- Email: [email protected]
TERMINATION BY PROSTAGLANDIN PELLETS IN VERY EARLY PREGNANCY
789 Our results
provide evidence that intravascular Cg
in T.M.A., and appears to be mostly dependent on the classical pathway. The nature of the Ca-splitting activity in these patients is unknown. A similar activity in S.L.E. sera is very likely to be due to circulating immune complexes,5which have not been demonstrated in H.u.s. However, C1 might be activated by proteolytic enzymes secondary to the intravascular coagulation, such as plasmin. Apart from their physiopthological significance, these findings may be of diagFurther study of nostic interest in patients with H.u.s. in such abnormalities cases, in relation to the complement clinical course, is now under way. Service de Néphrologie and W. STÜHLINGER* INSERM U 64, O. KOURILSKY Hôpital Tenon, A. KANFER 4 rue de la Chine, 75020 Paris, France. J. D. SRAER.
activation predominantly
occurs
Present address: Medizinische
Klinik, Innsbruck, Austria.
AGEING, IMMUNE RESPONSE,
AND
MORTALITY
SIR,—We read with interest the paper by Dr RobertsThomson and his colleagues (Aug. 17, p. 368), who confirmed depression of cell-mediated immunity (C.M.I.) in aged individuals and suggested higher mortality in old people with impaired C.M.I. It should be pointed out, however, that in those diseases in which C.M.I. plays a role in pathogenesis, depression of C.M.I. in elderly patients may be protective. We feel that may be so in systemic lupus
erythematosus (S.L.E.). In the elderly S.L.E. differs from the disease in younger patients in mode of onset, organ systems involved, severity, and prognosis. 6-9 Onset in the elderly is usually insidious rather than acute. Most patients present with a polymyalgia-rheumatica-like syndrome or with non-erosive rheumatoid-like arthritis. The clinical course is usually benign, serositis is less common, patients are more easily controlled on aspirin or small amounts of corticosteroids, and the progress of S.L.E. in the elderly is slow.4 It is accepted that serum-antibodies are important in the pathogenesis of lupus nephritis, but there is controversy concerning the role of cell-mediated immune injury in s.L.E. Several papers have shown selective impairment of C.M.I. in early S.L.E.10—12 when evaluated by response to non-nuclear antigens. In contrast, when C.M.I. is evaluated by stimulation with selected nuclear antigens, hyperreactivity is often found in S.L.E.IJ, 14 Using a macrophage migration-inhibition
and active s.L.E. nephritis was reported.13 In direct cytotoxic activity of peripheral blood lymphocytes against target cells coated with D.N.A. in patients with active s.L.E. has been shown. 15 Thus, there is evidence suggesting that C.M.I. plays a role in the pathogenesis of S.L.E. We have shown that patients with S.L.E. have a diminution of C.M.I. with advancing age. This hyporeactivity was demonstrated for pre-existing C.M.I. utilising the skin test response to candida antigen. In addition elderly controls and elderly patients with S.L.E. had a significant decrease in incidence and severity of skin test response when sensitised with 2-4-dinitrochlorobenzene, suggesting that the capacity to respond to a new antigen is impaired in the elderly with and without S.L.E.16 s.L.E. is a milder disease in the elderly. If as seems likely cell-mediated immune injury is of importance in the pathogenesis of S.L.E., then the above data are consistent with the hypothesis that a depressed state of C.M.I. in the elderly favourably modifies the clinical expression of S.L.E.
native
D.N.A.
addition,
a
Departments of Medicine and Microbiology, Medical College of Ohio at Toledo, and Division of Rheumatology, Toledo Clinic, Toledo, Ohio 43623, U.S.A.
ALLAN B. KIRSNER EARL H. FREIMER ROBERT P. SHEON.
