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RICKETTSIAL ENDOCARDITIS AND IgM GLOBULIN
1108 ESTIMATING SELECTIVITY OF PROTEINURIA SiR,-Dr. Cameron and Dr. Blandfordreport a simple method for assessing glomerular selectivity in the nephrotic syndrome. They used an index, expressed as the ratio of clearance of IgG to that of transferrin (Tf). We wondered whether it was possible to compare this selectivity index with other
methods, expressing
glomerular selectivity in angles and tangents of the slope of the regression line, calculated from the clearances of 5-7 proteins of different molecular weight. Using a similar method of radial immunodiffusion on agar plates to that used by Dr. Cameron and Dr. Blandford, we took as a standard the radius of the disc-precipitates of Fig. I-Selectivity index in six patients both IgG and Tf in a with nephrotic syndrome. mixture of sera from Abscissa= molecular weight (X 10-4). Ordinate=IgG clearance as twenty healthy blood donors. The selectivity percentage of Tf clearance. (Log-log indices were calculated scale.) and plotted on log-log graph-paper as percentage values, related to the clearance of Tf, which we estimated as 100%, and to the molecular weight of Tf and IgG (fig. 1). The tangents of the slopes were determined and plotted as their logarithms on semilogarithmic graph-paper against the index values; this relation has to be linear (fig. 2).
RICKETTSIAL ENDOCARDITIS AND IgM GLOBULIN SIR,-Abacterial endocarditis has always been a difficult
diagnosis, and, as already emphasised by one of US,2 complement-fixation tests for rickettsia resulted in false negatives before the demonstration that a distinct prozone can occur in this test (predicted in patient 1 in the accompanying table, because of the vast excess of IgM globulin found in his serum). Ideally, paired sera showing an increase in titre should be used to confirm a diagnosis of Q fever and these are not usually available by the time endocarditis is suspected. However, the table shows that patients with endocarditis have much higher titres than those without cardiac involvement, so that a single serum can be diagnostic, as recommended by Professor Grist and his colleagues (April 1, p. 727). RESULTS
IN
PATIENTS
WITH
WITHOUT ENDOCARDITIS), CARDIOTOMY SYNDROMES
*
RICKETTSIAL BACTERIAL
INFECTIONS
ENDOCARDITIS,
(WITH AND
AND POST-
Estimated as IgG 1200 mg. per 100 ml. (50-133%), IgA 270 mg. per 100 ml. (47-164%), IgM 100 mg. per 100 ml. (50-150%).
t 1/640 against typhus particles.
Fig. 2-Relation between selectivity index and its tangent. Abscissa=tan 8 X 10. Ordinate= selectivity index. Tan 6= horizontal tangent to slope shown in fig. 1. (Semilogarithmic scale.)
From these graphs the corresponding tangents and angles be read for any index value lower than 1-0. Thus the borderline between high and low selectivity is estimated as the index 0-2,1 this value being equivalent to tan 2-75 and to the angle 6 70°. This tangent of the slope is very similar to those already published for borderline values.2 We believe that Dr. Cameron’s conception of the selectivity index, as he has further shown (April 1, p. 729), is not only a very simple and easily available method in clinical practice but is also sufficiently accurate, and compares well with other methods. JAROSLAV SIMON University Medical Clinic, VLADIMÍR KULICH Charles University, JOSEF SOVA. Pilsen, Czechoslovakia. can
=
1.
2.
Cameron, J. S., Blandford, G. Lancet, 1966, ii, 242. Cameron, J. S., White, R. H. R. ibid. 1965, i, 463. Blainley, J. D., Brewer, D. B., Hardwicke, J. Q. Jl Med. 1960, 29, 235. Joachim, G. R., Cameron, J. S., Schwartz, M., Becker, E. L. J. clin. Invest. 1964, 43, 2332.
