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Meningococcal meningitis in a woman with inherited deficiency of the ninth component of complement
CLINICAL
IMMUNOLOGY
AND
IMMUNOPATHOLOGY
28, 413-417 (1983)
Meningococcal Meningitis in a Woman with Inherited Deficiency of the Ninth Component of Complement DOUGLAS P. FINE,~
HENRY
GEWURZ,
MCLEOD
GRIFFISS,
AND
THOMAS F. LINT The Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77550; The Department of Immunology/Microbiology, Rush Medical Center, Chicago, Illinois 60612; and The Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115
woman presented with acute pyogenic meningitis; Neisseria meningiwas isolated from blood on culture. Complement assays demonstrated a hemolytic complement titer of 12 u/ml; individual components were normal except for C9, which was absent by both functional and antigenic analysis. Family studies were consistent with a familial C9 deficiency, autosomal co-dominant inheritance. This is the first report of the association of C9 deficiency and disseminated neisseriaf infection; whether this complement deficiency predisposes to the neisserial infection remains to be established. A 17-year-old tidis group C
INTRODUCTION
Inherited deficiency of the ninth component of complement, C9, was the last of the classical component deficiencies to be described. Only a few cases have been reported and all have been healthy (l-4). Specifically, reported C9-deficient patients have not demonstrated the propensity to disseminated infection with Neisseria meningitidis or N. gonorrhoeae that is characteristic of other terminalcomponent deficiencies (5-7). Because of this lack of documented neisserial infections and because lysis of erythrocytes (2) and neisseria (4) occurs in the absence of C9 (albeit more slowly than in the presence of that molecule), it has been suggested (4) that C9 deficiency may not convey the same propensity to disseminated meningococcal and gonococcal infections that other terminal-component deficiencies do. However, we report a young woman, completely deficient in C9, who presented with meningococcal meningitis and bacteremia. CASE REPORT
A 17-year-old Hispanic women, previously in excellent health, presented with a l-day history of global headache and fever. She subsequently developed paresthesias of the right arm and leg. On the morning of admission, she developed nausea, vomiting, photophobia, and progressive confusion. On examination, she was found to be disoriented, combative, with nuchal rigidity and opisthotonic posturing. She did not have focal neurological signs, seizures, or petechiae. t Address reprint requests to Dr. Fine, Infectious Disease Section 11lC, V.A. Medical Center, 921 NE 13th Street, Oklahoma City, Oklahoma 73104. 413 0090-1229/83 Copyright AU rights
$1.50
@ 1983 by Academic Press, Inc. of reproduction in any form reserved
414
FINE
ET AL
Initial peripheral white blood cell count was 27,200/~1 (81% segmented neutrophils, 18% band forms, 1% lymphocytes), platelet count 250,OOO/l.~l, hemoglobin 13.5 g/dl, and hematocrit 39.9%. Initial spinal fluid glucose was 49 mg/dl (simultaneous peripheral glucose, 104 mg/dl), protein 123 mg/dl, erythrocytes 8001 ~1, and white blood cells 12OOil*.I (73% neutrophils). Blood culture yielded N. meningitidis group C. On parenteral aqueous penicillin G, the patient improved. She was oriented by her second hospital day and afebrile by the fifth day. She was discharged after 14 days therapy and has remained well. The patient’s parents and four siblings were alive and healthy. There was no family history of serious infections, other illnesses, or early deaths. MATERIALS
AND METHODS
