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Infection Before Birth
802 the trunk. The
patient (more often a girl)
thus reverts
to a condition in which, when fully clothed, she is not obviously deformed and can face the world with
greater equanimity. The price she pays for this is a long stay in hospital, with immobilisation in a grotesque position and perhaps several major operations ; and her back may still become painful later in life. What of the lesser thoracic curves that are treated only by remedial exercises designed to keep the body supple, and of the lumbar curves that often pass unrecognised for many years ? These are not so unsightly as to be an embarrassment during youth, but only too often they give rise to crippling pain in later life. They are very much commoner, and they present an even greater challenge to the surgeon, than the more severe deformities. Here there has been no real advance in a thousand years : we can neither prevent them from starting nor influence their course. We are unlikely to do so until as much effort is directed to aetiology as is now devoted to the mechanics of treatment..
Infection Before Birth INTRA-UTERINE infection as a cause of perinatal mortality has not attracted the attention it deserves. Forty years ago SLEMONS1 indicated that placental bactersemia was an important cause of foetal death late in labour, and BROWNE2 subsequently drew attention to the occurrence of intra-uterine pneumonia. Yet relatively few detailed pathological and bacteriological studies of this condition have been described. DOUGLAS and STANDERshowed that blood-cultures from infants stillborn after prolonged labour associated with intrapartum infection were usually positive, and in over half of this group the placenta showed histological evidence of acute infection. LABATE4 demonstrated pathological evidence of pneumonia in 8% of 868 consecutive necropsies of stillborn or neonatal infants. CORNER and his associates5 stated that asphyxia was the most important pathological finding in 79% of 53 stillbirths and neonatal deaths associated with prolonged labour. Of their whole series of 1233 perinatal deaths 82 (6-6%) were found at necropsy to be due to infection ; the commonest cause was pneumonia, which was often associated with and prolonged labour 6 of demonchorioamniotitis." SIDDALL evidence strated inflammatory changes in the placenta, amnion, chorion, and umbilical cord. It seems that many newborn who develop pneumonia in the first week of life have been infected in utero. AHVENAINENfound a surprisingly high incidence (63%) of pneumonia in 674 necropsies of live-born infants in the Children’s Clinic, University of Helsinki; in 15% pneumonia was judged to be the sole cause of death. Half of these children died in the first week of life, but surprisingly there was no convincing statistical evidence that the incidence of pneumonia was higher after complicated than after "
uncomplicated labours ;
nor
was
there
a
close
1. Slemons, J. M. J. Amer. med. Ass. 1915, 65, 1265. 2. Browne F. J. Brit. med. J. 1922, ii, 590. 3. Douglas, R. G., Stander, H. J. Amer. J. Obstet. Gynec. 1943, 46, 1. 4. Labate, J. S. Ibid, 1947, 54, 188. 5. Corner, G. W., Kistner, R. W., Wall, R. L. Ibid, 1951, 62, 1086. 6. Siddall, R. S. Ibid, 1950, 60, 1281. 7. Ahvenainen, E. K. Ann. Med. intern. Fenniœ, 1953, 42, 1.