The fluorescent-antibody technique of one of us (R.G.S.) has been very helpful and has been positive in all the cases shown as rickettsial infections in the table. The immunoglobulin pattern can also be helpful. The usually raised serum y-globulin in patients with bacterial and rickettsial endocarditis and with the confusing postcardiotomy syndrome is analysed in the table. Patients with bacterial endocarditis usually show about an equal increase (above mean normal) in IgG, IgA, and IgM globulins, a pattern seen throughout over 100 other patients with infectious diseases. Rickettsial endocarditis shows a predominantly IgM response maintained for months, similar to that seen in patients with malaria, trypanosomiasis,3 and bartonellosis’*—all diseases characterised by living organisms within the blood-stream-and it seems likely that it is this continued intravascular stimulation with particulate antigens that maintains the IgM globulin level. The patient with typhus and the patient with Q fever (who had an IgM level of 430%) both had rashes, possibly evidence of blood-stream infection. In contrast, the patients with postcardiotomy syndromes showed only the early IgG globulin increase typical in many autoimmune disorders,5 and this has been a helpful difference after cardiac surgery, when endocarditis is always a possibility. 1. Ball, K. Br. med. J. 1950, i, 1236. 2. McSwiggan, D. A. Lancet, April 29, 1967, p. 956. 3. Masseyeff, R., Lamy, J. Clin. chim. Acta, 1966, 14, 285. 4. Heremans, J. Les globulins sériques du système gamma; p. 283. 5.
Brussels, 1960. Hobbs, J. R. in The Scientific Basis of Medicine: Annual Reviews 1966; p. 123. London, 1966.
1109 Cold agglutinins (IgM) appeared in the sera of the 1st and 3rd of the patients with rickettsial endocarditis (see table), and it seems possible that, with low-output cardiac failure and subsequent cooling of the periphery, such cold agglutinins (rather than emboli) might account for the gangrene of the 1 ears recorded in patients with abacterial endocarditis. We
are
grateful
to
Dr. E. D.
Williams, who demonstrated
rickettsia in the heart-valve of the 1st patient with rickettsial endocarditis (see table), and to all the physicians and surgeons who have provided
sera
and details from their
Royal Postgraduate Medical School, London W.12.
patients.
J. R. HOBBS. R. G. SOMMERVILLE.
Belvidere Hospital, Glasgow E.1. Diagnostic Reference Laboratory, Central Public Health Laboratory,
D. A. MCSWIGGAN.
Colindale Avenue, London N.W.9.
BACTERIAL ENDOCARDITIS SIR,-We agree with Dr. McSwiggan (April 29, p. 956) that a prozone may be found in complement fixation tests in rickettsial endocarditis.2 We routinely test sera at two dilutions (1/8 and 1/80) when screening with antigens liable to give prozones, notably Rickettsia burnetii and the psittacosis group. It is also important to ensure that optimal doses of antigen are used for the test. Department of Infectious Diseases, N. R. GRIST. University of Glasgow. Regional Virus Laboratory, CONSTANCE A. C. ROSS. Ruchill Hospital, Glasgow N.W.
POTASSIUM, GLUCOSE, AND INSULIN
IN MYOCARDIAL INFARCTION SIR,-Following Mittra’s article3 on the results of oral potassium and glucose and injections of insulin (P.G.I.) in preventing arrhythmias after myocardial infarction, a similar trial was organised last year in this large general hospital. All non-diabetic male patients judged clinically to have myocardial infarction who survived longer than two hours after admission were randomly allocated to groups taking either the P.G.!. regimen using Mittra’s doses or a placebo tablet for 14 days. MORTALITY OF 49 PATIENTS ON P.G.I. REGIMEN AND 53 PATIENTS TAKING PLACEBO TABLETS IN THE TWENTY-EIGHT DAYS AFTER MYOCARDIAL INFARCTION
The accompanying table shows that in those patients over 60 years of age in whom the diagnosis was confirmed there was an encouraging reduction in mortality in the 28 days after the infarct. Younger patients were not helped in this small series. The two groups were comparable as regards age and coronary prognostic index.4 The only side-effects of the P.G.I. regimen were mild hypoglycsemia, rapidly responding to additional oral glucose, and weight gain. We feel that this form of therapy rightly merits the further investigation it is receiving in the present cooperative trial. We should like to of Dr. G. G. Gillam.