Serum. Blood was obtained by peripheral venipuncture and allowed to clot at 37°C for 1 hr, after which serum was separated, divided into aliquots, and frozen at - 70°C until use. The patient’s father refused to donate blood for study. Complement assays. Hemolytic whole-complement assays (CHSO) were performed according to the method of Rapp and Borsos (8). Hemolytic titrations of Cl, C4, and C2 (8); C3, C5, and C6 (9); C7 (IO); and C8 and C9 (2) were performed as described. Factor B levels were determined by radial immunodiffusion (11). C9 antigenic levels were measured by rocket immunoelectrophoresis (12, 13). Antibody titers. Antibodies to group C meningococcal polysaccharide were determined by the radioactive antigen-binding assay of Brandt and colleagues (14, 15). Results were expressed as nanograms of polysaccharide bound per microliter of serum. Acute serum was not available for this assay, which was instead performed on serum obtained 7 days after admission. RESULTS Complement values. The patient had a CH50 of 12 u/ml, which could be restored to normal by addition of purified human C9 obtained from Cordis Laboratories, Miami, Florida (data not shown). Hemolytic assays demonstrated normal or near normal values for Cl through CS (Table 1); factor B level (radial immunodiffusion) was 195 mg/dl (normal range 175-275 mg/dl). In contrast, C9 activity was undetectable in the patient’s serum by hemolytic assay (Table 1) and C9 antigen was less than 2% of a normal control by rocket immunoelectrophoresis (Table 2). The patient’s mother and 23-year-old brother both had approximately halfnormal serum concentrations of C9 antigen; the mother’s serum also had about half-normal C9 hemolytic activity as well (Table 2). Other family members had normal complement titers. Meningococcal antibody. The patient’s serum, obtained 8 days into illness, contained sufficient antibody to bind 112.4 ng group C polysaccharide per 50 l.~l serum. DISCUSSION
We describe a patient with familial deficiency of C9. As with the very few previously reported cases (l-4), inheritance appeared to be autosomal codomi-
MENINGOCOCCAL
MENINGITIS
AND
TABLE 1 COMPONENT TITRATIONS ON SERUM WITH MENINGOCOCCAL MENINGITIS
COMPLEMENT
Hemolytic Component
415
C9 DEFICIENCY
FROM PATIENT
assay0
Patient
Cl c4 c2 c3 CS C6 Cl C8 c9
79,629 157,366 297 3,081 6,537 461 6,658 77,470 < 10
Normal
(82)b (61) (81) (81) (97) (82) (78) (100) (<0.2)
L2Results are expressed as the reciprocal of the titer. b Numbers in parentheses indicate the patient’s value neously performed normal value.
96,644 256,330 363 3,818 6,743 510 8,507 77,489 5,087
expressed
as a percentage
of the simulta-
nant: the patient’s mother and one sibling had serum C9 values approximately half of normal. Regrettably, the father could not be tested. The apparently heterozygous 23-year-old brother had nearly normal hemolytic C9 levels; however, C9 antigen was clearly low. C9 deficiency was the last congenital classical pathway component deficiency to be described. It has been suggested (2) that this fact reflects the ability of the components Cl-8 to mediate erythrocyte lysis albeit slowly; thus, hemolytic complement titers of CPdeficient serum are low but not zero, a situation demonstrated by our patient. Patients with deficiencies of C3, 5-7, or 8 have a remarkable predisposition to disseminated gonococcal or meningococcal disease (5-7). The reported people with C9 deficiency though few, have been healthy-and specifically have not had WHOLE
Subject Mother Sister Brother Brother Propositus Sister Normal
COMPLEMENT
AND C9 LEVELS Age (years) 48 25 23 21 17 10 -
TABLE IN SERUM CHSO (U/ml) 38 35 23 48 12 37 -
2 FROM PATIENT
AND HER FAMILY
MEMBERS
c9 Hemolytic” 5,220 12,143 10,158 16,905
(43) (100) (84) (140) (76)
Antigenicb 63 92 50 84 <2 100 92c
u Results are expressed as the reciprocal of the dilution. Numbers in parentheses represent the percentage of a simultaneously determined control serum. b Results are expressed as the percentage of a standard serum sample and are representative of three determinations. c This value represents a single normal serum compared to a serially diluted standard on that day. Mean (k 1 SD) for 12 normal set-a so assayed on several occasions is 100 + 22%.
416
FINE ET AL.
