876 tification for any difference in the standard of protection of volunteers. In our view the experimenter’s duty to a volunteer goes beyond performing ethical experiments competently, for mishaps may still occur. Surely there is a duty to make provision for the possibility of such a mishap and to let the volunteer know what it is. Failing this, the absence of such provision should be made quite explicit. In either event the position should be stated in a document signed and witnessed as part of the record of informed consent. Consent might otherwise well be regarded as imperfect. It may not be widely realised that the cost of the premiums for such insurance are considerable and could represent a heavy financial burden on some academic departments insuring studies entirely from within their own resources. While we agree with Dr Smith’s views, we differ on the question of financial inducement to volunteer. The criteria for assessing whether a study should be permitted should include an independent assessment of benefits and risks. If a protocol survives this test the question of financial inducement is, in our view, irrelevant. Payment as compensation for inconvenience and risk-taking is a normal and widespread practice and there seems to be no special reason to discourage it in this context. In our opinion the wide interests of the community at large could well be served by its encouragement, and increased participation by the community in studies of this nature would certainly be welcome. Home
Farmhouse,
Oakley, Aylesbury HP18 9RE. Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow G11 6NT.
MICHAEL
J.
TIDD
LAWRENCE E. RAMSAY
GYNmCOMASTIA IN ALCOHOLIC CIRRHOSIS SIR)- The pathophysiological mechanism responsible for gynaecomastia and hypogonadism in men with advanced liver diseases is still unknown. New assay systems have shown in alcoholic cirrhotic patients that plasma-oestradiol levels are not uniformly elevated, testosterone levels are reduced, and plasma follicle-stimulating hormone and luteinising hormone concentrations are normal or moderately elevated. On the other hand, hyperplasia and hypertrophy of the prolactin cells have been described in the anterior pituitary of men dying from hepatic cirrhosis.2 Therefore we have measured plasma-prolactin levels in 7 alcoholic, cirrhotic male patients, 4 of whom had well-established gynaecomastia. Plasma-prolactin concentrations were determined by double-antibody radioimmunoassay in basal conditions and after
thyrotropin-releasing-hormone (T.R.H.) (400 (Jog. intravenously) stimulation test. Blood-samples were a
obtained at -10, 0, +10, +20, +30, +45, +60, +90, +120, and +150 minutes. The values were compared
with those of five normal male volunteers. The results are shown in the accompanying table. While basal values are only slightly elevated, plasma-prolactin concentrations after T.R.H. administration are significantly higher than in the controls; the rises in prolactin levels are similar in all patients examined, regardless of the presence of gynaeco. mastia. Although a relationship between prolactin and gynxcomastia is not always present in other pathological conditions,3 our results show that the enhanced pituitary prolactin reserve in alcoholic cirrhotic patients may be one of the manifold factors involved in the development of gynaecomastia in chronic liver diseases. Istituto di Clinica Medica IV dell ’Università di Milano
Padiglione Litta, via F. Sforza 35, 20122 Milano, Italy.
ALBERTO ZANOBONI WANDA ZANOBONI-MUCIACCIA
ILL-HEALTH AND CHILD ABUSE
SIR,-Dr Pasamanick’s letter (Sept. 20, p. 550) concerning abuse of neurologically damaged children raises an ethological point-whether failure of bonding in these cases is programmed, and has been preserved by natural selection, It would be extremely interesting to observe any primate examples in the wild of neglect, desertion, or infanticide, to see if damaged offspring are selected, and whether signs of damage or of non-response act as releasers of aggression or neutralisers of normal maternal feeling. It would be equally interesting to assess the response of normal women to the recorded crv of normal and brain-damaged infants. Much of the aggression released against children in our society is doubtless non-specific, and there are few mothers of a continuously crying baby who have never felt murderous, but if there are any atavistic releasers which formerly served a selective purpose it would be as well to know this. If we knew about them we might be able to guard against them. Institute for Higher Studies, 2311 Garden Street, Santa Barbara, California 93105, U.S.A.