Selly Oak Hospital, Birmingham 29. 2. 3. 4.
acknowledge
the
guidance
and encouragement
JEREMY PILCHER M. ETISHAMUDIN PETER EXON JOHN MOORE.
Grist, N. R. Int. Congr. trop. Med. Malar. 1964, 3, 277. Mittra, B. Lancet 1965, ii, 607. Peel, A. A. F., Semple, T., Wang, I., Lancaster, W. M., Doll, J. G. Br. Heart J. 1962, 24, 745.
ANTIBODY, ANTIMIND? SIR,-I should like to take exception to your leading article (April 15, p. 828). There is little doubt that it is desirable to apply the concepts of autoimmunity to all and any diseases of unknown mtiology and pathogenesis, such as psychoses, since these concepts tend to stimulate thinking and research. However, it is certainly premature to describe rheumatoid arthritis as an example of " known autoimmune conditions ". There is little or no concrete evidence to implicate autoimmunity in the Etiology and pathogenesis of rheumatoid arthritis. Many of the leading rheumatologists in the world today are leaning away from concepts of autoimmunity and are thinking in terms of other aetiologies, particularly infectious. In view of the present state of knowledge, it would be far more accurate and fruitful to classify rheumatoid arthritis as a disease of unknown xtiology and pathogenesis. Mount Sinai Hospital, HARRY SPIERA. New York 29.
DELAYED HYPERSENSITIVITY SIR,-You describe hypersensitivity reactions as belonging to one of the more baffling areas of medical research (May 6, p. 989). We venture to suggest that our unified theory 12 of growth-control and autoimmunity may help to shed some light on this dark area. We have proposed that the primary and intrinsic function of the complex lymphoid system is that of the central control and coordination of growth. When the target tissue is normally freely infiltrated by blood-borne cells, we postulate that one class of small lymphocyte acts as the mitogenic effector in the regulation of symmetrical mitosis in cells of the target tissue. However, when the target tissue lies behind a blood-tissue barrier, the mitogenic effector is necessarily humoral, and usually it appears to migrate on electrophoresis with the ots-globulin serum-protein fraction. The negative feedback control of growth and tissue size can be represented by the following highly simplified scheme: Effector mitotic-control protein Growth-control element( Affector
----*Tissue
element
tissue-coding factor
Every distinctive tissue in the body (there may be as many as 108 elements) has its own control element, and it is identified by a tissue-coding factor (T.C.F.) which includes histocompatibility antigens, tissue-specific antigens, and tissue mosaic specific antigens. Secreted in humoral lipoprotein form, T.C.F.s serve as affectors in the growth-control system. Forming repeating units of the cell membrane, they identify the target cell with its mitotic-control protein (M.C.P.). It should be emphasised that, in this negative feedback circuit, a decrease in the rate of arrival of afferent T.C.F.s at the lymphoid control element will increase the rate of flow of efferent M.c.p.s. Disturbed-tolerance autoimmunity is manifested when in growth-control spontaneous or induced somatic mutation " stem cells initiates the proliferation of a forbidden-clone "s of cells synthesising humoral or cellular autoantibodies. The attack of autoantibodies (" mutant " M.c.p.s, not immunoglobulins) on cells bearing complementary T.C.F.S gives rise to the symptoms and signs of disease. We deduce 24 that M.c.p.s, primary autoantibodies, T.C.F.S, and classical IgM and IgG immunoglobulins, probably share the same general form of unit molecular structure, and that at least four genes (and perhaps as many as seven) code for the polypeptide chains making up a given unit. The polypeptide Burwell, R. G. Lancet, 1963, ii, 69. Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959. 4. Burch, P. R. J. in Radiation and Ageing (edited by P. J. Lindop and G. A. Sacher); p. 117. London, 1966. 1. 2. 3.