neisserial infections. Harriman et al. (4) have quite clearly demonstrated that C9deficient serum kills Neisseria just as it can lyse erythrocytes-as completely as can normal serum but more slowly. They postulated that C9 deficiency either would not predispose to disseminated neisserial infection or would have only a limited deleterious effect on host defenses. Our case is therefore important for two reasons. First, since only a few patients have been reported with C9 deticiency, newly recognized families should be described. Second, and more importantly, this case represents the first reported associated of C9 deficiency and disseminated neisserial infection. The C9 deticiency was confirmed by both hemolytic and antigenic analyses; the neisserial infection, by isolation of N. meningitidis group C from blood cultures in a patient with acute meningitis. We would emphasize that our data do not, by any means, prove that the CY deficiency predisposed to the meningococcal disease. Meningococcal meningitis is not rare in adolescents, such as our patient. Only when greater numbers of C9deficient patients have been reported would any association be evident on statistical grounds. Another way to strengthen any claims of association would be to demonstrate that neisserial dissemination occurred in the face of serum antibodies to the organism’s capsular polysaccharide, since it is well established that such antibodies are protective in the presence of adequate complement (16). Unfortunately, our first serum antibody determination was obtained on the sample from Day 8 of illness; thus, we cannot say whether the titer observed represented a primary antibody response or preexisting antibody. The actual value was well within the range observed in healthy volunteers 14 days after vaccination with group C polysaccharide ( 15). Even if our data indicated a predisposition to neisserial infection, we would not be able to say that C9 deficiency carried as great a risk as, say, C6 deficiency (5). Therefore, more CPdeficient individuals will need to be studied and reported before any conclusions can be made. In the meantime, our experience would suggest that clinicians should manage C9 deficiency as if it might carry a risk of meningococcal disease. ACKNOWLEDGMENTS The authors wish to thank Kim A. Delano for expert technical assistance and Arnett Brown for manuscript typing. This work was supported in part by a grant (ROI CA 26143) from the National Cancer Institute, DHHS. H. G. holds the Thomas J. Coogan, Sr., Chair in Immunology at Rush Medical Center, established by Marjorie Lindheimer Everett. T.F.L. is a recipient of a Research Career Development Award (K04-CAOO558) from the NIH.
REFERENCES 1. 2. 3. 4.
Kitamura, H., Nagaki, K., and Inai, S., J. C/in. Lab. Zmmunol. 6, 7. 1981. Lint, T. F., Zeitz, H. J.. and Gewurz, H., J. Zmmunol. 125, 2252, 1980. Lint, T. F., Zeitz, H. J., and Gewurz, H.. lmmunobiology 158, 107, 1980. Harriman, G. R., Esser. A. F., Podack, E. R., Wunderlich, A. C., Braude, A. I., Lint. T. F., and Curd, J. G., J. Immunol. 127, 2386, 1981. 5. Lim. D., Gewurz, A., Lint, T. F., Ghaze. M., Sepheri, B., and Gewurz, H.. J. Pediutr. 89, 42, 1976. 6. Petersen, B. H., Lee, T. J., Snyderman, R., and Brooks, G. F.. Ann. Intern. Med. 90, 917. 1979.
MENINGOCOCCAL
MENINGITIS
AND C9 DEFICIENCY
417
7. Fine, D. P., “Complement and Infectious Diseases,” pp. 32-35, CRC Press, Boca Raton, Fla., 1981. 8. Rapp, H. J., and Borsos, T., “Molecular Basis of Complement Action,” Appleton-CenturyCrofts, New York, 1970. 9. Lachman, P. J., and Hobart, M. J., In “Handbook of Experimental Immunology” (D. M. Weir, Ed.), pp. 5A, l-23, Blackwell, Oxford, 1978. 10. Nemerow, G. R., Gewurz, H., Osofsky, S. Cl., and Lint, T. F., J. Clin. Invest. 61, 1602, 1978. 11. Gewurz, H., and Suyehira, L. A., In “Manual of Clinical Immunology” (N. R. Rose, and H. Friedman, Eds.), pp. 163-174, Amer. Sot. Microbial., Washington, D. C., 1980. 12. Ouchterlony, O., and Nilsson, L. A., In “Handbook of Experimental Immunology” (D. M. Weir, Ed.). pp. 19, l-44, Blackwell, Oxford, 1978. 13. Biesecker G., and Miiller-Eberhard, H. J., J. Zmmunol. 124, 1291, 1980. 14. Brandt, B. L., Wyle, F. A., and Artenstein, M. S., J. Zmmunol. 108, 913, 1972. 15. Brandt. B. L., Artenstein, M. S., and Smith, C. D., Infect. Zmmun. 8, 590, 1973. 16. Goldschneider, I., Gotschlich, E. C., and Artenstein, M. S., J. Exp. Med. 129, 1307, 1969. Received January 13, 1983; accepted with revisions February 7, 1983
