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and clinical trials of this unconventional method of CPRseem warranted.

We thank the Emergency Care Research Institute (Waltham, Mas-sachusetts) for the card-programmable cardiopulmonary resuscitationequipment, made to their specifications by Michigan Instruments, Inc.(Ann Arbor).

Requests for reprints should be addressed to M. L. W., Johns Hop-kins Medical Institutions, Baltimore, Maryland 21205, U.S.A.

Supported by grant no. P 50 HL 17655-03 from the National Heart,Lung and Blood Institute, Bethesda, Maryland. N. C. is a fellow of theMaryland Heart Association.

REFERENCES

1. Kouwenhoven WB, Jude JR, Knickerbocker GC. Closed heart cardiac mas-sage. JAMA 1960; 173: 1064-67.

2. Weale FE, Rothwell-Jackson RL. The efficiency of cardiac massage. Lancet1962; i: 990-92.

3. Rudikoff MT, Maughan WL, Effron M, Freund P, Weisfeldt ML. Mechan-isms of blood flow during cardiopulmonary resuscitation. Circulation

1977; 56: suppl III, 97 abstr; and Circulation (in press).4. Criley JM, Blaufuss AN, Kissel GL. Cough-induced cardiac compression.

JAMA 1976; 236: 1246-50.5. MacKenzie GJ, Taylor SH, McDonald AH, Donald KW. Hæmodynamic

effects of external cardiac compression. Lancet 1964; i: 1342-45.6. Thomson JE, Stenlund RR, Rowe GG. Intracardiac pressures during closed

chest cardiac massage. JAMA 1968; 205: 46-48.7. Chandra N, Rudikoff M, Tsitlik J, Weisfeldt ML. Augmentation of carotid

flow during cardiopulmonary resuscitation (CPR) in the dog by simul-taneous compression and ventilation with high airway pressure. Am J Car-diol 1979; 43: 422 abstr.

8. Wilder RJ, Weir D, Rush BF, Ravitch MM. Method of coordinating ventila-tion and closed chest cardiac massage in the dog. Surgery 1963; 53:186-94.

9. Harris LC, Kirimli B, Safar P. Ventilation-cardiac compression rates andratios in cardiopulmonary resuscitation. Anesthesiology 1967; 28:806-12.

10. Taylor GJ, Tucker WM, Greene HL, Rudikoff MT, Weisfeldt ML. Impor-tance of prolonged compression duration during cardiopulmonary resusci-tation in man. N Engl J Med 1977; 296: 1515-17.

Hypothesis

IS AUTOIMMUNITY A COMMONDENOMINATOR IN IMMUNE COMPLEX

DISEASES?

EDMUND J. LEWIS JIMMY L. ROBERTS

Section of Nephrology, Department of Medicine,Rush-Presbyterian-St. Luke’s Medical Center,

Chicago, Illinois 60612, U.S.A.

Summary In normal circumstances, antibodiesreactive with native DNA appear in the

plasma during the course of many clinical conditions as-sociated with inflammation. These antibodies seem to beelaborated in response to the release of exceptionalamounts of DNA by nucleated cells. As a result, DNA/anti-DNA complexes can be demonstrated in the cryo-precipitable fraction of plasma from patients with vari-ous inflammatory diseases. A significant proportion ofthese immune complexes contain low-molecular-weightpolynucleotide antigens. These polynucleotides are de-rived from DNA which has been degraded by plasmaDNAase. Because of the digestion of DNA in the plasmaa spectrum of antigen/antibody complexes forms. Whilelarge, relatively insoluble complexes would be expectedto be rapidly cleared by the reticuloendothelial system,low-molecular-weight complexes are removed more

slowly. It is proposed that the action of plasma DNAaseupon both free and immune bound-DNA can lead to a

preponderance of small, soluble, polynucleotide/anti-DNA complexes. Under appropriate conditions of vascu-lar permeability, these soluble complexes may be de-posited in vessel walls. Hence, regardless of the initiatinginfectious or inflammatory agent, polynucleotide anti-gen/anti-DNA antibody complexes form and can resultin immune-mediated inflammatory phenomena indiverse disease states.

