539
thromboembolism; they report that warfarin raises At III levels. There is little firm evidence that thrombosis commonly recurs after cessation of intravenous heparin therapy, and so far no data have been presented to suggest that these findings are applicable to patients on short-term low-dose heparin prophylaxis. While the danger of heparin-induced At III depletion may prove to be more of a theoretical hazard than an important clinical problem, the practice of giving prolonged high dose levels of heparin to patients with acute thromboembolism may need to be reassessed. About 30 000 i.u. of heparin per day by continuous intravenous infusion is sufficient for most patients;10.11 and the high incidence of heparin-induced haemorrhage reported by Mant et al.12 strengthens the case for a switch to oral anticoagulants (or perhaps even low-dose heparin) as soon as the acute phase of the illness is over.
type-14 pneumococci or group-D streptococci. He speculated on the attractive but unlikely possibility of using the harmless type-14 pneumococcal polysaccharide as a vaccine if lipopolysaccharide preparations proved too harmful. M. A. Apicella has continued his analysis’ of acidic polysaccharides as markers for serogroups, though we still do not know whether they are capsular or derived from lipopolysaccharide. By
an
ingenious staining technique involving dansyl
chloride enclosed in cyclohepta-amylase, K. H. Johnston has investigated the relation of proteins to the cell envelope. They may be soluble, or attached to or more or less buried in the peptidoglycan. There is hope that the 16 outer membrane proteins (O.M.P.) described by Johnston et al.8 and the 6, described by T. Buchanan will eventually be fused into a single set for serotyping. According to Buchanan, o.M.P.s act as specific antigens for bactericidal and opsonic antibodies. D. Kasper described bactericidal antibodies, largely IgG, in patients with gonorrhoea, and confirmed earlier observations9 that killing could be inhibited by lipopolysaccharide. The extensive antigenic variation found in pili was stressed by both C. Brinton and Buchanan. Buchanan showed that attachment of gonococci to cervical epithelial cells involved 104 receptor sites per cell or 10 pili/µm2 Attachment was enhanced by ferric ions, less by calcium, and was inhibited by secretory IgA (sIgA) from infected patients or by gangliosides. sIgA antibodies to gonococci have frequently been described in local secretions although, as the patients are infected, their protective value is not obvious. E. Tramont described specific sIgA antibodies in patients’ secretions able to block the adhesion of gonococci. sIgA may resist proteolytic enzymes in the gut but Plautl0 showed clearly how its heavy chain could be cut by a gonococcal protease, perhaps a nice example of an impedin. How much IgA antibody is in the protease-resistant subclass IgA2 is unknown. Gonorrhreal research is hampered by the lack of a suitable animal model. Chimpanzees are clearly impracticable. Infection of subcutaneous chambers in small animals may maintain virulence in gonococci and has produced useful general immunological informationll,12 but cannot elucidate problems of a mucosal infection. Here the infection of isolated human fallopian tubes" remains the most hopeful approach. Stimulated by the increasing importance of disseminated gonococcal infection, D. Drutz is developing a model bacteraemic infec’
PROGRESS IN GONORRHŒA THOUGH gonorrhoea has gained ground rapidly since the late 1950s there are signs that the rate of increase is slowing down. Some say that the slow-down is due as much to the general economic recession as to any publichealth measured In 1976 there were over 60 000 new cases of gonorrhoea reported in England2 and over 1000000 in the U.S.A.3 Unreported cases, largely seen privately, might well double or treble these figures. One result of the uncontrolled pandemic of gonorrhoea has been greatly increased support for research. The U.S.A. is currently spending about$4 million a year-a figure to be set against the$700-800 million that gonorrhoea costs the country each year through time lost, provision of care, contact tracing, and so on. A three-day meeting in San Francisco reviewed the immunobiology of gonorrhoea and gave some inkling of the likely future. Developing earlier work linking virulence to certain colonial forms4 and the subsequent demonstration5,6 that in such colonies the organisms were pilated, J. Swanson and his colleagues have now analysed the complex relations to underlying biochemical changes of variations in colony colour, edge, opacity, and twitching motility. The well-known fragility of gonococci was related by S. Morse and by B. Hebeler and F. E. Young to the effect of pH on rates of peptidoglycan hydrolysis. Autolysis was less at pH 6 than at pH 7.2 but unfortunately they did not examine the effect of pH 3.5-4 to which gonococci might be exposed in phagosomes. M. Perry described a possible core structure for gonococcal lipopolysaccharides. As the antigenic determinants are galactose and glucosamine, they should cross-react with 10. Basu, D., Gallus, A., Hirsh, J., Cade, J. New Engl. J. Med. 1972, 287, 324. 11. Salzman, E. W., Deykin, D., Shapiro, R. M., Rosenberg, R. ibid. 1975, 292, 1046. 12. Mant, M. J., O’Brien, B. D., Thong, K. L., Hammond, G. W., Birtwhistle, R. V., Grace, M. G. Lancet, 1977, i, 1133. 1. Science, 1976, 192, 245. 2. On the State of the Public Health; p. 61. H.M. Stationery Office, 1976. 3. VD Fact Sheet; p. 11. Department of Health Education and Welfare. Washington, D.C., 1976. 4. Kellog, D. S., Jr., Cohen, I. R., Norins, L. C., Schroeter, A. L., Reising, G. J. Bact. 1968, 96, 596. 5. Jephcott, A. E., Reyn, A., Birch-Andersen, A. Acta path. scand. B. 1971, 79, 437. 6. Swanson, J., Kraus, S. J., Gotschlich, E. C. J. exp. Med. 1971, 134, 886.