IMMUNOLOGY
AND
IMMUNOPATHOLOGY
28, 413-417 (1983)
Meningococcal Meningitis in a Woman with Inherited Deficiency of the Ninth Component of Complement DOUGLAS P. FINE,~
HENRY
GEWURZ,
MCLEOD
GRIFFISS,
AND
THOMAS F. LINT The Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77550; The Department of Immunology/Microbiology, Rush Medical Center, Chicago, Illinois 60612; and The Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115
woman presented with acute pyogenic meningitis; Neisseria meningiwas isolated from blood on culture. Complement assays demonstrated a hemolytic complement titer of 12 u/ml; individual components were normal except for C9, which was absent by both functional and antigenic analysis. Family studies were consistent with a familial C9 deficiency, autosomal co-dominant inheritance. This is the first report of the association of C9 deficiency and disseminated neisseriaf infection; whether this complement deficiency predisposes to the neisserial infection remains to be established. A 17-year-old tidis group C
INTRODUCTION
Inherited deficiency of the ninth component of complement, C9, was the last of the classical component deficiencies to be described. Only a few cases have been reported and all have been healthy (l-4). Specifically, reported C9-deficient patients have not demonstrated the propensity to disseminated infection with Neisseria meningitidis or N. gonorrhoeae that is characteristic of other terminalcomponent deficiencies (5-7). Because of this lack of documented neisserial infections and because lysis of erythrocytes (2) and neisseria (4) occurs in the absence of C9 (albeit more slowly than in the presence of that molecule), it has been suggested (4) that C9 deficiency may not convey the same propensity to disseminated meningococcal and gonococcal infections that other terminal-component deficiencies do. However, we report a young woman, completely deficient in C9, who presented with meningococcal meningitis and bacteremia. CASE REPORT
A 17-year-old Hispanic women, previously in excellent health, presented with a l-day history of global headache and fever. She subsequently developed paresthesias of the right arm and leg. On the morning of admission, she developed nausea, vomiting, photophobia, and progressive confusion. On examination, she was found to be disoriented, combative, with nuchal rigidity and opisthotonic posturing. She did not have focal neurological signs, seizures, or petechiae. t Address reprint requests to Dr. Fine, Infectious Disease Section 11lC, V.A. Medical Center, 921 NE 13th Street, Oklahoma City, Oklahoma 73104. 413 0090-1229/83 Copyright AU rights
$1.50
@ 1983 by Academic Press, Inc. of reproduction in any form reserved
414
FINE
ET AL
Initial peripheral white blood cell count was 27,200/~1 (81% segmented neutrophils, 18% band forms, 1% lymphocytes), platelet count 250,OOO/l.~l, hemoglobin 13.5 g/dl, and hematocrit 39.9%. Initial spinal fluid glucose was 49 mg/dl (simultaneous peripheral glucose, 104 mg/dl), protein 123 mg/dl, erythrocytes 8001 ~1, and white blood cells 12OOil*.I (73% neutrophils). Blood culture yielded N. meningitidis group C. On parenteral aqueous penicillin G, the patient improved. She was oriented by her second hospital day and afebrile by the fifth day. She was discharged after 14 days therapy and has remained well. The patient’s parents and four siblings were alive and healthy. There was no family history of serious infections, other illnesses, or early deaths. MATERIALS
AND METHODS