ALEX COMFORT
THE HANDICAPPED FAMILY
SIR,-Mrs Antonis and Dr Caplan rightly emphasise the
helping the families of handicapped children 603). However, I cannot accept their contention that many professional workers react, because of their lack of in-depth psychodynamic training, by denying and avoiding suffering in these families, and I do not agree that child psychotherapists should necessarily be the central coordinators of
difficulties of
(Sept. 27,
p.
care.
Surely the qualities required of the coordinating workersensitivity, understanding, and professionalism-may be possessed by workers in a number of the caring disciplines. Dr
1. Van
Thiel, D. H., Lester, R., Sherins, R. J. Gastroenterology, 1974, 67, 1188. 2. El Etreby, M. F., Gunzel, P. Acta endocr. Copenh. 1974, suppl. 189, p. 3.
PLASMA-PROLACTIN CONCENTRATIONS
(ng./ml.: T.R.H.
MEAN j:S.E.) IN
(400
(JLg.
3.
Hagen, C., McNeilly, A. S., Arroe, M., Emmertsen, K., Froland, A. Lancet, 1974, ii, 57. IN 7 CIRRHOTIC MALE STIMULATION TEST
5 NORMAL MEN AND
INTRAVENOUSLY)
PATIENTS, FOLLOWING
877
Simpkiss and his colleagues argue (Sept. 20, p. 554) that the of physical and intellectual handicaps makes medical qualification necessary. However, in South Wales and in Oslo care of multiple handicapped children has been most effectively coordinated by social workers. I believe we should concern ourselves less with which professional discipline coordinates, and make sure that the coordination does in fact take place. An ability to accept the often distressing problems of the handicapped family is not the prerogative of any one group, and understanding this should enable us together to help the families with whom we work. extent
St. Mary’s
Hospital,
Newport, Isle of
D. W. HIDE
Wight P030 5TG.
FAILURE OF CEPHRADINE IN INFECTIVE
ENDOCARDITIS
SCREENING FOR NEURAL-TUBE DEFECTS BY A HÆMAGGLUTINATION TEST FOR SERUM-ALPHA-FETOPROTEIN
SIR,-Measurement of maternal serum-alpha-fetoprotein is now used in prospective screening trials for neuraltube defects. The results should determine whether the test should be used more widely. Several problems arise in such trials, 12 especially difficulty in defining the "normal" range for maternal A.F.P. in relation to gestational age, doubt about gestational age, and methodological problems. The maternal-serum A.F.P. reference curve is now fairly well determined by several laboratories.3-7 An elevated serum-A.F.P. concentration at 15-16 weeks should be above the 90% reference curve-e.g., in our laboratory above 100-120 tg/1.7 In patients of uncertain gestational age, which comprise a significant proportion of all pregnancies, the A.F.P. result may be impossible to interpret unless other gestational-age parameters are available. Finally, the methodological problem is the need for a low-cost simple screening-test. Modifications of radioimmunological tests have been used up till now. An
(A.F.P.)
’
.
SIR,-For many years it was customary to treat infective endocarditis with a combination of antibiotics, often a penicillin and streptomycin. Lately, however, the tendency has been to use a single drug to which the organism isolated has been sensitive. In the case of Streptococcus viridans this will almost always be benzylpenicillin given intravenously at a dose of 10-20 megaunits daily. In patients hypersensitive to penicillins, a cephalosporin has been recommended.Of the cephalosporins, cephaloridine, in particular, may be nephrotoxic in high dosage. Cephradine, a new cephalosporin, has not been reported as having nephrotoxic side-effects.’ We present here a case where parenteral cephradine failed to control the bacterxmia of infective endocarditis. A 29-year-old Greek with rheumatic aortic stenosis and regurgitation presented with a pyrexia of 39°C. Strep. viridans was isolated from 12 blood-culture bottles. The M.i.c. of this organism against benzylpenicillin was 0.02 g/ml. Benzylpenicillin 20 megaunits daily was given intravenously in boluses three-hourly. Body-temperature fell to normal, and the organism disappeared from the blood. After a week’s therapy, the patient developed a progressively worsening itchy maculopapular rash. Penicillin was thought to be responsible, and the antibiotic was accordingly changed to cephradine given at the maximum recommended dosage of 500 mg three-hourly intravenously. The M.l.e. of the original streptococcus against this agent was 0.312 g/ml. Within two days the pyrexia returned, and the original streptococcus was isolated from 6 out of 6 bottles. A back titration of the patient’s serum before an injection inhibited the organism at a dilution of 1 in 8 but did not kill it at half dilution. Penicillin was reintroduced under antihistamine cover, without recurrence of the rash and with rapid resolution of the pyrexia.