BACKGROUND

ALTHOUGH reactivity of the immunological systemwith autoantigens is recognised in many forms of tissuedamage, the presence of antibodies directed againstnative DNA antigens is generally believed to be abnor-

mal and characteristic of autoimmune disease. The de-monstration of B lymphocytes which possess surface ariti-gen-binding sites for native DNA in normal, subjects hasprovided evidence that immune reactivity with extra-cellular DNA may be a normal function. Anti-native-DNA antibodies and double stranded DNA have beenfound in the cryoprecipitable fraction of plasma im-munoglobulins isolated from patients with diverse in-flammatory disorders, including otherwise normal indi-with intercurrent infectious diseases. Theseobservations support the notion that anti-DNA antibodysynthesis and the formation of DNA/anti-DNA com-plexes can occur during the inflammatory process.

Production of antibodies to native DNA has beenobserved in species other than man. In mice antibodiesto native and single-stranded DNA appeared in the cir-culation subsequent to experimental conditions whichcause DNA release.3 The concept of normal auto-reactiv-

ity to DNA and other nuclear antigens casts a new lightupon the importance of the formation of anti-DNA anti-bodies in clinical situations other than systemic lupuserythematosus (SLE). One is led to reject the concept ofa "forbidden clone" of lymphoid cells as the explanationfor the appearance of these autoantibodies. Rather, wepropose that the elaboration of anti-DNA antibodies

may be part of a homoeostatic reaction to the release ofDNA into the circulation.

HYPOTHESIS

Infection leads to the formation of immune complexescontaining foreign microbial antigens. However, the roleof these antigens has not been consistently established inimmune deposits. We propose that a common processcan underlie the pathogenetic events leading to many anti-gen/antibody-complex-mediated diseases. Cellular injuryresulting from infectious or inflammatory processeswould be expected to cause the release of DNA into thecirculation. DNA is enzymatically degraded to polynu-cleotides by plasma DNAase. Small polynucleotides de-rived from released DNA may not be cleared from thecirculation as rapidly as are larger molecules. Thesepolynucleotides stimulate anti-DNA antibody produc-tion. These latter immunoglobulins aid removal ofpolynucleotides from the blood. However, the low-molec-

179

ular-weight, soluble complexes derived from these reac-tions are cleared slowly. This allows the complexes tocirculate and be deposited within vessel walls, wherethey may participate in immunopathological reactions.Immune-complex-mediated phenomena in diverse clini-cal situations may thus have a common pathogenesisbased. upon immune reactivity to DNA antigen.

SUPPORTING OBSERVATIONS

Anti-native DNA antibodies and DNA/anti-nativeDNA complexes are not exclusive to patients with SLE.Antibodies to native DNA have been noted in patientswith other diseases, notably chronic hepatic diseases.4-6Cryoprecipitable DNA and anti-native-DNA antibodiesare found in the plasma in diverse inflammatory dis-orders, a number of which are associated with immune-complex-mediated glomerulonephritis.2 A major com-ponent of these cryoglobulins are of relatively lowmolecular weight, the sedimentation constant being inthe range 7-10 S.7 DNA and anti-native-DNA anti-bodies in cryoprecipitates appear to be in intimate con-tact, implying that they are immune complexes. Theparticipation of the polynucleotide as the antigenic com-ponent of immune complexes is suggested by the obser-vation that the immune complex does not fully reactwith ethidium bromide, a dye which normally interca-lates between the double helices.8 Protease digestion ofthe constituent anti-DNA antibodies allows this reactionbetween ethidium bromide and polynucleotides to pro-ceed to completion. In addition, DNA in cryoglobulinscannot be completely digested by DNAase. This impliesthat the antibodies are protecting the sites on the DNAmolecule which are susceptible to enzymatic activity.When the immunoglobulin component of cryoprecipi-table DNA/anti-DNA is enzymatically destroyed, diges-tion by DNAase becomes complete. Cryoglobulins de-rived from many immune-complex diseases containDNA and anti-DNA in amounts comparable to thoseseen in SLE.2 In the Raji cell assay and solid-phase Clqbinding assay, these cryoglobulins react in the same wayas known immune complexes. This accords with the con-cept that these reactants are indeed components of com-