Serum. Blood was obtained by peripheral venipuncture and allowed to clot at 37°C for 1 hr, after which serum was separated, divided into aliquots, and frozen at - 70°C until use. The patient’s father refused to donate blood for study. Complement assays. Hemolytic whole-complement assays (CHSO) were performed according to the method of Rapp and Borsos (8). Hemolytic titrations of Cl, C4, and C2 (8); C3, C5, and C6 (9); C7 (IO); and C8 and C9 (2) were performed as described. Factor B levels were determined by radial immunodiffusion (11). C9 antigenic levels were measured by rocket immunoelectrophoresis (12, 13). Antibody titers. Antibodies to group C meningococcal polysaccharide were determined by the radioactive antigen-binding assay of Brandt and colleagues (14, 15). Results were expressed as nanograms of polysaccharide bound per microliter of serum. Acute serum was not available for this assay, which was instead performed on serum obtained 7 days after admission. RESULTS Complement values. The patient had a CH50 of 12 u/ml, which could be restored to normal by addition of purified human C9 obtained from Cordis Laboratories, Miami, Florida (data not shown). Hemolytic assays demonstrated normal or near normal values for Cl through CS (Table 1); factor B level (radial immunodiffusion) was 195 mg/dl (normal range 175-275 mg/dl). In contrast, C9 activity was undetectable in the patient’s serum by hemolytic assay (Table 1) and C9 antigen was less than 2% of a normal control by rocket immunoelectrophoresis (Table 2). The patient’s mother and 23-year-old brother both had approximately halfnormal serum concentrations of C9 antigen; the mother’s serum also had about half-normal C9 hemolytic activity as well (Table 2). Other family members had normal complement titers. Meningococcal antibody. The patient’s serum, obtained 8 days into illness, contained sufficient antibody to bind 112.4 ng group C polysaccharide per 50 l.~l serum. DISCUSSION
We describe a patient with familial deficiency of C9. As with the very few previously reported cases (l-4), inheritance appeared to be autosomal codomi-
MENINGOCOCCAL
MENINGITIS
AND
TABLE 1 COMPONENT TITRATIONS ON SERUM WITH MENINGOCOCCAL MENINGITIS
COMPLEMENT
Hemolytic Component
415
C9 DEFICIENCY
FROM PATIENT
assay0
Patient
Cl c4 c2 c3 CS C6 Cl C8 c9
79,629 157,366 297 3,081 6,537 461 6,658 77,470 < 10
Normal
(82)b (61) (81) (81) (97) (82) (78) (100) (<0.2)
L2Results are expressed as the reciprocal of the titer. b Numbers in parentheses indicate the patient’s value neously performed normal value.
96,644 256,330 363 3,818 6,743 510 8,507 77,489 5,087
expressed
as a percentage
of the simulta-
nant: the patient’s mother and one sibling had serum C9 values approximately half of normal. Regrettably, the father could not be tested. The apparently heterozygous 23-year-old brother had nearly normal hemolytic C9 levels; however, C9 antigen was clearly low. C9 deficiency was the last congenital classical pathway component deficiency to be described. It has been suggested (2) that this fact reflects the ability of the components Cl-8 to mediate erythrocyte lysis albeit slowly; thus, hemolytic complement titers of CPdeficient serum are low but not zero, a situation demonstrated by our patient. Patients with deficiencies of C3, 5-7, or 8 have a remarkable predisposition to disseminated gonococcal or meningococcal disease (5-7). The reported people with C9 deficiency though few, have been healthy-and specifically have not had WHOLE
Subject Mother Sister Brother Brother Propositus Sister Normal
COMPLEMENT
AND C9 LEVELS Age (years) 48 25 23 21 17 10 -
TABLE IN SERUM CHSO (U/ml) 38 35 23 48 12 37 -
2 FROM PATIENT
AND HER FAMILY
MEMBERS
c9 Hemolytic” 5,220 12,143 10,158 16,905
(43) (100) (84) (140) (76)
Antigenicb 63 92 50 84 <2 100 92c
u Results are expressed as the reciprocal of the dilution. Numbers in parentheses represent the percentage of a simultaneously determined control serum. b Results are expressed as the percentage of a standard serum sample and are representative of three determinations. c This value represents a single normal serum compared to a serially diluted standard on that day. Mean (k 1 SD) for 12 normal set-a so assayed on several occasions is 100 + 22%.
416
FINE ET AL.