Cephradine is a cephalosporin closely related to cephalexin but having the advantage of nearly complete oral absorption.2 Its chief advantage when used parenterally is its lack of nephrotoxicity. Its antibacterial spectrum includes the majority of staphylococci and streptococci, although its M.t.c. in a study of group-D streptococci3 was higher than that of cephaloridine and much higher than that of ampicillin. For intravenous use in pdiatric infections, a dosage of 8to 300 mg/kg has been recommendedand this is clearly much higher than the maximum recommended dosage of this drug for an adult. Cephradine may be a useful oral antibiotic in many infections. In the presently recommended maximum intravenous dosage, however, it seems to be ineffective in endocarditis. The maximum recommended dosage is under reviewand once this is established, cephradine may be worthy of further trial. Department of Medicine, Middlesex Hospital, London W1N 8AA.
P. R. DAGGETT A. W. NATHAN
Garrod, L. P. Br. med. J. 1974, iii, 96. Scholand, J. F., Hodges, G. R., Fass, R. J., Saslaw, S. Am. J. med. Sci. 1974, 267, 111. 3. Hamilton-Miller, J. M. T. J. clin. Path. 1974, 27, 828. 4 Macias, E. G., Eller, J. J. Lancet, 1975, i, 38. 5 E. R. Squibb & Sons, Ltd. Personal communication.
1. 2.
Comparison between the R.I.F.P. profile and H.A. A.F.P. in
a
pregnant A.F.P.
woman
followed
test results for serum-
throughout pregnancy.
standards 40-640
,
flg/l.
alternative method may be a sensitive haemagglutination (H.A.) (Mochida, Japan). In 250 maternal-serum samples and in 115 sera from patients with hepatoma or teratocarcinoma a parallel estimation of A.F.P. by radioimmunoelectrophoresis (R.I.E.P.)6 and by the H.A. technique has been carried out. The assay procedure for the H.A. test is as follows: to an ampoule
test
of lyophilised chemically modified sheep erythrocytes coated with antihuman-A.F.p. rabbit gammaglobulin is added 400 VI of phosphate-buffered saline for suspension of the erythrocytes. To the suspension is added 100 1 of diluted serum (10-fold). After incubation for 2 hours at room remperature the bottom of the ampoule is inspected. A clear red ring means no agglutination of the cells and a negative reaction (less than 100 g/1), whereas a diffuse red-cell precipitate covering the bottom of the ampoule as a mat of cells is a positive reaction. In all sera with an A.F.P. concentration >110 g/1 (range 110-570 ;g/1) a distinctive positive reaction was found. In 8 sera from patients with tumours
rheumatoid factor
was
found, but
none
of these
patients gave
false-positive reaction for A.F.P. An improved method for R.i.E.p. was used. In order to obtain more distinct radioprecipitates, polyethyleneglycol 6000 was added to the anodic antibody in a concentration 5.0 g per dl of agarose gel. The World Health Organisation A.F.P. reference ,preparation supplied by the International Agency for Research on Cancer? was measured to 69 mg/1. The results of R.LE.P. and H.A. at different stages of pregnancy are compared in the figure. a
Brock, D. J. H., Scrimgeour, J. B., Bolton, A. E., Wald, N., Peto, R., Barker. S. Lancet, 1975, ii, 195. 2. Vince, J. D., McManus, T. J., Ferguson-Smith, M. A., Ratcliffe, J. G. Br. J. Obstet. Gynæc. (in the press). 3. Seppälä, M., Ruoslahti, E. Lancet, 1972, i, 375. 4. Ishiguro, T., Nishimuro, T. Am. J. Obstet. Gynec. 1973, 116, 27. 5. Brock, D. J. H., Bolton, A. E., Scrimgeour, J. B. Lancet, 1974, i, 767. 6. Seller, M. J., Singer, J. D., Coltart, T. M., Campbell, S. ibid. p. 428. 7. Nørgaard-Pedersen, B., Lindsten, J., Philip, J. Clin. Genet. 1975, 7, 170. 8. Nørgaard-Pedersen, B. Clin. chim. Acta, 1973, 48, 345. 9. Sizaret, P., Breslow, N., Anderson, S. G. J. biol. Standard. 1975, 3, 201. 1.
