the two books are concerned with the immunological relation between mother and fetus. Why, for instance, does the pregnant mother tolerate her baby which, being an allograft, should be incompatible with her and so be rejected ? C. A. Currie,22 discussing the current hypotheses, suggests that at about the time of implantation the mother’s immune mechanisms are confronted by blastocyst antigens and react to them. As the trophoblast continues to form, it produces a continual low dose of fetal antigens, and the mother probably responds by synthesising antibodies which localise on any fetal structure they can reach. Generally, this will be the trophoblast, since this is the only tissue in continuous and direct contact with maternal cells, but since trophoblast is of low antigenicity it is not killed by the antibody. Thus, the antibodies produced by the mother may adsorb to the surface of the trophoblast and inhibit cellular immune reactions in both directions-i.e., maternal-to-fetal and fetal-tomaternal. In this way the trophoblast may act as a site for antibody enhancement; in addition it acts as a physical barrier by severely limiting the number of cells which are able to pass from one circulation to the other. A similar view is put forward by Lanman.23 Another interesting and related topic is the question of the structural relation between fetal and maternal tissues at the placental area, especially under pathological conditions. U. M. Lister,24 who examined dysmature placentas by electron microscopy, reports destruction of both syncytium and stroma by the deposition of fibrinoid material, and severe damage to stromal capillaries. Other placental abnormalities are
animals, such
analysed by Wigglesworth.25 Several reports are concerned with blood-flow in the Our understanding of the way in which maternal blood circulates in the placenta owes much to the work of Ramsey.26 She has envisaged a system in which blood spurts in jets from openings in spiral arteries into the intervillous spaces, after which it drains away through venous channels. This idea has not been confirmed, however, in an experimental analysis carried out by H. G. Lemtis.2’His results are based mainly on X-ray cinematography of human placentas maintained in vitro in an artificial uterus and injected with radio-opaque materials. He concludes that the maternal blood in the placenta flows in circles along special tracks. Panigel ’28 who has examined by electron microsconv the ultrastructure of Derfused
placenta.
Wingfield,
O’CONNOR. Ciba Foundation Symposium. London: Churchill. 1969. Pp. 326. 70s. 20. Pœto-Placental Unit. Edited by A. PECILE and C. FINZI. Amsterdam: Excerpta Medica Foundation. 1969. Pp. 436. £11 19s.
or $28.50. 21.
beings and rhesus monkeys probably recognise that they are pregnant because of the luteotrophic activity of the implanted conceptus. Short, however, points out that this is not a universal mechanism, and in some
Short, R. V. in Foetal Autonomy; p. 2.
22. 23. 24. 25. 26.
Currie, C. A. ibid. p. 132. Lanman, J. T. in Fœto-Placental Unit; p. 43. Lister, U. M. ibid. p. 8. Wigglesworth, J. S. ibid. p. 34. Ramsey, E. M. in Obstetrics (edited by J. P. Greenhill); p. 101,
27. 28.
Philadelphia, 1965. Lemtis, H. G. in Fœto-Placental Unit; p. 23. Panigel, M. ibid. p. 279.
1057
human placental cotyledons, concludes that perfusion need cause little damage to the metabolic activity of the trophoblast. The importance of the hormone balance in the fetal and maternal tissues is emphasised by the fact that 13 papers are devoted to the subject in the Italian symposium and 3 in the British one. K. J. Ryan 29 considers the hormonal control of gestation from a comparative point of view. There is evidence that as gestation progresses the progesterone/cestrogen ratio
declines, and there is
some possibility that proand inhibits oestrogen promotes the congesterone traction of uterine muscle. Ryan has produced a scheme to show how the relative levels of oestrogen and progesterone produced by the placenta may be controlled by the growth of the fetus. The fetus would be the major source of oestrogen precursors, and, as pregnancy progresses, the increasing feto-placental weight ratio would favour the lowering of the progesterone relative to the oestrogen. G. C. Liggins 30 describes some experiments designed to test the factors responsible for parturition in the ewe. By stimulating the fetal adrenals with corticotrophin, premature parturition was provoked. Conversely, fetal adrenalectomy retarded parturition. A number of papers are concerned with steroid metabolism in the placenta and fetus, the considerable literature on the subject being reviewed in an important contribution by Diczfalusy. 31 The activity of the endocrines in the fetus itself is considered by J ost, 32 who concludes that most endocrine organs exert some physiological function before birth. Alexander et al. 33 analyse the metabolism of the sheep fetus in some detail. They conclude that glucose can be the only major metabolite and that, although fructose is present in high concentration, its oxidation is small. Tuchmann-Duplessis 34 reviews some of the ways in which teratological influences may act, and Fabro and Sieber 36 show how in the rabbit, at least, a number of drugs injected into the mother can penetrate even into the unimplanted blastocyst.