methods, expressing
glomerular selectivity in angles and tangents of the slope of the regression line, calculated from the clearances of 5-7 proteins of different molecular weight. Using a similar method of radial immunodiffusion on agar plates to that used by Dr. Cameron and Dr. Blandford, we took as a standard the radius of the disc-precipitates of Fig. I-Selectivity index in six patients both IgG and Tf in a with nephrotic syndrome. mixture of sera from Abscissa= molecular weight (X 10-4). Ordinate=IgG clearance as twenty healthy blood donors. The selectivity percentage of Tf clearance. (Log-log indices were calculated scale.) and plotted on log-log graph-paper as percentage values, related to the clearance of Tf, which we estimated as 100%, and to the molecular weight of Tf and IgG (fig. 1). The tangents of the slopes were determined and plotted as their logarithms on semilogarithmic graph-paper against the index values; this relation has to be linear (fig. 2).
RICKETTSIAL ENDOCARDITIS AND IgM GLOBULIN SIR,-Abacterial endocarditis has always been a difficult
diagnosis, and, as already emphasised by one of US,2 complement-fixation tests for rickettsia resulted in false negatives before the demonstration that a distinct prozone can occur in this test (predicted in patient 1 in the accompanying table, because of the vast excess of IgM globulin found in his serum). Ideally, paired sera showing an increase in titre should be used to confirm a diagnosis of Q fever and these are not usually available by the time endocarditis is suspected. However, the table shows that patients with endocarditis have much higher titres than those without cardiac involvement, so that a single serum can be diagnostic, as recommended by Professor Grist and his colleagues (April 1, p. 727). RESULTS
IN
PATIENTS
WITH
WITHOUT ENDOCARDITIS), CARDIOTOMY SYNDROMES
*
RICKETTSIAL BACTERIAL
INFECTIONS
ENDOCARDITIS,
(WITH AND
AND POST-
Estimated as IgG 1200 mg. per 100 ml. (50-133%), IgA 270 mg. per 100 ml. (47-164%), IgM 100 mg. per 100 ml. (50-150%).
t 1/640 against typhus particles.
Fig. 2-Relation between selectivity index and its tangent. Abscissa=tan 8 X 10. Ordinate= selectivity index. Tan 6= horizontal tangent to slope shown in fig. 1. (Semilogarithmic scale.)
From these graphs the corresponding tangents and angles be read for any index value lower than 1-0. Thus the borderline between high and low selectivity is estimated as the index 0-2,1 this value being equivalent to tan 2-75 and to the angle 6 70°. This tangent of the slope is very similar to those already published for borderline values.2 We believe that Dr. Cameron’s conception of the selectivity index, as he has further shown (April 1, p. 729), is not only a very simple and easily available method in clinical practice but is also sufficiently accurate, and compares well with other methods. JAROSLAV SIMON University Medical Clinic, VLADIMÍR KULICH Charles University, JOSEF SOVA. Pilsen, Czechoslovakia. can
=
1.
2.
Cameron, J. S., Blandford, G. Lancet, 1966, ii, 242. Cameron, J. S., White, R. H. R. ibid. 1965, i, 463. Blainley, J. D., Brewer, D. B., Hardwicke, J. Q. Jl Med. 1960, 29, 235. Joachim, G. R., Cameron, J. S., Schwartz, M., Becker, E. L. J. clin. Invest. 1964, 43, 2332.