correlation with neonatal asphyxia. BLANC8 emphasised the importance of early diagnosis of infection in the newborn. The time interval, anoxia, microbial virulence, and prematurity may all influence the relationship between maternal and foetal infection ; symptoms of maternal infection and the course of labour are not reliable guides to the state of the foetus. In his opinion ascending infection never involves the fcetus in the absence of He detects such inflamma. amniotic inflammation. a shred of amnion slide on a tion by placing from near the large placental vessels with its placental surface downwards, and staining this as with a smear. Examination of endotracheal or gastric fluid aspirated from the infant gives immediate proof of contamination. Other workers, seeking to combat infection promptly, have made out a case for the prophylactic administration of antibiotics to the mother when labour is prolonged, particularly when the membranes have been ruptured for some hours. CHARLES9 has described interesting work on the placental transmission of antibiotics. WoLTZ and his associates 10 " reported in 1945 that penicillin crossed the placental barrier as early as the tenth week of pregnancy ; and penicillin given late in labour was detected in the foetal blood in concentrations of from a quarter to a half that in the maternal blood.12 13 Clinical experience, notably in the treatment of syphilis, 14 supported these laboratory findings ;: and subsequently the passage of streptomycin, chloramphenicol, and aureomycin through the placenta was reported. Ross et al.1516 pointed to the need for maintaining a high maternal blood-level of antibiotic to ensure transference to the feetus. CHARLES now concludes that penicillin, streptomycin, chloramphenicol, aureomycin, and tetracycline are all transferred from the maternal to the fcetal organism in therapeutic concentrations. Of these substances all except penicillin enter the liquor amnii only in negligible amounts. Penicillin is retained in the liquor amnii, where its level remains high even after the maternal serum level has greatly fallen. This is difficult to explain since all these substances are of similar molecular weight and apparently the water, sodium, and possibly other constituents of the amniotic fluid are rapidly exchanged with the maternal serum.17 18 CHARLES suggests that the amniotic membrane absorbs penicillin selectively. EASTMAN19 states that in the management of uterine inertia " because of the threat of intrapartum infection whenever the membranes rupture prematurely it is customary to administer penicillin and sulphadiazine in cases in which the membranes have been ruptured 12 hours or more." In this country such a practice is perhaps less usual ; for the emergence 8. Blanc, W. A. Gynœcologia, 1953, 136, 101. 9. Charles, D. J. Obstet. Gynœc., Brit. Emp. 1954, 61, 750. 10. Woltz, J. H. E., Wiley, M. M. Proc. Soc. Exp. Biol., N.Y. 1945, 60, 105. 11. Woltz, J. H. E., Zintzel, H. A. Amer. J. Obstet. Gynec. 1945, 50, 338. 12. Green, H. J., Hobby, G. L. Proc. Soc. exp. Biol., N.Y. 1944, 57, 282. 13. Herrell, W. E., Nichols, D. It., Heilman, F. R. J. Amer. med. Ass. 1944, 125, 1003. 14. See Lancet, 1954, ii 1268. 15. Ross, S., Bischoff, H., Preisser, W., Orr, W. J. clin. Invest. 1949, 28, 1050. 16. Ross, S., Burke, F. G., Sites, J., Rice, E. C., Washington, J. A. J. Amer. med. Ass. 1950, 142, 1361. 17. Flexner, L. B., C’owie, D. B., Hellman, L. M., Wilde, W. S., Vosburgh, G. R. Amer. J. Obstet. Gynec. 1948, 55, 469. 18. Vosburgh, G. J., Flexner, L. B., Cowie, D. B., Hellman, L. M., Proctor, N. K., Wilde, W. S. Ibid, 1948, 56, 1156. 19. Eastman, N. J. Obstet. Surg., Balt. 1955, 10, 16; Williams Obstetrics. New York, 1950; p. 780.
803 of resistant strains of staphylococci has tempered enthusiasm for large-scale prophylactic administration of antibiotics. BOWIE20 points to the increasing importance of staphylococci in genital-tract infections. It is highly desirable that we should know what potential pathogens exist in the genital tract beforeembarking on the administration of antibiotics ; and when labour is prolonged the practice, followed by CHARLES, of plating high-vaginal swabs within twenty-four hours of rupture of the membranes seems sensible. It is generally agreed that administration of antibiotics is not indicated in the " latent interval " between spontaneous rupture of the membranes and the onset of labour. EASTMAN 21 remarks that in his series intensive antibiotic therapy throughout this latent period neither prevented intrapartum infection nor affected perinatal mortality.
Systemic Lupus Erythematosus
and joint disorders ; and 65 had some abnormality of the urine. What is more surprising is that 78 patients had a haemoglobin level below 11 g. per 100 ml. and 26 had thrombocytopenia; 56 patients had 16 with effusion ; as many as 45 had pericarditis. Enlargement of lymph-glands was detected in 58 patients ; this was generalised in 34. Splenomegaly was found in only 15, but the liver was enlarged in 32. Analysis of skin lesions showed that a butterfly " rash had been present in 39, mucosal lesions in 14, and a purpuric rash in 9. In 27 patients a typical rheumatoid arthritis with deformity " was recorded. The thrombocytopenia of systemic lupus erythematosus may be indistinguishable from the " idiopathic " form, and a full increase in platelets may follow splenectomy ; nor does the microscopic appearance of the spleen given any guidance. The plateletcount remains high until the patient ultimately dies from the other effects of systemic lupus. In the Johns Hopkins series a useful clue, in 6 cases, was that discoid lesions preceded the purpura, but in others there was no preliminary sign. It is no wonder that HARVEY and his colleagues say that " the disease may appear with a confusing array of manifestations resulting from multisystem involvement in which it is difficult to detect any obvious continuity. Joint and, with somewhat lesser frequency, mucocutaneous manifestations are commonly present in episodic fashion and are helpful in pointing towards the correct diagnosis."