.
Farmhouse,
Oakley, Aylesbury HP18 9RE. Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow G11 6NT.
MICHAEL
J.
TIDD
LAWRENCE E. RAMSAY
GYNmCOMASTIA IN ALCOHOLIC CIRRHOSIS SIR)- The pathophysiological mechanism responsible for gynaecomastia and hypogonadism in men with advanced liver diseases is still unknown. New assay systems have shown in alcoholic cirrhotic patients that plasma-oestradiol levels are not uniformly elevated, testosterone levels are reduced, and plasma follicle-stimulating hormone and luteinising hormone concentrations are normal or moderately elevated. On the other hand, hyperplasia and hypertrophy of the prolactin cells have been described in the anterior pituitary of men dying from hepatic cirrhosis.2 Therefore we have measured plasma-prolactin levels in 7 alcoholic, cirrhotic male patients, 4 of whom had well-established gynaecomastia. Plasma-prolactin concentrations were determined by double-antibody radioimmunoassay in basal conditions and after
thyrotropin-releasing-hormone (T.R.H.) (400 (Jog. intravenously) stimulation test. Blood-samples were a
obtained at -10, 0, +10, +20, +30, +45, +60, +90, +120, and +150 minutes. The values were compared
with those of five normal male volunteers. The results are shown in the accompanying table. While basal values are only slightly elevated, plasma-prolactin concentrations after T.R.H. administration are significantly higher than in the controls; the rises in prolactin levels are similar in all patients examined, regardless of the presence of gynaeco. mastia. Although a relationship between prolactin and gynxcomastia is not always present in other pathological conditions,3 our results show that the enhanced pituitary prolactin reserve in alcoholic cirrhotic patients may be one of the manifold factors involved in the development of gynaecomastia in chronic liver diseases. Istituto di Clinica Medica IV dell ’Università di Milano
Padiglione Litta, via F. Sforza 35, 20122 Milano, Italy.
ALBERTO ZANOBONI WANDA ZANOBONI-MUCIACCIA
ILL-HEALTH AND CHILD ABUSE
SIR,-Dr Pasamanick’s letter (Sept. 20, p. 550) concerning abuse of neurologically damaged children raises an ethological point-whether failure of bonding in these cases is programmed, and has been preserved by natural selection, It would be extremely interesting to observe any primate examples in the wild of neglect, desertion, or infanticide, to see if damaged offspring are selected, and whether signs of damage or of non-response act as releasers of aggression or neutralisers of normal maternal feeling. It would be equally interesting to assess the response of normal women to the recorded crv of normal and brain-damaged infants. Much of the aggression released against children in our society is doubtless non-specific, and there are few mothers of a continuously crying baby who have never felt murderous, but if there are any atavistic releasers which formerly served a selective purpose it would be as well to know this. If we knew about them we might be able to guard against them. Institute for Higher Studies, 2311 Garden Street, Santa Barbara, California 93105, U.S.A.
ALEX COMFORT
THE HANDICAPPED FAMILY
SIR,-Mrs Antonis and Dr Caplan rightly emphasise the
helping the families of handicapped children 603). However, I cannot accept their contention that many professional workers react, because of their lack of in-depth psychodynamic training, by denying and avoiding suffering in these families, and I do not agree that child psychotherapists should necessarily be the central coordinators of
difficulties of
(Sept. 27,
p.
care.
Surely the qualities required of the coordinating workersensitivity, understanding, and professionalism-may be possessed by workers in a number of the caring disciplines. Dr
1. Van
Thiel, D. H., Lester, R., Sherins, R. J. Gastroenterology, 1974, 67, 1188. 2. El Etreby, M. F., Gunzel, P. Acta endocr. Copenh. 1974, suppl. 189, p. 3.
