553
While calcification on X-ray, distinctive liverscang appearances, and angiographic abnormalities9 have been reported as helpful diagnostic points, far more important than any test is awareness that the condition may arise in any individual from an endemic area. Serological tests are important, but fallible. LASS and his colleaguesl0 found the intradermal Casoni test positive in its immediate phase in nearly 90% of patients, but urifortunately they noted a false-positive early in 15% of controls. The delayed response offered better discrimination, but the test was positive in only about 70% of those with active hydatid disease. LITTLE’ found the complement-fixation test disappointing in its accuracy but, as the only immunodiagnostic test to become negative after one or two years if the hydatid has died or has been successfully removed, it is useful for following progress of the disease. In’ the hands of LAss and his colleagues 10 the indirecthæmagglutination; latex-agglutination, and indirect fluorescent-antibody tests were more accurate than the complement-fixation test, but they had the disadvantage of remaining positive for many years after successful removal of hydatids. (The next editorial discusses tests in more detail.) There have been few substantial changes in surgical techniques for management of hydatid cysts. Various scolicidal agents have been injected into the cyst before removal of the laminated membrane and germinal epithelium--dilute’formalin and hypertonic saline are probably the most widely used. KAssis and TANNER 11 suggest that immune serum may prove both safe and effective. Complex methods for freezing the cyst 12 in order to facilitate its removal have not met with widespread acceptance. Emphasis on closing biliaryl3 and bronchial fistulas" has undoubtedly lowered the morbidity of surgery. The more widespread use of omentoplasty15 to cope with the large residual space created by cyst removal from the liver has also probably contributed to a smoother postoperative course. Surgery is still the mainstay of treatment. In elderly patients calcified cysts up to about 7-10 cm in diameter should probably be left alone if they are causing no symptoms, for the morbidity of surgery in these patients is formidable.’ Some promising drugs have as yet been used in a very limited way in man. Mebendazolei6 is certainly effective against the cystic form of E. granulosus infestation in laboratory animals and, more importantly, has reduced the size of experimental E. multilocularis
8 9
Morris, J., Doust, B., Hanks, T. Am.J. Roentg. 1967, 51, 519. Baltaxe, H. A., Fleming, R. J. Radiology, 1970, 97, 599. 10 Lass, N., Laver, Z., Lengy, J. Ann. Allergy, 1973, 31, 430. 11 Kassis, A. I., Tanner, C. E. Nature, 1976, 262, 588. 12 Saidi, F, Nazarian, I.New Engl. J. Med. 1971, 284, 1386. 13 De Heredia, J. B., Sanz Sanz, T. Int. J. Surg. 1970, 53, 393. 14 Sarsam, A. J. thorac. cardiovasc. Surg. 1971, 62, 663. 15 Papadimitriou, J., Mandrekas, A. Br. J. Surg. 1970, 47, 431. 16. Heath, D. D., Chevis, R. A. F. Lancet, 1974, ii, 218. 17. Campbell, W. C., McCracken, R. O., Blair. L. S. J. Parasitol. 1975, 61, 844.