TERMINATION BY PROSTAGLANDIN PELLETS IN VERY EARLY PREGNANCY SIR Termination in early pregnancy and at 6-20 weeks can be achieved by delivery of a large dose of prostaglandin (P.G.) in utero rather than by infusion or by repeated medium or small doses. In an earlier trial 17 5 mg. p.G.F2u was injected transcervically in 1 ml. solvent. We have now tried a modification in twenty volunteers. A 7 mm. long and 2 mm. wide " pellet " containing 2-5 mg. P.G.F.2a was delivered in utero by a thin intrauterine-device applicator. In these patients the mean menstrual delay was 12 days and all had a positive ’ Pregnosticon’ test. Sedation consisted of 100 mg. pethidine, 20 mg. diazepam, and 0-4 mg. atropine given intravenously. The semisolid pellet promptly melted at body temperature in utero and released its P.G. content. Uterine contracture developed within a few minutes (see table), lasted for about an hour,
were found to possess cellular native and it was suggested that D.N.A. hypersensitivity the prolonged presence of D.N.A.-sensitised lymphocytes in the patients’ blood might be responsible for the perpetuation of the renal lesion in the nephrotic syndrome..14 Hyperreactivity to nuclear antigens in S.L.E. has also been described when antigen-induced blastic transformation of peripheral blood lymphocytes was studied, and when nuclear antigens were used for skin testing. A significant association between lymphocyte culture stimulation by rabbit thymus
test
patients with active S.L.E. to
All values
5 Williams, D. G., Peters, D. K., Fallows, J., Petrie, A., Kourilsky, O., Morel-Maroger, L., Cameron, J. S. ibid. (in the press). 6. McCombs, R. P., Patterson, J. F. New Engl. J. Med. 1959, 260, 1195. 7 Joseph, R. R., Zarafonetis, C. J. D. J. Am. geriat. Soc. 1964, 12, 787. 8 Urowitz, M. B., Stevens, M. B., Shulman, L. E. Arthr. Rheum. 1967, 10, 319. 9 Foad, B. S. I., Sheon, R. P., Kirsner, A. B. Archs intern. Med. 1972, 130, 743. 10 Horwitz, D. A. Arthr. Rheum. 1972, 15, 353. 11 Hahn, B. H., Bagby, M. K., Osterland, C. K. Am. J. Med. 1973, 55, 25.
Abe, T., Homma, M. Acta rheum. scand. 1971, 17, 35. Goldman, J. A., Litwin, A., Adams, L. E., Krueger, R. C., Hess, E V. J. clin. Invest. 1972, 51, 2669. 14 Abe, T., Hara, M., Yamasaki, K., Homma, M. Arthr. Rheum. 1973, 16, 688.
12 13
are
means::!::
S.E.
Cycles of intrauterine pressure (11 cycles gradually during 2-4 hours bleeding started 4 hours after prostaglandin administration and lasted for about 10 days. There were no complications, except heavy bleeding in 1 patient (which was stopped by curettage after 4 days) and vomiting in two women. The pregnosticon test was
and then waned.
every 10 minutes) evolved and then declined. Uterine
15. Podleski, W. K., Podleski, U. G. Nature, 1973, 241, 278. 16. Foad, B. S. I., Khullar, S., Freimer, E. H., Kirsner, A. B., R. P., J. Lab. clin. Med. (in the press). 17. Csapo, A. I. Res. Prostagland. 1974, series G, no. 4.
Sheon,
790
negative at day 10 in all patients. Normal menses started 31 days after prostaglandin. This trial shows that a single dose of 2-5 mg. p.G.F’2a was sufficient to terminate very early pregnancy reliably if the drug was placed in utero via the cervix in the form of a pellet. The procedure is simple, suitable for outpatient services, and, if sufficient experience is gained, perhaps even suitable for paramedical application under medical supervision. Departments of Obstetrics and
Gynecology, Washington University School of Medicine, Louis, Missouri, U.S.A., and University of Debrecen, Hungary.