PLASMA-PROLACTIN CONCENTRATIONS
(ng./ml.: T.R.H.
MEAN j:S.E.) IN
(400
(JLg.
3.
Hagen, C., McNeilly, A. S., Arroe, M., Emmertsen, K., Froland, A. Lancet, 1974, ii, 57. IN 7 CIRRHOTIC MALE STIMULATION TEST
5 NORMAL MEN AND
INTRAVENOUSLY)
PATIENTS, FOLLOWING
877
Simpkiss and his colleagues argue (Sept. 20, p. 554) that the of physical and intellectual handicaps makes medical qualification necessary. However, in South Wales and in Oslo care of multiple handicapped children has been most effectively coordinated by social workers. I believe we should concern ourselves less with which professional discipline coordinates, and make sure that the coordination does in fact take place. An ability to accept the often distressing problems of the handicapped family is not the prerogative of any one group, and understanding this should enable us together to help the families with whom we work. extent
St. Mary’s
Hospital,
Newport, Isle of
D. W. HIDE
Wight P030 5TG.
FAILURE OF CEPHRADINE IN INFECTIVE
ENDOCARDITIS
SCREENING FOR NEURAL-TUBE DEFECTS BY A HÆMAGGLUTINATION TEST FOR SERUM-ALPHA-FETOPROTEIN
SIR,-Measurement of maternal serum-alpha-fetoprotein is now used in prospective screening trials for neuraltube defects. The results should determine whether the test should be used more widely. Several problems arise in such trials, 12 especially difficulty in defining the "normal" range for maternal A.F.P. in relation to gestational age, doubt about gestational age, and methodological problems. The maternal-serum A.F.P. reference curve is now fairly well determined by several laboratories.3-7 An elevated serum-A.F.P. concentration at 15-16 weeks should be above the 90% reference curve-e.g., in our laboratory above 100-120 tg/1.7 In patients of uncertain gestational age, which comprise a significant proportion of all pregnancies, the A.F.P. result may be impossible to interpret unless other gestational-age parameters are available. Finally, the methodological problem is the need for a low-cost simple screening-test. Modifications of radioimmunological tests have been used up till now. An
(A.F.P.)
’
.
SIR,-For many years it was customary to treat infective endocarditis with a combination of antibiotics, often a penicillin and streptomycin. Lately, however, the tendency has been to use a single drug to which the organism isolated has been sensitive. In the case of Streptococcus viridans this will almost always be benzylpenicillin given intravenously at a dose of 10-20 megaunits daily. In patients hypersensitive to penicillins, a cephalosporin has been recommended.Of the cephalosporins, cephaloridine, in particular, may be nephrotoxic in high dosage. Cephradine, a new cephalosporin, has not been reported as having nephrotoxic side-effects.’ We present here a case where parenteral cephradine failed to control the bacterxmia of infective endocarditis. A 29-year-old Greek with rheumatic aortic stenosis and regurgitation presented with a pyrexia of 39°C. Strep. viridans was isolated from 12 blood-culture bottles. The M.i.c. of this organism against benzylpenicillin was 0.02 g/ml. Benzylpenicillin 20 megaunits daily was given intravenously in boluses three-hourly. Body-temperature fell to normal, and the organism disappeared from the blood. After a week’s therapy, the patient developed a progressively worsening itchy maculopapular rash. Penicillin was thought to be responsible, and the antibiotic was accordingly changed to cephradine given at the maximum recommended dosage of 500 mg three-hourly intravenously. The M.l.e. of the original streptococcus against this agent was 0.312 g/ml. Within two days the pyrexia returned, and the original streptococcus was isolated from 6 out of 6 bottles. A back titration of the patient’s serum before an injection inhibited the organism at a dilution of 1 in 8 but did not kill it at half dilution. Penicillin was reintroduced under antihistamine cover, without recurrence of the rash and with rapid resolution of the pyrexia.