tion. The search for
serological diagnostic test continues. Using enzyme-linked immunosorbent assay (ELISA) with an envelope protein as antigen, Glynn and Ison’4 could detect antibody responses early in acute gonorrhcea and in carriers. They also found circulating specific IgA antibody, most of which turned out to be sIgA (see p. 557). Whether this can be used as an indicator of local antibody response remains to be seen. a
an
7. 8.
Apicella, M. A. J. infect. Dis. 1976, 134, 377. Johnston,
K.
H., Holmes, K. K., Gotschlich, E. C. J. exp. Med. 1976, 143,
741. 9. 10. 11.
Glynn, A. A., Ward, M. E. Infect. Immun. 1970, 2, 162.
Plaut, A. G., Gilbert, J. V., Wistar, R. ibid. 1977, 17, 130. Penn, C. W., Sen, D. R., Parsons, N. J., Smith, H. J. gen. Microbiol. 1976, 97, 35. 12. Arko, R. J. J. infect. Dis. 1974, 129, 451. 13. Ward, M. E., Watt, P. J., Robertson, J. N. ibid. p. 650. 14. Glynn, A. A., Ison, C. Br. J. vener. Dis. 1978, 54, 97.
540 Brinton also reported the use of ELISA with pili as antigen. The radiolabelled staphylococcal-protein-A method of P. A. Mardh, though sensitive, is inevitably limited to IgG antibodies. When, in 1975, Falkow" described plasmid-controlled &bgr;-lactamase production in Hœmophilus influenzae, he warned that there was no reason why Neisseria gonorrhœæ should not behave similarly. It was appropriate, therefore, that, in San Francisco he should have been the one to review gonococcal &bgr;-lactamase plasmids. In the Asian strain found in the U.S.A. the R plasmid is transferred only if a 24tmegadalton plasmid is also present. However, the latter is absent in the West African strains from which the U.K. &bgr;-lactamase-producing gonococci are derived. Although they are the cause of much concern, the &bgr;-lactamase gonococci have so far shown no signs of spreading widely either in the U.S.A. or in Britain. Possibly they flourished under the selective pressure due to the indiscriminate use of penicillin in parts of Asia and Africa but are less competitive in regions where antibiotics are better regulated. P. F. Sparling reviewed four genes controlling lesser degrees of resistance to penicillin, related to changes in the degree of cross-linking in peptidoglycan and increased production of the 50 000 dalton outer membrane protein. Until lately a vaccine for gonorrhoea was regarded as a pipe-dream. Now, what such a vaccine should contain and the problems it could create are being seriously discussed. Brinton has already shown in volunteers that immunisation with pili induces antibody and raises the threshold infecting d6se a thousand fold. Since it prevents adhesion, antibody to pili should not increase the number of carriers. However, even if successful a single component vaccine might give rise to antigenic drift. Who should be offered a vaccine? If it is true that spread is mainly through a relatively small number of "core" cases, an effective approach might be to vaccinate all patients with gonorrhoea. Licensing a vaccine implies surveillance to determine its efficiency and detect harmful reactions early. One possible consequence is a rise in the incidence of syphilis if, as many believe, this disease is now being suppressed by penicillin given for
gonorrhoea. FELTY’S SYNDROME IN 1924 Felty described five adults with chronic arthritis, splenomegaly, and leucopenia.1 He was not sure whether this represented one or more entities, but present-day thinking accepts a syndrome of splenomegaly and hypersplenism superimposed upon severe and usually long-standing rheumatoid arthritis. Rheumatoid arthritis is common while Felty’s syndrome is rare, affecting less than 1% of patients seeking hospital advice
for their rheumatoid disease.2 In patients with Felty’s syndrome the arthritis tends to be severe and extra-articular features are frequent. 3-5