pleurisy,
"
"
THE diagnosis of systemic lupus erythematosus has become so fashionable that physicians can be forgiven for thinking that it is a newly distinguished condition. But this is not so : sixty years ago Sir WILLIAM OSLER 22 described almost all aspects of the varied clinical picture that we now recognise. HARVEY et al.23 have lately reviewed this disorder at length and have described 138 cases seen at Johns Hopkins Hospital, Baltimore. In systemic lupus erythematosus skin lesions may (as OSLER recognised) be absent, or they may consist With so complex a clinical picture, it is not surprising of the well-known " butterfly " erythema on the face that or a discoid lesion; and the course varies from acute and physicians turn to the laboratory for help in short to chronic and lasting many years. HARVEY and diagnosis. The " L.E. cell phenomenon," originally his colleagues agree with ARNOLD 24 and lIASERlcK,25 described by HARGRAVES and his co-workers in 1948, is the basis of the most useful test for confirming who use the term " systemic lupus erythematosus " the diagnosis.26 The phenomenon is now known to be for the generalised form of the disease, and the terms " due to a plasma factor associated with the gammadiscoid " and " disseminate" only for the skin lesions. They suggest that the clinical picture varies globulin fraction. With proper technique it can be detected using only the patient’s own blood ; no boneso much that it is useless to classify the disorder into distinct types. Like others they found that most of marrow or normal polymorphs are needed. HARVEY their patients (78%) were females; 80% were aged et al. use heparinised blood from the patient and They think that other 10-40 years. In no less than 55 out of 105 cases that examine the buffy coat. techniques, especially those using clotted blood, were carefully analysed allergic manifestations, such are more liable to give false-positive results. They as urticaria or hay-fever, or sensitivity to various results 82 out of 96 obtained in 20 positive were of these cases did patients but in recorded ; only drugs, such manifestations appear before systemic lupus was known to have systemic lupus erythematosus whose diagnosed. HARVEY et al. list twenty-four diagnoses blood was examined ; and in a group of over 700 made by various physicians in the early stages ; patients with clinically similar skin, joint, blood, and symptoms, due to various other diseases, there they fall roughly into the groups " pyrexia of unknown other all. Another laboratory test that were no ,origin," rheumatic diseases, blood diseases, skin has beenpositivesisatexamination of the plasma-proteins. helpful diseases, diseases of the central nervous system, and the 105 Of Johns Hopkins patients, 58% had serum"functional illness." In the 105 cases that were 100 levels of over 3 ml., and values g. per analysed the initial manifestations were related most globulin ml. were unusual. In 4 100 not excess of in g. per commonly tojoints ; 34 were diagnosed as " acute half the to less than amounted albumin patients migratory polyarthritis" and 16 had arthralgia. 3-5 and it lower some was than 100 in ml., g. per Fever was the leading sign in 24 patients, and some was level ml. The 2 100 plasma-fibrinogen sort of erythematous skin lesion in 21 ; fatigue and g. per it be case where was tested. to in found increased every weakness were the main complaints in 18, weight loss in 7 ; other initial symptoms were much less Electrophoresis also showed high fibrinogen and high gamma-globulin levels. Other plasma-protein tests common. As might be expected, in the course of the disease most patients showed weight loss, skin lesions, have given results that are too variable to be useful. Biopsy of lymph-nodes, skin, and muscle, though it 20. Bowie, H. Edinb. med. J. 1954, 61 ; Transactions of the has been widely practised, seldom yields a pathoEdinburgh Obstetrical Society, p. 1. 21. Eastman, N. J. Obstet. Surv., Baltimore, 1955, 10, 16. gnomonic picture. Thus in HARVEY’S group of patients 22. Osler, W. Amer. J. med. Sci. 1895, 110, 629. 23. Harvey, A. McG., Shulman, L. E., Tumulty, P. A., Conley, C. L., lymph-node biopsy was inconclusive in 11 and positive Schoenrich, E. H. Medicine, Baltimore, 1954, 33, 291. 24. Arnold, H. jun. Arch. Derm. Syph. 1950, 62, 632. 25. Haserick, J. R. J. invest. Derm. 1951, 16, 211.