plement-fixing immune complexes. 7Immune complexes isolated from the plasma have a

surprisingly low ultracentrifuge sedimentation con-

stant.9-’Z We found DNA and anti-native-DNA anti-bodies in the 7S immune complex-reactive material iso-lated from patients with non SLE-cryoglobulinsemias, aswell as in similar material from patients with SLE.13The presence of such antibodies in the serum of patientswith SLE led Agnello et awl. to propose the existence ofcomplexes composed of small polynucleotides and anti-native-DNA antibodies.While the precise molecular weight of antigenic DNA

isolated from immune complexes is not known, some evi-dence derived from SLE patients confirms that it can berelatively low. Bruneau et al. dissociated immune com-plexes from the plasma of patients with SLE by treat-ment with acid pH.14 They found DNA dissociated fromthese immune complexes in the 4-6S ultracentrifugefractions. Winfield et al. also described 7S DNA in theplasma of patients with SLE.15 These findings accordwitbj experimental evidence that DNA released into the

circulation in endotoxin-treated mice appears in the4-6S fractions of the plasma.16 It seems that polynucleo-tide-anti-DNA complexes can be of low molecular weight.The molecular weight of the polynucleotide-anti-DNAcomplexes helps to determine the ability of the reticulo-endothelial system to clear complexes from the circulation.Lower-molecular-weight immune complexes may persistin the circulation and be deposited in vessel walls. 17 I

In view of the presence of DNAase in the blood, it islikely that DNA released from cells is subjected to enzy-matic degradation. Hence, the clearance of releasedDNA can involve both enzyme and antibody mediatedsystems. In SLE, DNAase activity is present in inverseproportion to anti-DNA antibody concentrations. 18These results raise the interesting possibility that anti-DNA antibodies may be formed when the homceostatic

enzyme-mediated DNA degradative system is inadequatefor a given substrate load. The interaction of DNA

antigen with DNAase and subsequent reactivity withanti-DNA antibody can thus lead to the presence of rela-tively small complexes.The premise that small circulating polynucleotide/

anti-native DNA complexes may ultimately result in im-portant immunological vascular damage in states otherthan SLE finds support in several animal models. Endo-toxin-induced release of DNA causes a thousandfold in-crease in circulating DNA levels in mice.3 Later, anti-DNA antibodies developed in these animals. The

presence of anti-DNA in immune deposits in the miceglomeruli suggested that DNA/anti-DNA complexescould form in situ along the glomerular basement mem-brane.16 Weening et al.19 have also shown that glomeru-lar immune damage can be mediated by antibody to nuc-lear antigens. They produced glomerulonephritis in ratsby administering mercuric chloride. Immune-complex-mediated glomerulopathy often develops in rats surviv-ing acute mercury intoxication. The antigenic nature ofthe immune complex in this experimental situation hasremained obscure. However, Weening et al. found thatthe immune complexes were deposited in the glomeruluswhen antinuclear antibodies first appeared in the serum.Glomerular eluates contained antibody directed againsta nuclear antigen. This is evidence for the mediation ofvascular damage by a nuclear autoantigen/antibody sys-tem. Immune complex formation in both human andexperimental infectious states has also been shown to in-volve the DNA/anti-DNA system. Hillyer20 observed thathamsters with experimental schistosomiasis (Schisto-soma masonz) and patients with S. japonicum have DNAand anti-DNA antibodies in their plasma during the per-iod of active infection. Immune-complex glomerulone-phritis is a common occurrence in both animals and

patients with schistosomal infection. Hillyer and Lewertdemonstrated that DNA was present in the glomeruli ofthese hamsters after glomerulopathy developed.21 Thepresence of the DNA/anti-DNA system suggested thatthe latter could contribute to the observed immune-com-

plex-mediated lesions.In man antigen/antibody complexes are involved in

the pathogenesis of the glomerular lesions of many viral,bacterial, and parasitic diseases including bacterialendocarditis and endarteritis, hepatitis-B infections,syphilis, malaria, kala-azar, and schistosomiasis. Whileantigen/antibody systems related to specific foreign

180

antigens may contribute to the pathogenesis of theseconditions, DNA/anti-DNA may be common to all. Evi-dence that DNA/anti-DNA complexes are present indiverse states associated with immune-complex-mediatedphenomena, suggests that such complexes are involvedin the pathogenesis of many diseases other than SLE.