infestation.17 Eradication of Echinococcus from primary hosts has become a more realistic proposition since the introduction of anthelmintics, including mebendazole and bunamidine, effective against E. granulosus in the dog. Preliminary work by HERD and his colleagues18 in Victoria suggests that it may be possible to protect dogs by immunisation;
if so, this might be the most effective means for interrupting a most resilient life-cycle. To many readers, safe in their cyst-free castles, interest in hydatid disease may seem academic in the most pejorative sense of the word. The mobility of world populations has already created publichealth problems of sometimes alarming dimensions. A hydatid travels well by ship or aeroplane, first or economy class. It is a puzzling clinical entity, and its management requires a good working knowledge of the parasite’s biology. It is unwise to dismiss hydatid disease as a curiosity. The worm is alive and well and living in many parts of the
world. TESTING FOR HYDATID DISEASE TESTS for hydatid disease vary in sensitivity and in the length of time they remain positive after successful
excision of a cyst (see above). Matossian and Araj19compared three tests-haemagglutination (H.A.), complement fixation (c.F.), and indirect fluorescent antibody (I.F.)—as indicators of postoperative persistence or recurrence of hydatid cysts in man. Sera from patients tested at the time of operation and when the disease had recurred were more frequently positive by H.A. and i.F. than by c.F., but positive results by c.F. were substantially fewer than those by H.A. and I.F. in sera from patients who had been operated on but who did not seem to have recurrent infection. Matossian and Araj agreed with earlier workers20-23 that the c.F. test can be of considerable prognostic value. The lower sensitivity of the c.F. test at the time of operation and after recurrence, reported by them and by others,24-28 stems from the use of an insufficiently sensitive technique. Many workers ;102133.29 30 have stressed the precautions needed to ensure high sensitivity, including careful standardisation of hydatid fluid by chessboard titration to ascertain the optimal dilution for testing, selection of a suitable concentration of complement and the best time and temperature for its incubation with antigen and antibody, and chessboard titration on sera showing atypical reactions in routine straight-line tests. A disadvantage of C.F., seemingly rare with H.A., is its occasional lack of specificity. Minor hydatid antigens Herd, R. P., Chappel, R. J., Biddell, D. Int. J. Parasitol. 1975, 5, 395. Matossian, R. M., Araj, G. F. J. Hyg., Camb. 1975, 75, 333. Fairley, N. H. Q. Jl Med. 1922, 15, 244. 21. Bensted, H. J., Atkinson, J. D. Lancet, 1953, i, 265. 22. Magath, T. B.Am.J. clin. Path. 1959, 31, 1. 23. Bradstreet, C. M. P. J. med. Microbiol. 1969, 2, 419. 24. Kagan, I. G., Allain, D. S., Norman, L. Am. J. trop. Med. Hyg. 1959, 8, 18. 19. 20.
. 51. 25. Garabedian, G. A., Matossian, R. M., Suidan, F. G. ibid. p. 67. 26. Arabatzis, G., Papapanagiotou, J. Bull. Wld Hlth Org. 1963, 28, 266. 27. Cowling, D. C. Med. J. Aust. 1964, i, 146. 28. Abou-Daoud, K. T. Am. J. trop. Med. Hyg. 1965, 14, 760. 29. Goldsworthy, N. E. J. Path. Bact. 1928, 31, 435. 30. Dennis, E. W. J. Parasit. 1937, 23, 62.
554 with antigens in other helminths. Confusion will be reduced in c.F. tests if the optimal dilution of hydatid fluid is used instead of the low dilutions (1/2 or 1/4) which are selected empirically by some workers. Such low dilutions are almost certain to display all antigens present in whole hydatid fluid, where an optimal one (1/20-1/50 or greater) may reveal little more than the specific antigen. There are other possible causes of non-specific reactions: Kagan et al. 31 suggested that autoantibodies might react with host protein in hydatid antigen; but more important are the false-positive results in some patients with cancer.32 Norris33 suggested that a neoplastic condition in blood-group Plnegative subjects might be associated with an enhanced immunological response to the P substance present in hydatid fluids. Matossian and Araj34 found positive results by c.F. in three of fifty subjects who were in hospital with non-hydatid diseases. In serology it is not unusual to find antibody to a pathogenic organism in healthy persons who live and work in areas where the organism is endemic. For this reason it is not clear why H.A., a highly sensitive test, detects little or no antibody in sera from healthy persons living in areas where hydatid disease is endemic 25 32 34 36 even though specific H.A. antibodies to hydatid antigen are known to persist for a long time. This is in contrast to c.F. antibodies which, although they decline and sometimes disappear quite rapidly after infection is eradicated, are frequently reported in sera from these controls. Sometimes the c.F. antibodies may be due to infections with different parasites bearing common antigens, but this is not always the case since C.F. antibodies in control subjects were detected more often in one Welsh county where hydatid disease is common than in another where it is not,23 and the positive findings seem to be specific, since in the Welsh areas there is no likelihood of confusion from infections due to other parasites. Results of tests to detect antibodies to IgM, IgG, and IgA at different stages of the disease have been inconsistent. Matossian et al. 36 concluded that in c.F. the antigens reacted mainly with IgM antibodies and in H.A. with IgG. However, there is poor correlation between the tests which are alleged to react with the same specific immunoglobulin. Moreover, Matossian and Araj’9 could not confirm the previously reported usefulness of I.F. for detecting IgM antibodies, and no clear explanation was forthcoming. The blocking of specific IgM and IgA antibodies by high concentrations of IgG3’ is a possibility which has yet to be studied in hydatid serology. Patients are rarely investigated for hydatid disease in the early stages of infection so that, by the time symptoms arise, IgM antibodies may seldom be present. Since both H.A. and c.F. detect IgG antibodies, poor correlation in results might reflect participation in each test of different hydatid antigens. Perhaps the c.F. test applied simultaneously with H.A. (or a similar test like latex aggcross-react
31.