Joint deformity is very common and many patients have radiological evidence of destruction of cartilage and bone. As well as splenomegaly, nodules and lymphadenopathy are common. Patients are usually ansemic and some have a symptomless thrombocytopenia. Other clinical features which are more common in Felty’s syndrome than in classic rheumatoid arthritis are leg ulcers, skin pigmentation, Sjogren’s syndrome, pulmonary fibrosis, and pleurisy. The mechanism producing splenomegaly is not clear. Histologically there may be hyperplasia of sinusoidal macrophages in the splenic pulp and of large lymphocytes in germinal centres.4,5 The macrophages sometimes contain red-cell debris indicating erythrophagocytosis, and so their hyperplasia probably reflects increased destruction of red cells together with white cells and platelets and contributes to the enlarged spleen. This becomes a circular argument since the enlarged spleen may itself be the explanation of increased destruction. Germinal-centre hyperplasia in the spleen and in other lymphoid tissue suggests stimulation of the B lymphocyte system which is responsible for circulating antibodies. This is borne out by high immunoglobulin levels of all classes-IgG, IgA, and IgM-and a high titre of rheumatoid factor. Antinuclear factor is common and lupus-erythematosus cells may be detected, but D.N.A. binding is not increased, which distinguishes Felty’s syndrome from systemic lupus erythematosus. In a small proportion of patients primary liver disease may cause splenomegaly. Impaired handling of bromsulphthalein and mild increases of alkaline phosphatase and transaminases are found in nearly a quarter of patients.5 The histological basis for these abnormalities varies. A nodular regenerative hyperplasia has been described which might interfere with portal blood-flow.6 There have been a few reports of cirrhosis with portal hypertension and of lymphocytic infiltration of the sinusoidsand portal triads.7,8 Leucopenia in Felty’s syndrome is secondary to splenomegaly. There is a lack of neutrophils rather than lymphocytes, although the lymphocyte-count may be depressed.5 Bone-marrow usually shows increased granulocyte production, with a shift towards more immature forms suggesting increased peripheral destruction. Tests involving stimuli to mobilise neutrophils show decreased reserves. Splenectomy corrects these abnormalities in most patients; peripheral-blood leucocyte count, bone-marrow morphology, and mobilisable neutrophil reserve all return to normal. Postoperatively there is also an improvement in anaemia and a rise in the platelet-count. Whether leucocyte destruction in the spleen results simply from pooling (i.e., hypersplenism) or from a more specific immunological mechanism is not clear. A leucocyte-specific antinuclear factor has been described in Felty’s syndrome but its titre does not correlate with the leucocyte-count and similar antibodies are detected in rheumatoid arthritis without leucopenia.9 Patients with Felty’s syndrome tend to have frequent bacterial infections, particularly pneumonia due to com-
15. Falkow, S., Elwell,
L. P., de Graaff, J. Heffron, F., Mayer, L. in Sexually Transmitted Diseases (edited by R. D. Catterall and C. S. Nicol); p. 120, London 1976. 1. Felty, A. R. Bull. Johns Hopk. Hosp. 1924, 35, 16. 2. Moore, R. A., Brunner, C. M., Sandusky, W. R., Lavell, B. S. Ann. intern.
Med. 1971, 75, 381. 3. Ruderman, M., Miller, L. M., Pinals, R. S. Arthritis Rheum. 1968, 11, 377. 4. Barnes, C. G., Turnbull, A. L., Vernon-Roberts, B. Ann. rheumat. Dis.
1971, 30, 359.
5. Sienknecht, C. W., Urowitz, M. D., Pruzanski, W., Stein, H. B. ibid. 1977,
36, 500. Blendis, L. M., Parkinson, M. C., Shilkin, K. B., Williams, R. Q. J. Med. 1974, 43, 25. 7. Hutt, M. S. R., Richardson, J. S., Staffurth, J. S. ibid. 1951, 20, 57. 8. Ritland, S. Scand. J. Rheumat. 1973, 2, 29. 9. Calabresi, P., Edwards, E. A. and Schilling, R. F. J. clin. Invest. 1959, 38, 6.