A. I. CSAPO P. MOCSARY.
St.
country needs
a
national health insurance scheme, it is
pathetically unprepared for putting one into practice; the homework has simply not been done. In Britain the Press, public, and professions had been discussing the of a national health scheme for many years, it is now clear that gross mistakes were made. Very few detailed discussions have been held here, and the Medicare and Medicaid schemes are seen to have severe defects. New York State has been caring for the health needs of its employees by means of private insurance companies; inquiries are now being made because it seems that premiums have been grossly inflated, and paid without complaint, while there has been little or no concern for the adequacy or quality of care, nor any cost controls. It is perhaps no bad thing that Congress has not moved too
pros and
but
cons
even so
hastily. SCIENTIFIC DISCOVERY SIR,-We were a little surprised to read a quotation in a recent Lancet (Aug. 10, p. 307) concerning the " logic of scientific discovery " which was published in such a way that the reader was left to assume that the author quoted was Prof. C. R. Lowe. The paragraph was, however, quite clearly the work of Karl Popper, and on referring to the original article, Professor Lowe rightly attributed the quotation to him. Apart from the embarrassment that such an editorial lapse must have caused Professor Lowe, it serves to remind one of the care that must be taken to ensure priority of
original thought. 40 Perrers Road, London W6.
JOE COLLIER ROHAN COLLIER.
** * The words in the quotation are Professor Lowe’s. But the original paragraph did begin: " Second, as Karl Popper has stressed there is a logical asymmetry between verification and falsification."-ED. L.
Round the World United States HEALTH PLANS DELAYED AGAIN
The area of uncertainty in the U.S. Government’s policies seems to have enlarged again following the abrupt ending of the honeymoon period of the new President with the old Congress, soon to be electorally renewed. There are rumours of changes in Cabinet posts, with a possible of faces in H.E.W. But there has been a curious the production of a national health insurance compromise Bill. Our new President had asked for speedy action, but the Ways and Means Committee, despite the best efforts of Chairman Wilbur Mills, remained hopelessly deadlocked, and totally unable to produce any agreed measure. Every group seems party to the breakdown. Those inclined to a comprehensive system, especially organised labour, are waiting to see the complexion of the A considerable number of Committee new Congress. members backed the A.M.A.’s Medicredit Scheme; perhaps one of them could explain this proposal in detail, and meet the objection that it seems designed only to ensure that physicians get paid before anyone else, including the Internal Revenue System. But the supporters could not carry the Committee, and nor could the supporters of any of the other proposals. Unless the President exerts all his powers the issue is a dead one until the new Congress assembles. But perhaps this is no bad thing. The more one reads of the discussions the clearer it becomes that, badly as this new set
setback
to
Obituary FERGUS ROBERT FERGUSON M.D.Manc., F.R.C.P., D.P.H.
Dr Fergus R. Ferguson, consultant physician and neurologist at Manchester Royal Infirmary, died on Aug. 26 at the age of 74. He started his medical course when only 16 and graduated from the University of Manchester in 1920, with distinctions in medicine, surgery, and obstetrics. Following his house-appointments, his early postgraduate work was in anatomy and then in bacteriology, and he obtained his M.D. (with gold medal) in 1924. In 1925 he was appointed resident medical officer at Manchester Royal Infirmary, and thereafter his progress in neurology was rapid. He spent two years at the National Hospital, Queen Square, London, and returned to Manchester Royal Infirmary in 1929 as an assistant honorary physician with a special interest in neurology. In 1932 he was a founder member of the Association of British Neurologists and in 1934 he became F.R.C.P. and was elected a corresponding member of the French Neurological Society. During the war he acted as consulting neurologist to Western Command and the Emergency Medical Service. Subsequently he was president of the Manchester Medical Society, the Section of Neurology of the Royal Society of Medicine, the Northern Neurological Association, and the Association of British Neurologists. He is survived by his wife (also a doctor) and two sons, one of whom is a medical specialist in Nepal. M.B.