I. G., Norman, L., Allain, D. S., Goodchild, C. G. J. Immun. 1960, 84, 635. 32. Kagan, I. G., Bull. Wld Hlth Org. 1968, 39, 25. 33. Norris, T. J. Med. J. Aust. 1965, i, 792. 34. Garabedian, G. A., Matossian, R. M., Djanian, A. Y. J. Immun. 1957, 78,
Kagan,
269.
G., Osimani, J. J., Varela, J. C., Allain, D. S. Am. J. trop. Med. Hyg. 1966, 15, 172. 36. Matossian, R. M., Kane, G. J., Chantler, S. M., Batty, I., Sarhadian, H. Immunology, 1972, 22, 423. 37. Cohen, I. R., Norins, L. C., Julian, A. J. J. Immun. 1967, 98, 143.
35.
Kagan,
I.
lutination) would yield the highest number of true-positive results and at the same time give the best prognostic indications. At present there seems to be no in using immunofluorescence for diagnosis.
advantage
PSORIATIC ARTHRITIS THE frequency of psoriasis in the general population is believed to be around 1-2%.’The frequency of inflammatory polyarthritis in a psoriatic population has been reckoned at 6.8%.3 Patients with extensive psoriasis requiring admission to hospital may have an
unexpectedly high incidence of psoriatic arthritis-as high as 32% in one survey.4 An important follow-up5 of patients with psoriatic arthritis provides valuable information for rheumatologists and dermatologists. This paper, from the Rheumatism Research Unit, Leeds, and Stoke Mandeville Hospital, reviews 168 patients, of whom 94 have been followed for more than 10 years, The patients were divided into three types according to the pattern of their arthritis. 132 (78%) had an arthritis indistinguishable from rheumatoid arthritis; 28 (16.6%) had distal joint arthritis, affecting most commonly the distal interphalangeal joints of the fingers; and 8 (48 ! had a deforming arthritis affecting the spine, resembling ankylosing spondylitis, as well as severe involvement of peripheral joints. The sex ratio of the 168 pa tients showed a predominance of women in the
"indistinguishable" group (almost 2/1), an equal ratio in the "deforming" group, and a mild male preponderance in the "distal" group. The peak age of onset of the arthritis was between 36 and 45 years, although arthritis began three times more frequently before the age of 20 in the deforming group than in the indistinguishable group. Arthritis came on acutely in 42% of the patients, and half the patients in the deforming group had constitutional disturbances, sometimes with pyrexia. Psoriasis usually preceded the arthritis, but in 16% of patients arthritis preceded the skin lesions, often by several years. There was no consistent pattern of change in pre-existing psoriasis at the onset of arthritis As judged by the number of admissions to hospital and time off work, psoriatic arthritis was mild except in the deforming group. The distal group had the mildest arthritis, with 60% of patients not requiring admission to hospital. Certainly there was nothing to suggest that these patients are bad employment risks, and the patients with deforming arthritis made up the smallest group of all-8 most
out
of 168. It is in this last group that
complication of seronegative arthritis, was frequent, being found in a quarter of the men. It
uveitis,
a
also present in 12% of men with a distal arthritis. and in 4% of men and 9% of women with indistinguishable arthritis. On annual radiographic follow-up of the hands and feet, only a small number of joints deteriorated, and ar annual sheep-cell agglutination test (S.C.A.T.) was negative in most of the patients. However, 16% of the indistwas
1. Ingram, J. T. Lancet, 1964, i, 121. 2. Baker, H. Br. J. Derm. 1966, 78, 249. 3. Leczinsky, C. G. Acta derm-venereol., Stockh. 1948, 28, 483. 4. Little, H., Harvie, J. N., Lester, R. S. Can. med. Ass.J. 1975, 112, 31 5. Roberts, M. E. T., Wright, V., Hill, A. G. S., Mehra, A. C. Ann. rheum Dis.
1976, 35, 206.