2091.
thromboembolism; they report that warfarin raises At III levels. There is little firm evidence that thrombosis commonly recurs after cessation of intravenous heparin therapy, and so far no data have been presented to suggest that these findings are applicable to patients on short-term low-dose heparin prophylaxis. While the danger of heparin-induced At III depletion may prove to be more of a theoretical hazard than an important clinical problem, the practice of giving prolonged high dose levels of heparin to patients with acute thromboembolism may need to be reassessed. About 30 000 i.u. of heparin per day by continuous intravenous infusion is sufficient for most patients;10.11 and the high incidence of heparin-induced haemorrhage reported by Mant et al.12 strengthens the case for a switch to oral anticoagulants (or perhaps even low-dose heparin) as soon as the acute phase of the illness is over.
type-14 pneumococci or group-D streptococci. He speculated on the attractive but unlikely possibility of using the harmless type-14 pneumococcal polysaccharide as a vaccine if lipopolysaccharide preparations proved too harmful. M. A. Apicella has continued his analysis’ of acidic polysaccharides as markers for serogroups, though we still do not know whether they are capsular or derived from lipopolysaccharide. By
an
ingenious staining technique involving dansyl
chloride enclosed in cyclohepta-amylase, K. H. Johnston has investigated the relation of proteins to the cell envelope. They may be soluble, or attached to or more or less buried in the peptidoglycan. There is hope that the 16 outer membrane proteins (O.M.P.) described by Johnston et al.8 and the 6, described by T. Buchanan will eventually be fused into a single set for serotyping. According to Buchanan, o.M.P.s act as specific antigens for bactericidal and opsonic antibodies. D. Kasper described bactericidal antibodies, largely IgG, in patients with gonorrhoea, and confirmed earlier observations9 that killing could be inhibited by lipopolysaccharide. The extensive antigenic variation found in pili was stressed by both C. Brinton and Buchanan. Buchanan showed that attachment of gonococci to cervical epithelial cells involved 104 receptor sites per cell or 10 pili/µm2 Attachment was enhanced by ferric ions, less by calcium, and was inhibited by secretory IgA (sIgA) from infected patients or by gangliosides. sIgA antibodies to gonococci have frequently been described in local secretions although, as the patients are infected, their protective value is not obvious. E. Tramont described specific sIgA antibodies in patients’ secretions able to block the adhesion of gonococci. sIgA may resist proteolytic enzymes in the gut but Plautl0 showed clearly how its heavy chain could be cut by a gonococcal protease, perhaps a nice example of an impedin. How much IgA antibody is in the protease-resistant subclass IgA2 is unknown. Gonorrhreal research is hampered by the lack of a suitable animal model. Chimpanzees are clearly impracticable. Infection of subcutaneous chambers in small animals may maintain virulence in gonococci and has produced useful general immunological informationll,12 but cannot elucidate problems of a mucosal infection. Here the infection of isolated human fallopian tubes" remains the most hopeful approach. Stimulated by the increasing importance of disseminated gonococcal infection, D. Drutz is developing a model bacteraemic infec’
PROGRESS IN GONORRHŒA THOUGH gonorrhoea has gained ground rapidly since the late 1950s there are signs that the rate of increase is slowing down. Some say that the slow-down is due as much to the general economic recession as to any publichealth measured In 1976 there were over 60 000 new cases of gonorrhoea reported in England2 and over 1000000 in the U.S.A.3 Unreported cases, largely seen privately, might well double or treble these figures. One result of the uncontrolled pandemic of gonorrhoea has been greatly increased support for research. The U.S.A. is currently spending about$4 million a year-a figure to be set against the$700-800 million that gonorrhoea costs the country each year through time lost, provision of care, contact tracing, and so on. A three-day meeting in San Francisco reviewed the immunobiology of gonorrhoea and gave some inkling of the likely future. Developing earlier work linking virulence to certain colonial forms4 and the subsequent demonstration5,6 that in such colonies the organisms were pilated, J. Swanson and his colleagues have now analysed the complex relations to underlying biochemical changes of variations in colony colour, edge, opacity, and twitching motility. The well-known fragility of gonococci was related by S. Morse and by B. Hebeler and F. E. Young to the effect of pH on rates of peptidoglycan hydrolysis. Autolysis was less at pH 6 than at pH 7.2 but unfortunately they did not examine the effect of pH 3.5-4 to which gonococci might be exposed in phagosomes. M. Perry described a possible core structure for gonococcal lipopolysaccharides. As the antigenic determinants are galactose and glucosamine, they should cross-react with 10. Basu, D., Gallus, A., Hirsh, J., Cade, J. New Engl. J. Med. 1972, 287, 324. 11. Salzman, E. W., Deykin, D., Shapiro, R. M., Rosenberg, R. ibid. 1975, 292, 1046. 12. Mant, M. J., O’Brien, B. D., Thong, K. L., Hammond, G. W., Birtwhistle, R. V., Grace, M. G. Lancet, 1977, i, 1133. 1. Science, 1976, 192, 245. 2. On the State of the Public Health; p. 61. H.M. Stationery Office, 1976. 3. VD Fact Sheet; p. 11. Department of Health Education and Welfare. Washington, D.C., 1976. 4. Kellog, D. S., Jr., Cohen, I. R., Norins, L. C., Schroeter, A. L., Reising, G. J. Bact. 1968, 96, 596. 5. Jephcott, A. E., Reyn, A., Birch-Andersen, A. Acta path. scand. B. 1971, 79, 437. 6. Swanson, J., Kraus, S. J., Gotschlich, E. C. J. exp. Med. 1971, 134, 886.