L. A. L. writes: "
he did not publish very much in the literature extensive clinical work occupied the majority of his (his time), Fergus exerted a remarkable influence on the development of clinical neurology in Britain. He will be remembered by many people for his paper with Dr McDonali Critchley entitled A Clinical Study of an Heredofamillai Disease Resembling Disseminated Sclerosis, but his later interests were in the practical details of migraine and myasthenia. This academic activity, however, playedJ relatively minor part in his professional life in comparisonn with his passionate enthusiasm for the practice of clinics neurology and the training of clinical neurologists. He 1125
Though
always ready to support new ideas in neurology, accepting readily, but not without thought, the advance of neuroradiology and neurophysiology, which came in his tin:; in order to ensure that neurology in Manchester should embrace these innovations at the earliest opportunity Though inclined naturally to conservatism in medicine; he had a radical approach to the reorganisation of :.è "
provide evidence that intravascular Cg
in T.M.A., and appears to be mostly dependent on the classical pathway. The nature of the Ca-splitting activity in these patients is unknown. A similar activity in S.L.E. sera is very likely to be due to circulating immune complexes,5which have not been demonstrated in H.u.s. However, C1 might be activated by proteolytic enzymes secondary to the intravascular coagulation, such as plasmin. Apart from their physiopthological significance, these findings may be of diagFurther study of nostic interest in patients with H.u.s. in such abnormalities cases, in relation to the complement clinical course, is now under way. Service de Néphrologie and W. STÜHLINGER* INSERM U 64, O. KOURILSKY Hôpital Tenon, A. KANFER 4 rue de la Chine, 75020 Paris, France. J. D. SRAER.
activation predominantly
occurs
Present address: Medizinische
Klinik, Innsbruck, Austria.
AGEING, IMMUNE RESPONSE,
AND
MORTALITY
SIR,—We read with interest the paper by Dr RobertsThomson and his colleagues (Aug. 17, p. 368), who confirmed depression of cell-mediated immunity (C.M.I.) in aged individuals and suggested higher mortality in old people with impaired C.M.I. It should be pointed out, however, that in those diseases in which C.M.I. plays a role in pathogenesis, depression of C.M.I. in elderly patients may be protective. We feel that may be so in systemic lupus
erythematosus (S.L.E.). In the elderly S.L.E. differs from the disease in younger patients in mode of onset, organ systems involved, severity, and prognosis. 6-9 Onset in the elderly is usually insidious rather than acute. Most patients present with a polymyalgia-rheumatica-like syndrome or with non-erosive rheumatoid-like arthritis. The clinical course is usually benign, serositis is less common, patients are more easily controlled on aspirin or small amounts of corticosteroids, and the progress of S.L.E. in the elderly is slow.4 It is accepted that serum-antibodies are important in the pathogenesis of lupus nephritis, but there is controversy concerning the role of cell-mediated immune injury in s.L.E. Several papers have shown selective impairment of C.M.I. in early S.L.E.10—12 when evaluated by response to non-nuclear antigens. In contrast, when C.M.I. is evaluated by stimulation with selected nuclear antigens, hyperreactivity is often found in S.L.E.IJ, 14 Using a macrophage migration-inhibition
and active s.L.E. nephritis was reported.13 In direct cytotoxic activity of peripheral blood lymphocytes against target cells coated with D.N.A. in patients with active s.L.E. has been shown. 15 Thus, there is evidence suggesting that C.M.I. plays a role in the pathogenesis of S.L.E. We have shown that patients with S.L.E. have a diminution of C.M.I. with advancing age. This hyporeactivity was demonstrated for pre-existing C.M.I. utilising the skin test response to candida antigen. In addition elderly controls and elderly patients with S.L.E. had a significant decrease in incidence and severity of skin test response when sensitised with 2-4-dinitrochlorobenzene, suggesting that the capacity to respond to a new antigen is impaired in the elderly with and without S.L.E.16 s.L.E. is a milder disease in the elderly. If as seems likely cell-mediated immune injury is of importance in the pathogenesis of S.L.E., then the above data are consistent with the hypothesis that a depressed state of C.M.I. in the elderly favourably modifies the clinical expression of S.L.E.
native
D.N.A.
addition,
a
Departments of Medicine and Microbiology, Medical College of Ohio at Toledo, and Division of Rheumatology, Toledo Clinic, Toledo, Ohio 43623, U.S.A.
ALLAN B. KIRSNER EARL H. FREIMER ROBERT P. SHEON.