While calcification on X-ray, distinctive liverscang appearances, and angiographic abnormalities9 have been reported as helpful diagnostic points, far more important than any test is awareness that the condition may arise in any individual from an endemic area. Serological tests are important, but fallible. LASS and his colleaguesl0 found the intradermal Casoni test positive in its immediate phase in nearly 90% of patients, but urifortunately they noted a false-positive early in 15% of controls. The delayed response offered better discrimination, but the test was positive in only about 70% of those with active hydatid disease. LITTLE’ found the complement-fixation test disappointing in its accuracy but, as the only immunodiagnostic test to become negative after one or two years if the hydatid has died or has been successfully removed, it is useful for following progress of the disease. In’ the hands of LAss and his colleagues 10 the indirecthæmagglutination; latex-agglutination, and indirect fluorescent-antibody tests were more accurate than the complement-fixation test, but they had the disadvantage of remaining positive for many years after successful removal of hydatids. (The next editorial discusses tests in more detail.) There have been few substantial changes in surgical techniques for management of hydatid cysts. Various scolicidal agents have been injected into the cyst before removal of the laminated membrane and germinal epithelium--dilute’formalin and hypertonic saline are probably the most widely used. KAssis and TANNER 11 suggest that immune serum may prove both safe and effective. Complex methods for freezing the cyst 12 in order to facilitate its removal have not met with widespread acceptance. Emphasis on closing biliaryl3 and bronchial fistulas" has undoubtedly lowered the morbidity of surgery. The more widespread use of omentoplasty15 to cope with the large residual space created by cyst removal from the liver has also probably contributed to a smoother postoperative course. Surgery is still the mainstay of treatment. In elderly patients calcified cysts up to about 7-10 cm in diameter should probably be left alone if they are causing no symptoms, for the morbidity of surgery in these patients is formidable.’ Some promising drugs have as yet been used in a very limited way in man. Mebendazolei6 is certainly effective against the cystic form of E. granulosus infestation in laboratory animals and, more importantly, has reduced the size of experimental E. multilocularis
8 9
Morris, J., Doust, B., Hanks, T. Am.J. Roentg. 1967, 51, 519. Baltaxe, H. A., Fleming, R. J. Radiology, 1970, 97, 599. 10 Lass, N., Laver, Z., Lengy, J. Ann. Allergy, 1973, 31, 430. 11 Kassis, A. I., Tanner, C. E. Nature, 1976, 262, 588. 12 Saidi, F, Nazarian, I.New Engl. J. Med. 1971, 284, 1386. 13 De Heredia, J. B., Sanz Sanz, T. Int. J. Surg. 1970, 53, 393. 14 Sarsam, A. J. thorac. cardiovasc. Surg. 1971, 62, 663. 15 Papadimitriou, J., Mandrekas, A. Br. J. Surg. 1970, 47, 431. 16. Heath, D. D., Chevis, R. A. F. Lancet, 1974, ii, 218. 17. Campbell, W. C., McCracken, R. O., Blair. L. S. J. Parasitol. 1975, 61, 844.