26. See
Lancet, 1951, ii,
110.
patient (more often a girl)
thus reverts
to a condition in which, when fully clothed, she is not obviously deformed and can face the world with
greater equanimity. The price she pays for this is a long stay in hospital, with immobilisation in a grotesque position and perhaps several major operations ; and her back may still become painful later in life. What of the lesser thoracic curves that are treated only by remedial exercises designed to keep the body supple, and of the lumbar curves that often pass unrecognised for many years ? These are not so unsightly as to be an embarrassment during youth, but only too often they give rise to crippling pain in later life. They are very much commoner, and they present an even greater challenge to the surgeon, than the more severe deformities. Here there has been no real advance in a thousand years : we can neither prevent them from starting nor influence their course. We are unlikely to do so until as much effort is directed to aetiology as is now devoted to the mechanics of treatment..
Infection Before Birth INTRA-UTERINE infection as a cause of perinatal mortality has not attracted the attention it deserves. Forty years ago SLEMONS1 indicated that placental bactersemia was an important cause of foetal death late in labour, and BROWNE2 subsequently drew attention to the occurrence of intra-uterine pneumonia. Yet relatively few detailed pathological and bacteriological studies of this condition have been described. DOUGLAS and STANDERshowed that blood-cultures from infants stillborn after prolonged labour associated with intrapartum infection were usually positive, and in over half of this group the placenta showed histological evidence of acute infection. LABATE4 demonstrated pathological evidence of pneumonia in 8% of 868 consecutive necropsies of stillborn or neonatal infants. CORNER and his associates5 stated that asphyxia was the most important pathological finding in 79% of 53 stillbirths and neonatal deaths associated with prolonged labour. Of their whole series of 1233 perinatal deaths 82 (6-6%) were found at necropsy to be due to infection ; the commonest cause was pneumonia, which was often associated with and prolonged labour 6 of demonchorioamniotitis." SIDDALL evidence strated inflammatory changes in the placenta, amnion, chorion, and umbilical cord. It seems that many newborn who develop pneumonia in the first week of life have been infected in utero. AHVENAINENfound a surprisingly high incidence (63%) of pneumonia in 674 necropsies of live-born infants in the Children’s Clinic, University of Helsinki; in 15% pneumonia was judged to be the sole cause of death. Half of these children died in the first week of life, but surprisingly there was no convincing statistical evidence that the incidence of pneumonia was higher after complicated than after "
uncomplicated labours ;
nor
was
there
a
close
1. Slemons, J. M. J. Amer. med. Ass. 1915, 65, 1265. 2. Browne F. J. Brit. med. J. 1922, ii, 590. 3. Douglas, R. G., Stander, H. J. Amer. J. Obstet. Gynec. 1943, 46, 1. 4. Labate, J. S. Ibid, 1947, 54, 188. 5. Corner, G. W., Kistner, R. W., Wall, R. L. Ibid, 1951, 62, 1086. 6. Siddall, R. S. Ibid, 1950, 60, 1281. 7. Ahvenainen, E. K. Ann. Med. intern. Fenniœ, 1953, 42, 1.
correlation with neonatal asphyxia. BLANC8 emphasised the importance of early diagnosis of infection in the newborn. The time interval, anoxia, microbial virulence, and prematurity may all influence the relationship between maternal and foetal infection ; symptoms of maternal infection and the course of labour are not reliable guides to the state of the foetus. In his opinion ascending infection never involves the fcetus in the absence of He detects such inflamma. amniotic inflammation. a shred of amnion slide on a tion by placing from near the large placental vessels with its placental surface downwards, and staining this as with a smear. Examination of endotracheal or gastric fluid aspirated from the infant gives immediate proof of contamination. Other workers, seeking to combat infection promptly, have made out a case for the prophylactic administration of antibiotics to the mother when labour is prolonged, particularly when the membranes have been ruptured for some hours. CHARLES9 has described interesting work on the placental transmission of antibiotics. WoLTZ and his associates 10 " reported in 1945 that penicillin crossed the placental barrier as early as the tenth week of pregnancy ; and penicillin given late in labour was detected in the foetal blood in concentrations of from a quarter to a half that in the maternal blood.12 13 Clinical experience, notably in the treatment of syphilis, 14 