TERMINATION BY PROSTAGLANDIN PELLETS IN VERY EARLY PREGNANCY SIR Termination in early pregnancy and at 6-20 weeks can be achieved by delivery of a large dose of prostaglandin (P.G.) in utero rather than by infusion or by repeated medium or small doses. In an earlier trial 17 5 mg. p.G.F2u was injected transcervically in 1 ml. solvent. We have now tried a modification in twenty volunteers. A 7 mm. long and 2 mm. wide " pellet " containing 2-5 mg. P.G.F.2a was delivered in utero by a thin intrauterine-device applicator. In these patients the mean menstrual delay was 12 days and all had a positive ’ Pregnosticon’ test. Sedation consisted of 100 mg. pethidine, 20 mg. diazepam, and 0-4 mg. atropine given intravenously. The semisolid pellet promptly melted at body temperature in utero and released its P.G. content. Uterine contracture developed within a few minutes (see table), lasted for about an hour,
were found to possess cellular native and it was suggested that D.N.A. hypersensitivity the prolonged presence of D.N.A.-sensitised lymphocytes in the patients’ blood might be responsible for the perpetuation of the renal lesion in the nephrotic syndrome..14 Hyperreactivity to nuclear antigens in S.L.E. has also been described when antigen-induced blastic transformation of peripheral blood lymphocytes was studied, and when nuclear antigens were used for skin testing. A significant association between lymphocyte culture stimulation by rabbit thymus
test
patients with active S.L.E. to
All values
5 Williams, D. G., Peters, D. K., Fallows, J., Petrie, A., Kourilsky, O., Morel-Maroger, L., Cameron, J. S. ibid. (in the press). 6. McCombs, R. P., Patterson, J. F. New Engl. J. Med. 1959, 260, 1195. 7 Joseph, R. R., Zarafonetis, C. J. D. J. Am. geriat. Soc. 1964, 12, 787. 8 Urowitz, M. B., Stevens, M. B., Shulman, L. E. Arthr. Rheum. 1967, 10, 319. 9 Foad, B. S. I., Sheon, R. P., Kirsner, A. B. Archs intern. Med. 1972, 130, 743. 10 Horwitz, D. A. Arthr. Rheum. 1972, 15, 353. 11 Hahn, B. H., Bagby, M. K., Osterland, C. K. Am. J. Med. 1973, 55, 25.
Abe, T., Homma, M. Acta rheum. scand. 1971, 17, 35. Goldman, J. A., Litwin, A., Adams, L. E., Krueger, R. C., Hess, E V. J. clin. Invest. 1972, 51, 2669. 14 Abe, T., Hara, M., Yamasaki, K., Homma, M. Arthr. Rheum. 1973, 16, 688.
12 13
are
means::!::
S.E.
Cycles of intrauterine pressure (11 cycles gradually during 2-4 hours bleeding started 4 hours after prostaglandin administration and lasted for about 10 days. There were no complications, except heavy bleeding in 1 patient (which was stopped by curettage after 4 days) and vomiting in two women. The pregnosticon test was
and then waned.
every 10 minutes) evolved and then declined. Uterine
15. Podleski, W. K., Podleski, U. G. Nature, 1973, 241, 278. 16. Foad, B. S. I., Khullar, S., Freimer, E. H., Kirsner, A. B., R. P., J. Lab. clin. Med. (in the press). 17. Csapo, A. I. Res. Prostagland. 1974, series G, no. 4.
Sheon,
790
negative at day 10 in all patients. Normal menses started 31 days after prostaglandin. This trial shows that a single dose of 2-5 mg. p.G.F’2a was sufficient to terminate very early pregnancy reliably if the drug was placed in utero via the cervix in the form of a pellet. The procedure is simple, suitable for outpatient services, and, if sufficient experience is gained, perhaps even suitable for paramedical application under medical supervision. Departments of Obstetrics and
Gynecology, Washington University School of Medicine, Louis, Missouri, U.S.A., and University of Debrecen, Hungary.
A. I. CSAPO P. MOCSARY.
St.
country needs
a
national health insurance scheme, it is
pathetically unprepared for putting one into practice; the homework has simply not been done. In Britain the Press, public, and professions had been discussing the of a national health scheme for many years, it is now clear that gross mistakes were made. Very few detailed discussions have been held here, and the Medicare and Medicaid schemes are seen to have severe defects. New York State has been caring for the health needs of its employees by means of private insurance companies; inquiries are now being made because it seems that premiums have been grossly inflated, and paid without complaint, while there has been little or no concern for the adequacy or quality of care, nor any cost controls. It is perhaps no bad thing that Congress has not moved too
pros and
but
cons
even so
hastily. SCIENTIFIC DISCOVERY SIR,-We were a little surprised to read a quotation in a recent Lancet (Aug. 10, p. 307) concerning the " logic of scientific discovery " which was published in such a way that the reader was left to assume that the author quoted was Prof. C. R. Lowe. The paragraph was, however, quite clearly the work of Karl Popper, and on referring to the original article, Professor Lowe rightly attributed the quotation to him. Apart from the embarrassment that such an editorial lapse must have caused Professor Lowe, it serves to remind one of the care that must be taken to ensure priority of
original thought. 40 Perrers Road, London W6.