infestation.17 Eradication of Echinococcus from primary hosts has become a more realistic proposition since the introduction of anthelmintics, including mebendazole and bunamidine, effective against E. granulosus in the dog. Preliminary work by HERD and his colleagues18 in Victoria suggests that it may be possible to protect dogs by immunisation;
if so, this might be the most effective means for interrupting a most resilient life-cycle. To many readers, safe in their cyst-free castles, interest in hydatid disease may seem academic in the most pejorative sense of the word. The mobility of world populations has already created publichealth problems of sometimes alarming dimensions. A hydatid travels well by ship or aeroplane, first or economy class. It is a puzzling clinical entity, and its management requires a good working knowledge of the parasite’s biology. It is unwise to dismiss hydatid disease as a curiosity. The worm is alive and well and living in many parts of the
world. TESTING FOR HYDATID DISEASE TESTS for hydatid disease vary in sensitivity and in the length of time they remain positive after successful
excision of a cyst (see above). Matossian and Araj19compared three tests-haemagglutination (H.A.), complement fixation (c.F.), and indirect fluorescent antibody (I.F.)—as indicators of postoperative persistence or recurrence of hydatid cysts in man. Sera from patients tested at the time of operation and when the disease had recurred were more frequently positive by H.A. and i.F. than by c.F., but positive results by c.F. were substantially fewer than those by H.A. and I.F. in sera from patients who had been operated on but who did not seem to have recurrent infection. Matossian and Araj agreed with earlier workers20-23 that the c.F. test can be of considerable prognostic value. The lower sensitivity of the c.F. test at the time of operation and after recurrence, reported by them and by others,24-28 stems from the use of an insufficiently sensitive technique. Many workers ;102133.29 30 have stressed the precautions needed to ensure high sensitivity, including careful standardisation of hydatid fluid by chessboard titration to ascertain the optimal dilution for testing, selection of a suitable concentration of complement and the best time and temperature for its incubation with antigen and antibody, and chessboard titration on sera showing atypical reactions in routine straight-line tests. A disadvantage of C.F., seemingly rare with H.A., is its occasional lack of specificity. Minor hydatid antigens Herd, R. P., Chappel, R. J., Biddell, D. Int. J. Parasitol. 1975, 5, 395. Matossian, R. M., Araj, G. F. J. Hyg., Camb. 1975, 75, 333. Fairley, N. H. Q. Jl Med. 1922, 15, 244. 21. Bensted, H. J., Atkinson, J. D. Lancet, 1953, i, 265. 22. Magath, T. B.Am.J. clin. Path. 1959, 31, 1. 23. Bradstreet, C. M. P. J. med. Microbiol. 1969, 2, 419. 24. Kagan, I. G., Allain, D. S., Norman, L. Am. J. trop. Med. Hyg. 1959, 8, 18. 19. 20.
. 51. 25. Garabedian, G. A., Matossian, R. M., Suidan, F. G. ibid. p. 67. 26. Arabatzis, G., Papapanagiotou, J. Bull. Wld Hlth Org. 1963, 28, 266. 27. Cowling, D. C. Med. J. Aust. 1964, i, 146. 28. Abou-Daoud, K. T. Am. J. trop. Med. Hyg. 1965, 14, 760. 29. Goldsworthy, N. E. J. Path. Bact. 1928, 31, 435. 30. Dennis, E. W. J. Parasit. 1937, 23, 62.
554 with antigens in other helminths. Confusion will be reduced in c.F. tests if the optimal dilution of hydatid fluid is used instead of the low dilutions (1/2 or 1/4) which are selected empirically by some workers. Such low dilutions are almost certain to display all antigens present in whole hydatid fluid, where an optimal one (1/20-1/50 or greater) may reveal little more than the specific antigen. There are other possible causes of non-specific reactions: Kagan et al. 31 suggested that autoantibodies might react with host protein in hydatid antigen; but more important are the false-positive results in some patients with cancer.32 Norris33 suggested that a neoplastic condition in blood-group Plnegative subjects might be associated with an enhanced immunological response to the P substance present in hydatid fluids. Matossian and Araj34 found positive results by c.F. in three of fifty subjects who were in hospital with non-hydatid diseases. In serology it is not unusual to find antibody to a pathogenic organism in healthy persons who live and work in areas where the organism is endemic. For this reason it is not clear why H.A., a highly sensitive test, detects little or no antibody in sera from healthy persons living in areas where hydatid disease is endemic 25 32 34 36 even though specific H.A. antibodies to hydatid antigen are known to persist for a long time. This is in contrast to c.F. antibodies which, although they decline and sometimes disappear quite rapidly after infection is eradicated, are frequently reported in sera from these controls. Sometimes the c.F. antibodies may be due to infections with different parasites bearing common antigens, but this is not always the case since C.F. antibodies in control subjects were detected more often in one Welsh county where hydatid disease is common than in another where it is not,23 and the positive findings seem to be specific, since in the Welsh areas there is no likelihood of confusion from infections due to other parasites. Results of tests to detect antibodies to IgM, IgG, and IgA at different stages of the disease have been inconsistent. Matossian et al. 36 concluded that in c.F. the antigens reacted mainly with IgM antibodies and in H.A. with IgG. However, there is poor correlation between the tests which are alleged to react with the same specific immunoglobulin. Moreover, Matossian and Araj’9 could not confirm the previously reported usefulness of I.F. for detecting IgM antibodies, and no clear explanation was forthcoming. The blocking of specific IgM and IgA antibodies by high concentrations of IgG3’ is a possibility which has yet to be studied in hydatid serology. Patients are rarely investigated for hydatid disease in the early stages of infection so that, by the time symptoms arise, IgM antibodies may seldom be present. Since both H.A. and c.F. detect IgG antibodies, poor correlation in results might reflect participation in each test of different hydatid antigens. Perhaps the c.F. test applied simultaneously with H.A. (or a similar test like latex aggcross-react
31.