supported these laboratory findings ;: and subsequently the passage of streptomycin, chloramphenicol, and aureomycin through the placenta was reported. Ross et al.1516 pointed to the need for maintaining a high maternal blood-level of antibiotic to ensure transference to the feetus. CHARLES now concludes that penicillin, streptomycin, chloramphenicol, aureomycin, and tetracycline are all transferred from the maternal to the fcetal organism in therapeutic concentrations. Of these substances all except penicillin enter the liquor amnii only in negligible amounts. Penicillin is retained in the liquor amnii, where its level remains high even after the maternal serum level has greatly fallen. This is difficult to explain since all these substances are of similar molecular weight and apparently the water, sodium, and possibly other constituents of the amniotic fluid are rapidly exchanged with the maternal serum.17 18 CHARLES suggests that the amniotic membrane absorbs penicillin selectively. EASTMAN19 states that in the management of uterine inertia " because of the threat of intrapartum infection whenever the membranes rupture prematurely it is customary to administer penicillin and sulphadiazine in cases in which the membranes have been ruptured 12 hours or more." In this country such a practice is perhaps less usual ; for the emergence 8. Blanc, W. A. Gynœcologia, 1953, 136, 101. 9. Charles, D. J. Obstet. Gynœc., Brit. Emp. 1954, 61, 750. 10. Woltz, J. H. E., Wiley, M. M. Proc. Soc. Exp. Biol., N.Y. 1945, 60, 105. 11. Woltz, J. H. E., Zintzel, H. A. Amer. J. Obstet. Gynec. 1945, 50, 338. 12. Green, H. J., Hobby, G. L. Proc. Soc. exp. Biol., N.Y. 1944, 57, 282. 13. Herrell, W. E., Nichols, D. It., Heilman, F. R. J. Amer. med. Ass. 1944, 125, 1003. 14. See Lancet, 1954, ii 1268. 15. Ross, S., Bischoff, H., Preisser, W., Orr, W. J. clin. Invest. 1949, 28, 1050. 16. Ross, S., Burke, F. G., Sites, J., Rice, E. C., Washington, J. A. J. Amer. med. Ass. 1950, 142, 1361. 17. Flexner, L. B., C’owie, D. B., Hellman, L. M., Wilde, W. S., Vosburgh, G. R. Amer. J. Obstet. Gynec. 1948, 55, 469. 18. Vosburgh, G. J., Flexner, L. B., Cowie, D. B., Hellman, L. M., Proctor, N. K., Wilde, W. S. Ibid, 1948, 56, 1156. 19. Eastman, N. J. Obstet. Surg., Balt. 1955, 10, 16; Williams Obstetrics. New York, 1950; p. 780.
803 of resistant strains of staphylococci has tempered enthusiasm for large-scale prophylactic administration of antibiotics. BOWIE20 points to the increasing importance of staphylococci in genital-tract infections. It is highly desirable that we should know what potential pathogens exist in the genital tract beforeembarking on the administration of antibiotics ; and when labour is prolonged the practice, followed by CHARLES, of plating high-vaginal swabs within twenty-four hours of rupture of the membranes seems sensible. It is generally agreed that administration of antibiotics is not indicated in the " latent interval " between spontaneous rupture of the membranes and the onset of labour. EASTMAN 21 remarks that in his series intensive antibiotic therapy throughout this latent period neither prevented intrapartum infection nor affected perinatal mortality.
Systemic Lupus Erythematosus
and joint disorders ; and 65 had some abnormality of the urine. What is more surprising is that 78 patients had a haemoglobin level below 11 g. per 100 ml. and 26 had thrombocytopenia; 56 patients had 16 with effusion ; as many as 45 had pericarditis. Enlargement of lymph-glands was detected in 58 patients ; this was generalised in 34. Splenomegaly was found in only 15, but the liver was enlarged in 32. Analysis of skin lesions showed that a butterfly " rash had been present in 39, mucosal lesions in 14, and a purpuric rash in 9. In 27 patients a typical rheumatoid arthritis with deformity " was recorded. The thrombocytopenia of systemic lupus erythematosus may be indistinguishable from the " idiopathic " form, and a full increase in platelets may follow splenectomy ; nor does the microscopic appearance of the spleen given any guidance. The plateletcount remains high until the patient ultimately dies from the other effects of systemic lupus. In the Johns Hopkins series a useful clue, in 6 cases, was that discoid lesions preceded the purpura, but in others there was no preliminary sign. It is no wonder that HARVEY and his colleagues say that " the disease may appear with a confusing array of manifestations resulting from multisystem involvement in which it is difficult to detect any obvious continuity. Joint and, with somewhat lesser frequency, mucocutaneous manifestations are commonly present in episodic fashion and are helpful in pointing towards the correct diagnosis."