The fluorescent-antibody technique of one of us (R.G.S.) has been very helpful and has been positive in all the cases shown as rickettsial infections in the table. The immunoglobulin pattern can also be helpful. The usually raised serum y-globulin in patients with bacterial and rickettsial endocarditis and with the confusing postcardiotomy syndrome is analysed in the table. Patients with bacterial endocarditis usually show about an equal increase (above mean normal) in IgG, IgA, and IgM globulins, a pattern seen throughout over 100 other patients with infectious diseases. Rickettsial endocarditis shows a predominantly IgM response maintained for months, similar to that seen in patients with malaria, trypanosomiasis,3 and bartonellosis’*—all diseases characterised by living organisms within the blood-stream-and it seems likely that it is this continued intravascular stimulation with particulate antigens that maintains the IgM globulin level. The patient with typhus and the patient with Q fever (who had an IgM level of 430%) both had rashes, possibly evidence of blood-stream infection. In contrast, the patients with postcardiotomy syndromes showed only the early IgG globulin increase typical in many autoimmune disorders,5 and this has been a helpful difference after cardiac surgery, when endocarditis is always a possibility. 1. Ball, K. Br. med. J. 1950, i, 1236. 2. McSwiggan, D. A. Lancet, April 29, 1967, p. 956. 3. Masseyeff, R., Lamy, J. Clin. chim. Acta, 1966, 14, 285. 4. Heremans, J. Les globulins sériques du système gamma; p. 283. 5.
Brussels, 1960. Hobbs, J. R. in The Scientific Basis of Medicine: Annual Reviews 1966; p. 123. London, 1966.
1109 Cold agglutinins (IgM) appeared in the sera of the 1st and 3rd of the patients with rickettsial endocarditis (see table), and it seems possible that, with low-output cardiac failure and subsequent cooling of the periphery, such cold agglutinins (rather than emboli) might account for the gangrene of the 1 ears recorded in patients with abacterial endocarditis. We
are
grateful
to
Dr. E. D.
Williams, who demonstrated
rickettsia in the heart-valve of the 1st patient with rickettsial endocarditis (see table), and to all the physicians and surgeons who have provided
sera
and details from their
Royal Postgraduate Medical School, London W.12.
patients.
J. R. HOBBS. R. G. SOMMERVILLE.
Belvidere Hospital, Glasgow E.1. Diagnostic Reference Laboratory, Central Public Health Laboratory,
D. A. MCSWIGGAN.
Colindale Avenue, London N.W.9.
BACTERIAL ENDOCARDITIS SIR,-We agree with Dr. McSwiggan (April 29, p. 956) that a prozone may be found in complement fixation tests in rickettsial endocarditis.2 We routinely test sera at two dilutions (1/8 and 1/80) when screening with antigens liable to give prozones, notably Rickettsia burnetii and the psittacosis group. It is also important to ensure that optimal doses of antigen are used for the test. Department of Infectious Diseases, N. R. GRIST. University of Glasgow. Regional Virus Laboratory, CONSTANCE A. C. ROSS. Ruchill Hospital, Glasgow N.W.
POTASSIUM, GLUCOSE, AND INSULIN
IN MYOCARDIAL INFARCTION SIR,-Following Mittra’s article3 on the results of oral potassium and glucose and injections of insulin (P.G.I.) in preventing arrhythmias after myocardial infarction, a similar trial was organised last year in this large general hospital. All non-diabetic male patients judged clinically to have myocardial infarction who survived longer than two hours after admission were randomly allocated to groups taking either the P.G.!. regimen using Mittra’s doses or a placebo tablet for 14 days. MORTALITY OF 49 PATIENTS ON P.G.I. REGIMEN AND 53 PATIENTS TAKING PLACEBO TABLETS IN THE TWENTY-EIGHT DAYS AFTER MYOCARDIAL INFARCTION
The accompanying table shows that in those patients over 60 years of age in whom the diagnosis was confirmed there was an encouraging reduction in mortality in the 28 days after the infarct. Younger patients were not helped in this small series. The two groups were comparable as regards age and coronary prognostic index.4 The only side-effects of the P.G.I. regimen were mild hypoglycsemia, rapidly responding to additional oral glucose, and weight gain. We feel that this form of therapy rightly merits the further investigation it is receiving in the present cooperative trial. We should like to of Dr. G. G. Gillam.