I. G., Norman, L., Allain, D. S., Goodchild, C. G. J. Immun. 1960, 84, 635. 32. Kagan, I. G., Bull. Wld Hlth Org. 1968, 39, 25. 33. Norris, T. J. Med. J. Aust. 1965, i, 792. 34. Garabedian, G. A., Matossian, R. M., Djanian, A. Y. J. Immun. 1957, 78,
Kagan,
269.
G., Osimani, J. J., Varela, J. C., Allain, D. S. Am. J. trop. Med. Hyg. 1966, 15, 172. 36. Matossian, R. M., Kane, G. J., Chantler, S. M., Batty, I., Sarhadian, H. Immunology, 1972, 22, 423. 37. Cohen, I. R., Norins, L. C., Julian, A. J. J. Immun. 1967, 98, 143.
35.
Kagan,
I.
lutination) would yield the highest number of true-positive results and at the same time give the best prognostic indications. At present there seems to be no in using immunofluorescence for diagnosis.
advantage
PSORIATIC ARTHRITIS THE frequency of psoriasis in the general population is believed to be around 1-2%.’The frequency of inflammatory polyarthritis in a psoriatic population has been reckoned at 6.8%.3 Patients with extensive psoriasis requiring admission to hospital may have an
unexpectedly high incidence of psoriatic arthritis-as high as 32% in one survey.4 An important follow-up5 of patients with psoriatic arthritis provides valuable information for rheumatologists and dermatologists. This paper, from the Rheumatism Research Unit, Leeds, and Stoke Mandeville Hospital, reviews 168 patients, of whom 94 have been followed for more than 10 years, The patients were divided into three types according to the pattern of their arthritis. 132 (78%) had an arthritis indistinguishable from rheumatoid arthritis; 28 (16.6%) had distal joint arthritis, affecting most commonly the distal interphalangeal joints of the fingers; and 8 (48 ! had a deforming arthritis affecting the spine, resembling ankylosing spondylitis, as well as severe involvement of peripheral joints. The sex ratio of the 168 pa tients showed a predominance of women in the
"indistinguishable" group (almost 2/1), an equal ratio in the "deforming" group, and a mild male preponderance in the "distal" group. The peak age of onset of the arthritis was between 36 and 45 years, although arthritis began three times more frequently before the age of 20 in the deforming group than in the indistinguishable group. Arthritis came on acutely in 42% of the patients, and half the patients in the deforming group had constitutional disturbances, sometimes with pyrexia. Psoriasis usually preceded the arthritis, but in 16% of patients arthritis preceded the skin lesions, often by several years. There was no consistent pattern of change in pre-existing psoriasis at the onset of arthritis As judged by the number of admissions to hospital and time off work, psoriatic arthritis was mild except in the deforming group. The distal group had the mildest arthritis, with 60% of patients not requiring admission to hospital. Certainly there was nothing to suggest that these patients are bad employment risks, and the patients with deforming arthritis made up the smallest group of all-8 most
out
of 168. It is in this last group that
complication of seronegative arthritis, was frequent, being found in a quarter of the men. It
uveitis,
a
also present in 12% of men with a distal arthritis. and in 4% of men and 9% of women with indistinguishable arthritis. On annual radiographic follow-up of the hands and feet, only a small number of joints deteriorated, and ar annual sheep-cell agglutination test (S.C.A.T.) was negative in most of the patients. However, 16% of the indistwas
1. Ingram, J. T. Lancet, 1964, i, 121. 2. Baker, H. Br. J. Derm. 1966, 78, 249. 3. Leczinsky, C. G. Acta derm-venereol., Stockh. 1948, 28, 483. 4. Little, H., Harvie, J. N., Lester, R. S. Can. med. Ass.J. 1975, 112, 31 5. Roberts, M. E. T., Wright, V., Hill, A. G. S., Mehra, A. C. Ann. rheum Dis.
1976, 35, 206.