Cephradine is a cephalosporin closely related to cephalexin but having the advantage of nearly complete oral absorption.2 Its chief advantage when used parenterally is its lack of nephrotoxicity. Its antibacterial spectrum includes the majority of staphylococci and streptococci, although its M.t.c. in a study of group-D streptococci3 was higher than that of cephaloridine and much higher than that of ampicillin. For intravenous use in pdiatric infections, a dosage of 8to 300 mg/kg has been recommendedand this is clearly much higher than the maximum recommended dosage of this drug for an adult. Cephradine may be a useful oral antibiotic in many infections. In the presently recommended maximum intravenous dosage, however, it seems to be ineffective in endocarditis. The maximum recommended dosage is under reviewand once this is established, cephradine may be worthy of further trial. Department of Medicine, Middlesex Hospital, London W1N 8AA.
P. R. DAGGETT A. W. NATHAN
Garrod, L. P. Br. med. J. 1974, iii, 96. Scholand, J. F., Hodges, G. R., Fass, R. J., Saslaw, S. Am. J. med. Sci. 1974, 267, 111. 3. Hamilton-Miller, J. M. T. J. clin. Path. 1974, 27, 828. 4 Macias, E. G., Eller, J. J. Lancet, 1975, i, 38. 5 E. R. Squibb & Sons, Ltd. Personal communication.
1. 2.
Comparison between the R.I.F.P. profile and H.A. A.F.P. in
a
pregnant A.F.P.
woman
followed
test results for serum-
throughout pregnancy.
standards 40-640
,
flg/l.
alternative method may be a sensitive haemagglutination (H.A.) (Mochida, Japan). In 250 maternal-serum samples and in 115 sera from patients with hepatoma or teratocarcinoma a parallel estimation of A.F.P. by radioimmunoelectrophoresis (R.I.E.P.)6 and by the H.A. technique has been carried out. The assay procedure for the H.A. test is as follows: to an ampoule
test
of lyophilised chemically modified sheep erythrocytes coated with antihuman-A.F.p. rabbit gammaglobulin is added 400 VI of phosphate-buffered saline for suspension of the erythrocytes. To the suspension is added 100 1 of diluted serum (10-fold). After incubation for 2 hours at room remperature the bottom of the ampoule is inspected. A clear red ring means no agglutination of the cells and a negative reaction (less than 100 g/1), whereas a diffuse red-cell precipitate covering the bottom of the ampoule as a mat of cells is a positive reaction. In all sera with an A.F.P. concentration >110 g/1 (range 110-570 ;g/1) a distinctive positive reaction was found. In 8 sera from patients with tumours
rheumatoid factor
was
found, but
none
of these
patients gave
false-positive reaction for A.F.P. An improved method for R.i.E.p. was used. In order to obtain more distinct radioprecipitates, polyethyleneglycol 6000 was added to the anodic antibody in a concentration 5.0 g per dl of agarose gel. The World Health Organisation A.F.P. reference ,preparation supplied by the International Agency for Research on Cancer? was measured to 69 mg/1. The results of R.LE.P. and H.A. at different stages of pregnancy are compared in the figure. a
Brock, D. J. H., Scrimgeour, J. B., Bolton, A. E., Wald, N., Peto, R., Barker. S. Lancet, 1975, ii, 195. 2. Vince, J. D., McManus, T. J., Ferguson-Smith, M. A., Ratcliffe, J. G. Br. J. Obstet. Gynæc. (in the press). 3. Seppälä, M., Ruoslahti, E. Lancet, 1972, i, 375. 4. Ishiguro, T., Nishimuro, T. Am. J. Obstet. Gynec. 1973, 116, 27. 5. Brock, D. J. H., Bolton, A. E., Scrimgeour, J. B. Lancet, 1974, i, 767. 6. Seller, M. J., Singer, J. D., Coltart, T. M., Campbell, S. ibid. p. 428. 7. Nørgaard-Pedersen, B., Lindsten, J., Philip, J. Clin. Genet. 1975, 7, 170. 8. Nørgaard-Pedersen, B. Clin. chim. Acta, 1973, 48, 345. 9. Sizaret, P., Breslow, N., Anderson, S. G. J. biol. Standard. 1975, 3, 201. 1.
.