WORKING-HOURS OF JUNIOR HOSPITAL DOCTORS
THE work of junior hospital staff is much under debate following the report 36 of the Royal Commission and the report on responsibilities of the consultant
grades The charter of the Junior Hospital Doctors’ Association (seep. 1082) mentions " the principle of eight hours work, eight hours study and recreation, and eight hours for sleep ". When arguing for shorter working hours, however, it is not enough to produce in evidence 29. Ryan, K. J. ibid. p. 120. 30. Liggins, G. C. in Foetal Autonomy; p. 218. 31. Diczfalusy, E. in Fœtal-Placental Unit; p. 65. 32. Jost, A. in Foetal Autonomy; p. 79. 33. Alexander, D. P. ibid. p. 95. 34. Tuchmann-Duplessis, H. ibid. p. 245. 35. Fabro, S., Sieber, S. M. in Fœto-Placental Unit; p. 313. 36. Report of the Royal Commission on Medical Education. H.M. Stationery Office, 1968. See Lancet, 1968, i, 809. 37. The Responsibilities of the Consultant Grade. H.M. Stationery Office, 1969. See Lancet, 1969, i, 1134.
image of the bleary-eyed, sleepless house-officer, coping gallantly with continual emergencies throughout the night. Facts are badly needed if sensible working patterns for hospital staffs are to be designed for the 1970s. Few work studies have been done in depth, but a report 38from Scotland exemplifies
the
how useful information can be obtained. For a fortnight the work done by the juniors in a modern 450-bed district hospital in Kirkcaldy was carefully recorded. A return was completed by the doctor for every call he received outside " office hours ", and as a check the nursing staff logged all the calls they made.
The three-man
study team observed the experiment satisfied that the returns accurately reflected the work done (except for a technical hitch with the anaesthetists, who had to be exluded). Basic figures showed house-officers (including senior houseofficers) working an average 52 1/2 hours a week plus 47 hours on call, with only 68 hours off-duty, though there were wide variations. Registrars averaged 49 closely and
were
hours’ clinical work and 45 hours
on
call.
One of the aims
was to discover whether the hoswork could be done as well with pital’s emergency fewer doctors available at a time, providing them all with more off-duty. The answer to this question is difficult, depending as it does on value judgments, such as the degree of urgency of the calls. It seems that only 13-2% of calls both to house-officers and to registrars required a doctor within five minutes, though this assessment was made by the doctors themselves after dealing with the situation, and the urgency might have seemed greater to the nurse at the time the calls were made. House-officers felt that as many as 59% of the calls could have been dealt with by any house-officer, of any specialty, and the study team suggest that even this figure is low. Nevertheless, however trivial the need may seem, there is no-one as well fitted to deal with a situation as a doctor who knows the patient. The study team analysed nearly 1000 occasions at 15-minute intervals during the night and weekends, when a minimum of six house-officers were on duty, to see how many were actually working. Three doctors had urgent business simultaneously on only 30 occasions, and four were in action together a mere six times, though one doctor was usually doing some non-urgent work at the same time. On 78% of the occasions at least four houseofficers were not engaged in hospital work, and on only two occasions was every doctor actually working. If the team’s belief in the interchangeability of houseofficer work is accepted, these figures indicate that in Kirkcaldy fewer doctors need be on duty " out of hours ".
importance of this report lies not so much in interesting facts, which are open to a variety of interpretations, as in the demonstration that doctors’ work is not so mysterious as to be impenetrable by work-study techniques. Far more of these inquiries The
its
needed if we doctors the have. are
extra
38.
are not to waste
the time of the
Royal Commission
urges
us
to
Walker, R. G., Miller, W. R., McLean, I. G. A Study of the Work of Hospital Junior Medical Staff, 1969. Scottish Health Service Studies no. 10. Scottish Home and Health Department, Edinburgh.