pleurisy,
"
"
THE diagnosis of systemic lupus erythematosus has become so fashionable that physicians can be forgiven for thinking that it is a newly distinguished condition. But this is not so : sixty years ago Sir WILLIAM OSLER 22 described almost all aspects of the varied clinical picture that we now recognise. HARVEY et al.23 have lately reviewed this disorder at length and have described 138 cases seen at Johns Hopkins Hospital, Baltimore. In systemic lupus erythematosus skin lesions may (as OSLER recognised) be absent, or they may consist With so complex a clinical picture, it is not surprising of the well-known " butterfly " erythema on the face that or a discoid lesion; and the course varies from acute and physicians turn to the laboratory for help in short to chronic and lasting many years. HARVEY and diagnosis. The " L.E. cell phenomenon," originally his colleagues agree with ARNOLD 24 and lIASERlcK,25 described by HARGRAVES and his co-workers in 1948, is the basis of the most useful test for confirming who use the term " systemic lupus erythematosus " the diagnosis.26 The phenomenon is now known to be for the generalised form of the disease, and the terms " due to a plasma factor associated with the gammadiscoid " and " disseminate" only for the skin lesions. They suggest that the clinical picture varies globulin fraction. With proper technique it can be detected using only the patient’s own blood ; no boneso much that it is useless to classify the disorder into distinct types. Like others they found that most of marrow or normal polymorphs are needed. HARVEY their patients (78%) were females; 80% were aged et al. use heparinised blood from the patient and They think that other 10-40 years. In no less than 55 out of 105 cases that examine the buffy coat. techniques, especially those using clotted blood, were carefully analysed allergic manifestations, such are more liable to give false-positive results. They as urticaria or hay-fever, or sensitivity to various results 82 out of 96 obtained in 20 positive were of these cases did patients but in recorded ; only drugs, such manifestations appear before systemic lupus was known to have systemic lupus erythematosus whose diagnosed. HARVEY et al. list twenty-four diagnoses blood was examined ; and in a group of over 700 made by various physicians in the early stages ; patients with clinically similar skin, joint, blood, and symptoms, due to various other diseases, there they fall roughly into the groups " pyrexia of unknown other all. Another laboratory test that were no ,origin," rheumatic diseases, blood diseases, skin has beenpositivesisatexamination of the plasma-proteins. helpful diseases, diseases of the central nervous system, and the 105 Of Johns Hopkins patients, 58% had serum"functional illness." In the 105 cases that were 100 levels of over 3 ml., and values g. per analysed the initial manifestations were related most globulin ml. were unusual. In 4 100 not excess of in g. per commonly tojoints ; 34 were diagnosed as " acute half the to less than amounted albumin patients migratory polyarthritis" and 16 had arthralgia. 3-5 and it lower some was than 100 in ml., g. per Fever was the leading sign in 24 patients, and some was level ml. The 2 100 plasma-fibrinogen sort of erythematous skin lesion in 21 ; fatigue and g. per it be case where was tested. to in found increased every weakness were the main complaints in 18, weight loss in 7 ; other initial symptoms were much less Electrophoresis also showed high fibrinogen and high gamma-globulin levels. Other plasma-protein tests common. As might be expected, in the course of the disease most patients showed weight loss, skin lesions, have given results that are too variable to be useful. Biopsy of lymph-nodes, skin, and muscle, though it 20. Bowie, H. Edinb. med. J. 1954, 61 ; Transactions of the has been widely practised, seldom yields a pathoEdinburgh Obstetrical Society, p. 1. 21. Eastman, N. J. Obstet. Surv., Baltimore, 1955, 10, 16. gnomonic picture. Thus in HARVEY’S group of patients 22. Osler, W. Amer. J. med. Sci. 1895, 110, 629. 23. Harvey, A. McG., Shulman, L. E., Tumulty, P. A., Conley, C. L., lymph-node biopsy was inconclusive in 11 and positive Schoenrich, E. H. Medicine, Baltimore, 1954, 33, 291. 24. Arnold, H. jun. Arch. Derm. Syph. 1950, 62, 632. 25. Haserick, J. R. J. invest. Derm. 1951, 16, 211.
26. See
Lancet, 1951, ii,
110.