tion. The search for
serological diagnostic test continues. Using enzyme-linked immunosorbent assay (ELISA) with an envelope protein as antigen, Glynn and Ison’4 could detect antibody responses early in acute gonorrhcea and in carriers. They also found circulating specific IgA antibody, most of which turned out to be sIgA (see p. 557). Whether this can be used as an indicator of local antibody response remains to be seen. a
an
7. 8.
Apicella, M. A. J. infect. Dis. 1976, 134, 377. Johnston,
K.
H., Holmes, K. K., Gotschlich, E. C. J. exp. Med. 1976, 143,
741. 9. 10. 11.
Glynn, A. A., Ward, M. E. Infect. Immun. 1970, 2, 162.
Plaut, A. G., Gilbert, J. V., Wistar, R. ibid. 1977, 17, 130. Penn, C. W., Sen, D. R., Parsons, N. J., Smith, H. J. gen. Microbiol. 1976, 97, 35. 12. Arko, R. J. J. infect. Dis. 1974, 129, 451. 13. Ward, M. E., Watt, P. J., Robertson, J. N. ibid. p. 650. 14. Glynn, A. A., Ison, C. Br. J. vener. Dis. 1978, 54, 97.
540 Brinton also reported the use of ELISA with pili as antigen. The radiolabelled staphylococcal-protein-A method of P. A. Mardh, though sensitive, is inevitably limited to IgG antibodies. When, in 1975, Falkow" described plasmid-controlled &bgr;-lactamase production in Hœmophilus influenzae, he warned that there was no reason why Neisseria gonorrhœæ should not behave similarly. It was appropriate, therefore, that, in San Francisco he should have been the one to review gonococcal &bgr;-lactamase plasmids. In the Asian strain found in the U.S.A. the R plasmid is transferred only if a 24tmegadalton plasmid is also present. However, the latter is absent in the West African strains from which the U.K. &bgr;-lactamase-producing gonococci are derived. Although they are the cause of much concern, the &bgr;-lactamase gonococci have so far shown no signs of spreading widely either in the U.S.A. or in Britain. Possibly they flourished under the selective pressure due to the indiscriminate use of penicillin in parts of Asia and Africa but are less competitive in regions where antibiotics are better regulated. P. F. Sparling reviewed four genes controlling lesser degrees of resistance to penicillin, related to changes in the degree of cross-linking in peptidoglycan and increased production of the 50 000 dalton outer membrane protein. Until lately a vaccine for gonorrhoea was regarded as a pipe-dream. Now, what such a vaccine should contain and the problems it could create are being seriously discussed. Brinton has already shown in volunteers that immunisation with pili induces antibody and raises the threshold infecting d6se a thousand fold. Since it prevents adhesion, antibody to pili should not increase the number of carriers. However, even if successful a single component vaccine might give rise to antigenic drift. Who should be offered a vaccine? If it is true that spread is mainly through a relatively small number of "core" cases, an effective approach might be to vaccinate all patients with gonorrhoea. Licensing a vaccine implies surveillance to determine its efficiency and detect harmful reactions early. One possible consequence is a rise in the incidence of syphilis if, as many believe, this disease is now being suppressed by penicillin given for
gonorrhoea. FELTY’S SYNDROME IN 1924 Felty described five adults with chronic arthritis, splenomegaly, and leucopenia.1 He was not sure whether this represented one or more entities, but present-day thinking accepts a syndrome of splenomegaly and hypersplenism superimposed upon severe and usually long-standing rheumatoid arthritis. Rheumatoid arthritis is common while Felty’s syndrome is rare, affecting less than 1% of patients seeking hospital advice
for their rheumatoid disease.2 In patients with Felty’s syndrome the arthritis tends to be severe and extra-articular features are frequent. 3-5