JOE COLLIER ROHAN COLLIER.
** * The words in the quotation are Professor Lowe’s. But the original paragraph did begin: " Second, as Karl Popper has stressed there is a logical asymmetry between verification and falsification."-ED. L.
Round the World United States HEALTH PLANS DELAYED AGAIN
The area of uncertainty in the U.S. Government’s policies seems to have enlarged again following the abrupt ending of the honeymoon period of the new President with the old Congress, soon to be electorally renewed. There are rumours of changes in Cabinet posts, with a possible of faces in H.E.W. But there has been a curious the production of a national health insurance compromise Bill. Our new President had asked for speedy action, but the Ways and Means Committee, despite the best efforts of Chairman Wilbur Mills, remained hopelessly deadlocked, and totally unable to produce any agreed measure. Every group seems party to the breakdown. Those inclined to a comprehensive system, especially organised labour, are waiting to see the complexion of the A considerable number of Committee new Congress. members backed the A.M.A.’s Medicredit Scheme; perhaps one of them could explain this proposal in detail, and meet the objection that it seems designed only to ensure that physicians get paid before anyone else, including the Internal Revenue System. But the supporters could not carry the Committee, and nor could the supporters of any of the other proposals. Unless the President exerts all his powers the issue is a dead one until the new Congress assembles. But perhaps this is no bad thing. The more one reads of the discussions the clearer it becomes that, badly as this new set
setback
to
Obituary FERGUS ROBERT FERGUSON M.D.Manc., F.R.C.P., D.P.H.
Dr Fergus R. Ferguson, consultant physician and neurologist at Manchester Royal Infirmary, died on Aug. 26 at the age of 74. He started his medical course when only 16 and graduated from the University of Manchester in 1920, with distinctions in medicine, surgery, and obstetrics. Following his house-appointments, his early postgraduate work was in anatomy and then in bacteriology, and he obtained his M.D. (with gold medal) in 1924. In 1925 he was appointed resident medical officer at Manchester Royal Infirmary, and thereafter his progress in neurology was rapid. He spent two years at the National Hospital, Queen Square, London, and returned to Manchester Royal Infirmary in 1929 as an assistant honorary physician with a special interest in neurology. In 1932 he was a founder member of the Association of British Neurologists and in 1934 he became F.R.C.P. and was elected a corresponding member of the French Neurological Society. During the war he acted as consulting neurologist to Western Command and the Emergency Medical Service. Subsequently he was president of the Manchester Medical Society, the Section of Neurology of the Royal Society of Medicine, the Northern Neurological Association, and the Association of British Neurologists. He is survived by his wife (also a doctor) and two sons, one of whom is a medical specialist in Nepal. M.B.
L. A. L. writes: "
he did not publish very much in the literature extensive clinical work occupied the majority of his (his time), Fergus exerted a remarkable influence on the development of clinical neurology in Britain. He will be remembered by many people for his paper with Dr McDonali Critchley entitled A Clinical Study of an Heredofamillai Disease Resembling Disseminated Sclerosis, but his later interests were in the practical details of migraine and myasthenia. This academic activity, however, playedJ relatively minor part in his professional life in comparisonn with his passionate enthusiasm for the practice of clinics neurology and the training of clinical neurologists. He 1125
Though
always ready to support new ideas in neurology, accepting readily, but not without thought, the advance of neuroradiology and neurophysiology, which came in his tin:; in order to ensure that neurology in Manchester should embrace these innovations at the earliest opportunity Though inclined naturally to conservatism in medicine; he had a radical approach to the reorganisation of :.è "