Requests for reprints should be addressed to E.J.L., Section ofNephrology, Rush-Presbyterian-St. Luke’s Medical Center, 1753 WestCongress Parkway, Chicago, Illinois 60612.

REFERENCES

1. Bankhurst AD, Williams RC. Identification of DNA-binding lymphocytes inpatients with systemic lupus erythematosus. J Clin Invest 1975; 56:1378-85.

2. Roberts JL, Lewis EJ. Identification of antinative DNA antibodies in cryo-globulinemic states. Am J Med 1978; 65: 437-45.

3. Fournié GJ, Lambert PH, Miescher PA. Release of DNA in circulating bloodand induction of anti-DNA antibodies after injection of bacterial lipopoly-saccharides. J Exp Med 1974; 140: 1189-206.

4. Davis P, Read AE. Antibodies to double-stranded (native) DNA in activechronic hepatitis. Gut 1975; 16: 413-15.

5. Jain S, Markham R, Thomas HC, et al. Double-stranded DNA-binding capa-city of serum in acute and chronic liver disease. Clin Exp Immunol 1976;26: 35-41.

6. Epstein WV, Tan M, Easterbrook M. Serum antibody to double-strandedRNA and DNA in patients with idiopathic and secondary uveitis. N EnglJ Med 1971; 285: 1502-06.

7. Robinson MF, Roberts JL, Jones JV, Lewis EJ. Circulating Immune complexassays in patients with lupus and membranous glomerulonephritis. ClinImmunol Immunopathol 1979; 14: 348-60.

8. Roberts JL, Lewis EJ. Immunochemical demonstration of cryoprecipitableanti-native DNA antibody and DNA in the serum of patients with glomer-ulonephritit. J Immunol 1980; 124: 127-33.

9. Agnello V, Koffler D, Eisenberg JW, Winchester RS, Kunkel HG. Clq preci-pitins in the sera of patients with systemic lupus erythematosus and otherhypocomplementemic states. J Exp Med 1971, 134: 228s-41s.

10. Woodroffe AJ, Border WA, Theofilopoulos AN, Götze O, Glassock RJ, DixonFJ, Wilson CB. Detection of circulating immune complexes in patientswith glomerulonephritis. Kidney Int 1977; 12: 268-78.

11. Bruneau CD, Edmonds JP, Hughes GRV, Aarden L. Detection and charac-terization of DNA:antiDNA complexes in a patient with specific lupuserythematosus. Clin Exp Immunol 1977; 28: 433-36.

12. Hodgson HJF, Potter BJ, Jewell DP. Immune complexes in ulcerative colitisand Crohn’s disease. Clin Exp Immunol 1977; 29: 187-96.

13. Roberts JL, Lewis EJ. The composition of cryoprecipitable immune com-plexes in glomerulopathies. Kidney Int 1979; 16: 800.

14. Bruneau C, Benveniste J. Circulating DNA: antiDNA complexes in systemiclupus erythematosus. Detection and characterization by ultracentrifuga-tion. J Clin Invest 1979; 64: 191-98.

15. Winfield JB, Koffler D, Kunkel HG. Specific concentration of polynucleotideimmune complexes in the cryoprecipitates of patients with systemic lupuserythematosus. J Clin Invest 1975; 56: 563-70.

16. Izui S, Lambert PH, Fournié GJ, et al. Features of systemic lupus erythema-tosus in mice injected with bacterial lipopolysaccharides. Identification ofcirculating DNA and renal localization of DNA-anti-DNA complexes. JExp Med 1977; 145: 1115-30.

17. Mannik M, Arend WP. Fate of preformed immune complexes in rabbits andrhesus monkeys. J Exp Med 1971; 134: 19s-31s.

18. Zöllner EJ, Heicke B, Zahn RK. Serum desoxyribonucleasen and DNA-antikörper bie lupus erythematodes. ZKlin Chem Klin Biochem 1974; 12:459-63.