Joint deformity is very common and many patients have radiological evidence of destruction of cartilage and bone. As well as splenomegaly, nodules and lymphadenopathy are common. Patients are usually ansemic and some have a symptomless thrombocytopenia. Other clinical features which are more common in Felty’s syndrome than in classic rheumatoid arthritis are leg ulcers, skin pigmentation, Sjogren’s syndrome, pulmonary fibrosis, and pleurisy. The mechanism producing splenomegaly is not clear. Histologically there may be hyperplasia of sinusoidal macrophages in the splenic pulp and of large lymphocytes in germinal centres.4,5 The macrophages sometimes contain red-cell debris indicating erythrophagocytosis, and so their hyperplasia probably reflects increased destruction of red cells together with white cells and platelets and contributes to the enlarged spleen. This becomes a circular argument since the enlarged spleen may itself be the explanation of increased destruction. Germinal-centre hyperplasia in the spleen and in other lymphoid tissue suggests stimulation of the B lymphocyte system which is responsible for circulating antibodies. This is borne out by high immunoglobulin levels of all classes-IgG, IgA, and IgM-and a high titre of rheumatoid factor. Antinuclear factor is common and lupus-erythematosus cells may be detected, but D.N.A. binding is not increased, which distinguishes Felty’s syndrome from systemic lupus erythematosus. In a small proportion of patients primary liver disease may cause splenomegaly. Impaired handling of bromsulphthalein and mild increases of alkaline phosphatase and transaminases are found in nearly a quarter of patients.5 The histological basis for these abnormalities varies. A nodular regenerative hyperplasia has been described which might interfere with portal blood-flow.6 There have been a few reports of cirrhosis with portal hypertension and of lymphocytic infiltration of the sinusoidsand portal triads.7,8 Leucopenia in Felty’s syndrome is secondary to splenomegaly. There is a lack of neutrophils rather than lymphocytes, although the lymphocyte-count may be depressed.5 Bone-marrow usually shows increased granulocyte production, with a shift towards more immature forms suggesting increased peripheral destruction. Tests involving stimuli to mobilise neutrophils show decreased reserves. Splenectomy corrects these abnormalities in most patients; peripheral-blood leucocyte count, bone-marrow morphology, and mobilisable neutrophil reserve all return to normal. Postoperatively there is also an improvement in anaemia and a rise in the platelet-count. Whether leucocyte destruction in the spleen results simply from pooling (i.e., hypersplenism) or from a more specific immunological mechanism is not clear. A leucocyte-specific antinuclear factor has been described in Felty’s syndrome but its titre does not correlate with the leucocyte-count and similar antibodies are detected in rheumatoid arthritis without leucopenia.9 Patients with Felty’s syndrome tend to have frequent bacterial infections, particularly pneumonia due to com-
15. Falkow, S., Elwell,
L. P., de Graaff, J. Heffron, F., Mayer, L. in Sexually Transmitted Diseases (edited by R. D. Catterall and C. S. Nicol); p. 120, London 1976. 1. Felty, A. R. Bull. Johns Hopk. Hosp. 1924, 35, 16. 2. Moore, R. A., Brunner, C. M., Sandusky, W. R., Lavell, B. S. Ann. intern.
Med. 1971, 75, 381. 3. Ruderman, M., Miller, L. M., Pinals, R. S. Arthritis Rheum. 1968, 11, 377. 4. Barnes, C. G., Turnbull, A. L., Vernon-Roberts, B. Ann. rheumat. Dis.
1971, 30, 359.
5. Sienknecht, C. W., Urowitz, M. D., Pruzanski, W., Stein, H. B. ibid. 1977,
36, 500. Blendis, L. M., Parkinson, M. C., Shilkin, K. B., Williams, R. Q. J. Med. 1974, 43, 25. 7. Hutt, M. S. R., Richardson, J. S., Staffurth, J. S. ibid. 1951, 20, 57. 8. Ritland, S. Scand. J. Rheumat. 1973, 2, 29. 9. Calabresi, P., Edwards, E. A. and Schilling, R. F. J. clin. Invest. 1959, 38, 6.
2091.