neisserial infections. Harriman et al. (4) have quite clearly demonstrated that C9deficient serum kills Neisseria just as it can lyse erythrocytes-as completely as can normal serum but more slowly. They postulated that C9 deficiency either would not predispose to disseminated neisserial infection or would have only a limited deleterious effect on host defenses. Our case is therefore important for two reasons. First, since only a few patients have been reported with C9 deticiency, newly recognized families should be described. Second, and more importantly, this case represents the first reported associated of C9 deficiency and disseminated neisserial infection. The C9 deticiency was confirmed by both hemolytic and antigenic analyses; the neisserial infection, by isolation of N. meningitidis group C from blood cultures in a patient with acute meningitis. We would emphasize that our data do not, by any means, prove that the CY deficiency predisposed to the meningococcal disease. Meningococcal meningitis is not rare in adolescents, such as our patient. Only when greater numbers of C9deficient patients have been reported would any association be evident on statistical grounds. Another way to strengthen any claims of association would be to demonstrate that neisserial dissemination occurred in the face of serum antibodies to the organism’s capsular polysaccharide, since it is well established that such antibodies are protective in the presence of adequate complement (16). Unfortunately, our first serum antibody determination was obtained on the sample from Day 8 of illness; thus, we cannot say whether the titer observed represented a primary antibody response or preexisting antibody. The actual value was well within the range observed in healthy volunteers 14 days after vaccination with group C polysaccharide ( 15). Even if our data indicated a predisposition to neisserial infection, we would not be able to say that C9 deficiency carried as great a risk as, say, C6 deficiency (5). Therefore, more CPdeficient individuals will need to be studied and reported before any conclusions can be made. In the meantime, our experience would suggest that clinicians should manage C9 deficiency as if it might carry a risk of meningococcal disease. ACKNOWLEDGMENTS The authors wish to thank Kim A. Delano for expert technical assistance and Arnett Brown for manuscript typing. This work was supported in part by a grant (ROI CA 26143) from the National Cancer Institute, DHHS. H. G. holds the Thomas J. Coogan, Sr., Chair in Immunology at Rush Medical Center, established by Marjorie Lindheimer Everett. T.F.L. is a recipient of a Research Career Development Award (K04-CAOO558) from the NIH.
REFERENCES 1. 2. 3. 4.
Kitamura, H., Nagaki, K., and Inai, S., J. C/in. Lab. Zmmunol. 6, 7. 1981. Lint, T. F., Zeitz, H. J.. and Gewurz, H., J. Zmmunol. 125, 2252, 1980. Lint, T. F., Zeitz, H. J., and Gewurz, H.. lmmunobiology 158, 107, 1980. Harriman, G. R., Esser. A. F., Podack, E. R., Wunderlich, A. C., Braude, A. I., Lint. T. F., and Curd, J. G., J. Immunol. 127, 2386, 1981. 5. Lim. D., Gewurz, A., Lint, T. F., Ghaze. M., Sepheri, B., and Gewurz, H.. J. Pediutr. 89, 42, 1976. 6. Petersen, B. H., Lee, T. J., Snyderman, R., and Brooks, G. F.. Ann. Intern. Med. 90, 917. 1979.
MENINGOCOCCAL
MENINGITIS
AND C9 DEFICIENCY
417
7. Fine, D. P., “Complement and Infectious Diseases,” pp. 32-35, CRC Press, Boca Raton, Fla., 1981. 8. Rapp, H. J., and Borsos, T., “Molecular Basis of Complement Action,” Appleton-CenturyCrofts, New York, 1970. 9. Lachman, P. J., and Hobart, M. J., In “Handbook of Experimental Immunology” (D. M. Weir, Ed.), pp. 5A, l-23, Blackwell, Oxford, 1978. 10. Nemerow, G. R., Gewurz, H., Osofsky, S. Cl., and Lint, T. F., J. Clin. Invest. 61, 1602, 1978. 11. Gewurz, H., and Suyehira, L. A., In “Manual of Clinical Immunology” (N. R. Rose, and H. Friedman, Eds.), pp. 163-174, Amer. Sot. Microbial., Washington, D. C., 1980. 12. Ouchterlony, O., and Nilsson, L. A., In “Handbook of Experimental Immunology” (D. M. Weir, Ed.). pp. 19, l-44, Blackwell, Oxford, 1978. 13. Biesecker G., and Miiller-Eberhard, H. J., J. Zmmunol. 124, 1291, 1980. 14. Brandt, B. L., Wyle, F. A., and Artenstein, M. S., J. Zmmunol. 108, 913, 1972. 15. Brandt. B. L., Artenstein, M. S., and Smith, C. D., Infect. Zmmun. 8, 590, 1973. 16. Goldschneider, I., Gotschlich, E. C., and Artenstein, M. S., J. Exp. Med. 129, 1307, 1969. Received January 13, 1983; accepted with revisions February 7, 1983