19. Weening JJ, Fleuren GJ, Hoedemaeker PJ. Demonstration of antinuclearantibodies in mercuric chloride-induced glomerulopathy in the rat. LabInvest 1978; 39: 405-11.

20. Hillyer GV. Deoxyribonucleic acid (DNA) and antibodies to DNA in theserum of hamsters and man infected with schistosomes. Proc Soc Exp BiolMed 1971; 136: 880-83.

21. Hillyer GV, Lewert RM. Studies in renal pathology in hamsters infected withS. mansoni and S. japonicum. Am J Trop Med Hyg 1974; 23: 404-11.

Physical Sign

ABSENT THIGH ADDUCTOR REFLEX INOBTURATOR HERNIA

J. G. HANNINGTON-KIFFPain Relief Centre, Frimley Park Hospital, Surrey

THE diagnosis of strangulated obturator hernia as the causeof intestinal obstruction is often missed preoperatively becauseit is a rare condition with no obvious external manifes-tations.1.2 This complication should be particularly suspectedin elderly debilitated women with a history of intermittentsmall-bowel obstruction. An important diagnostic clue inabout half of the cases is the reference of pain or tingling toa patch of skin on the medial aspect of the thigh just above theknee on the side of the hernia. This tingling is caused by irri-tation of the obsturator nerve by pressure from the hernial sac.This Howship-Romberg sign can be made more specific by not-ing whether coughing and certain movements of the leg, typi-cally extension, abduction, and internal rotation make the painor tingling worse. However, this sign is subjective, and thismakes it unreliable in sick and confused elderly patients whenthe diagnosis is most urgent. Clearly, a more objective testwould be most valuable in these patients, in whom a delay inthe diagnosis will seriously affect the prognosis. I report the

diagnostic value of testing the thigh adductor reflex in two pa-tients with strangulated obturator hernia.

PRINCIPLE OF THE TEST

The obturator nerve is a mixed nerve, supplying the adduc-tor muscles of the thigh as well as a patch of the overlyingskin. Consequently pressure on the nerve by an obturator her-nia may affect the action of the adductor muscles as well as

causing sensory changes. Whereas attempts to assess adductormusclepower proved difficult in both patients, I found that

testing the adductor stretch reflexes proved a useful objectivesign with the opposite side for comparison.The adductor reflex is not a routine clinical test but I find

it can be elicited with practice by a firm blow from a patellarhammer over thumb or index finger laid at rightangles acrossthe adductor muscles about 5 cm above the medial epicondyleof the femur. In this way any contraction of the adductor mus-cles can be felt as well as seen, and the patient will be savedsome discomfort from the blow of the hammer.

CASE-REPORTS

Case 1.-A woman of 90 presented with small-bowelobstruction. The Howship-Romberg sign was absent, and theright-sided strangulated obturator hernia subsequently foundat laparotomy was not diagnosed preoperatively. In the recov-ery room I found the adductor reflex was absent on the sideof the hernia but was brisk on the opposite side. A few weekslater the adductor reflex had returned on the affected side.

Case 2.-A woman of 92 presented with small-bowelobstruction and the Howship-Romberg sign was present in theright thigh. The adductor reflex was absent on the affected sideand laparotomy confirmed the suspected right-sided strangu-lated obturator hernia. The adductor reflex had not returned

by the second postoperative day when the patient died.The patellar tendon reflex was intact in each patient on the

side of the absent adductor reflex. Since both reflexes involvethe second to fourth lumbar spinal segments, the isolated lossof the adductor reflex showed that the lesion lay in the obtura-tor nerve and was not caused by unilateral root-compressionin a degenerative spine. Finally, whilst thigh-pain in the

elderly is most likely to be associated with disease of the hip,routine testing of the adductor reflex may promote the earlierrecognition of the rare but potentially lethal condition ofobturator hernia.

REFERENCES

1. Gray SW, Skandalakis JE, Soria RE, Rowe JS. Strangulated obturator her-nia. Surgery 1974; 75: 20-27.

2. Kozlowski JM, Beal JM. Obturator hernia: an elusive diagnosis. Arch Sur-gery 1977; 112: 1001-02.