Selly Oak Hospital, Birmingham 29. 2. 3. 4.
acknowledge
the
guidance
and encouragement
JEREMY PILCHER M. ETISHAMUDIN PETER EXON JOHN MOORE.
Grist, N. R. Int. Congr. trop. Med. Malar. 1964, 3, 277. Mittra, B. Lancet 1965, ii, 607. Peel, A. A. F., Semple, T., Wang, I., Lancaster, W. M., Doll, J. G. Br. Heart J. 1962, 24, 745.
ANTIBODY, ANTIMIND? SIR,-I should like to take exception to your leading article (April 15, p. 828). There is little doubt that it is desirable to apply the concepts of autoimmunity to all and any diseases of unknown mtiology and pathogenesis, such as psychoses, since these concepts tend to stimulate thinking and research. However, it is certainly premature to describe rheumatoid arthritis as an example of " known autoimmune conditions ". There is little or no concrete evidence to implicate autoimmunity in the Etiology and pathogenesis of rheumatoid arthritis. Many of the leading rheumatologists in the world today are leaning away from concepts of autoimmunity and are thinking in terms of other aetiologies, particularly infectious. In view of the present state of knowledge, it would be far more accurate and fruitful to classify rheumatoid arthritis as a disease of unknown xtiology and pathogenesis. Mount Sinai Hospital, HARRY SPIERA. New York 29.
DELAYED HYPERSENSITIVITY SIR,-You describe hypersensitivity reactions as belonging to one of the more baffling areas of medical research (May 6, p. 989). We venture to suggest that our unified theory 12 of growth-control and autoimmunity may help to shed some light on this dark area. We have proposed that the primary and intrinsic function of the complex lymphoid system is that of the central control and coordination of growth. When the target tissue is normally freely infiltrated by blood-borne cells, we postulate that one class of small lymphocyte acts as the mitogenic effector in the regulation of symmetrical mitosis in cells of the target tissue. However, when the target tissue lies behind a blood-tissue barrier, the mitogenic effector is necessarily humoral, and usually it appears to migrate on electrophoresis with the ots-globulin serum-protein fraction. The negative feedback control of growth and tissue size can be represented by the following highly simplified scheme: Effector mitotic-control protein Growth-control element( Affector
----*Tissue
element
tissue-coding factor
Every distinctive tissue in the body (there may be as many as 108 elements) has its own control element, and it is identified by a tissue-coding factor (T.C.F.) which includes histocompatibility antigens, tissue-specific antigens, and tissue mosaic specific antigens. Secreted in humoral lipoprotein form, T.C.F.s serve as affectors in the growth-control system. Forming repeating units of the cell membrane, they identify the target cell with its mitotic-control protein (M.C.P.). It should be emphasised that, in this negative feedback circuit, a decrease in the rate of arrival of afferent T.C.F.s at the lymphoid control element will increase the rate of flow of efferent M.c.p.s. Disturbed-tolerance autoimmunity is manifested when in growth-control spontaneous or induced somatic mutation " stem cells initiates the proliferation of a forbidden-clone "s of cells synthesising humoral or cellular autoantibodies. The attack of autoantibodies (" mutant " M.c.p.s, not immunoglobulins) on cells bearing complementary T.C.F.S gives rise to the symptoms and signs of disease. We deduce 24 that M.c.p.s, primary autoantibodies, T.C.F.S, and classical IgM and IgG immunoglobulins, probably share the same general form of unit molecular structure, and that at least four genes (and perhaps as many as seven) code for the polypeptide chains making up a given unit. The polypeptide Burwell, R. G. Lancet, 1963, ii, 69. Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959. 4. Burch, P. R. J. in Radiation and Ageing (edited by P. J. Lindop and G. A. Sacher); p. 117. London, 1966. 1. 2. 3.