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CHRONIC CARRIAGE OF AUSTRALIA ANTIGEN
844 and oxyhsmoglobin made for age and sex.
Radcliffe Infirmary, Oxford.
dissociation, with due allowance K. G. M. M. ALBERTI PAULINE M. EMERSON J. H. DARLEY T. D. R. HOCKADAY.
THE SINGLE-HANDED PRACTITIONER
SiR,—The urban single-handed general practitioner can same (increasingly appreciated) advantages to his patients, and suffers the same disadvantages as those rural doctors described by Dr. Bowden (April 1, p. 755). Moreover, living expenses in the centre of a large city, especially "Reversal of London, are disproportionately heavy. justice " is too high-sounding. The sordid reality is that there is a deliberate policy to squeeze out those who are presently seen as untidy anachronisms. -offer the
8 Orange Street, Haymarket, London W.C.2.
BENJAMIN LEE.
THE WIEDEMANN-BECKWITH SYNDROME: GENETIC CONSIDERATIONS AND A DIAGNOSTIC SIGN
SiR,—There have been several reports of familial occurof the Wiedemann-Beckwith syndrome (w.B.S.).l-6 It has been suggested 7-9 that the W.B.S. is determined by -the homozygous state of an autosomal recessive mutation. We have studied a family (fig. 1) in which the syndrome occurred in two pairs of sibs who are second cousins. Two rence
sib-first cousins once removed died neonatally, and at least of them had omphalocele. The parents of the affected children were not known to be consanguineous, and trans-
one
1. 2. 3. 4. 5. 6. 7.
8. 9.
Wiedemann, H.-R. J. Génét. hum. 1964, 13, 223. Irving, I. M. J. pediat. Surg. 1967, 2, 499. Borit, A., Kosek, J. Archs Path. 1969, 88, 58. Chambionnat, D. Thèse, Faculté de Médecine, Paris, 1969. Rossier, A., Lustosa, M. L. Ann. Pediat. 1970, 17, 452. Bohlmann, H.-G., Havers, W. Arch. Kinderheilk, 1971, 183, 175. Beckwith, J. B. Birth Defects: Original Article Series; vol. v, p. 188. New York, 1969. Fillippi, G., McKusick, V. A. Medicine, 1970, 49, 279. McKusick, V. A. Mendelian Inheritance in Man; p. 275. Baltimore, 1971.
Fig. 2-Indented
ear
lesions
on
the
posterior
rim of the helix
of IV-26.
mission of the w.B.s. in this family is not consistent with recessive inheritance. Similarly, the hypothesis of recessive inheritance is not supported by the famiiy reported by Irving2 in which two brothers, their second cousin, and possibly a first cousin were affected with the w.B.s. In addition to the previously described malformations, we have found an ear anomaly in all five of the WiedemannBeckwith patients we have examined. It consists of one or more bilateral, focal, well-demarcated, indented areas on the posterior rim of the helix measuring 1-2 mm. in diameter (fig. 2). We have not seen this lesion in other syndromes. Though probably not pathognomonic of and obligatory in the w.B.s., we think that it is very helpful in the diagnosis of that condition. Departments of Pediatrics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53706, U.S.A.
ANDREW L. KOSSEFF JÜRGEN HERRMANN JOHN M. OPITZ.
CHRONIC CARRIAGE OF AUSTRALIA ANTIGEN SIR,-We reportedtwo apparent types of chronic carriage of Australia antigen associated with hepatitis, namely, (a) patients recovering from hepatitis showing high stable c.F. titres (1024-2048) in whom the antigen was " free ", and (b) patients with low c.F. titres (4-16) in whom antigen was " bound " and could be detected only
Fig. 1-Dominant inheritance in W.B.S. Note transmission through apparently normal individuals. Blackened symbols indicate cases of w.B.s. Bar over symbol :indicates family members examined by us. III-1 died neonatally and had omphalocele. III-3 died neonatally. IV-11 -died at nine months of age with multiple congenital anomalies.
by heating the serum at 85’C for 1 hour before testing. We suggested that these low titres of " bound " antigen were probably liberated from antigen-antibody complexes. We have now circumstantial evidence that a male nurse, aged 28, showing persistent hepatitis with stable high c.F. titres of free antigen for 1 year, acquired his initial acute hepatitis infection while nursing a man age 53 with chronic active hepatitis who, at the time of probable infection of the nurse and during the subsequent year, had low titres of " bound " antigen. This suggests that cross-infection with the virus bound in antigen-antibody complexes may result in persistent infection. Two possible mechanisms may be involved in such persistence-namely, inhibition of the patient’s own antibody response, and slow release of virus from such 1. Ross, C. A. C.,
Pringle,
R. C.
Lancet, 1971, ii, 434.
complexes. In individuals with normal immunological responses, infection with an Australia antigen-antibody complex may therefore be more likely to result in a symptomless infection and prolonged carriage of Australia antigen than infection with " free " virus. Virus Laboratory, Ruchill Hospital, Glasgow G20 9NB.
Regional Ayrshire
Central
CONSTANCE A. C. ROSS.
Hospital,
Irvine,
Ayrshire KA12 8SS. Ballochmyle Hospital, Mauchline, Ayrshire.
W. S. ROBERTS. A. SLESSOR.
PERIPHERAL VENOUS SCANNING WITH 125I-TAGGED FIBRINOGEN
SIR,-Mr. Mavor and his colleagues (March 25, p. 661) rightly question some extravagant claims made for the 125I-fibrinogen test in peripheral venous scanning,
particularly
when it is used
coagulant therapy.
as an
index of need for anti-
However, they have chosen
weapon for debate. We take their description of method to
a
poor
mean
that
125I-tagged fibrinogen was given to patients after the diagnosis of pulmonary embolism or iliofemoral thrombosis. Administration of tagged fibrinogen subsequent to established thrombosis or embolism is bound to be relatively useless since (a) thrombolysis is likely to be taking place and the tagged fibrinogen will find no thrombus in which to be incorporated; (b) in those patients with embolism the clot may have left the periphery entirely. (Shown in their paper by the 36% of patients with negative phlebography.) Their arguments would have gained validity only if their patients had undergone peripheral venous scanning using 125I-fibrinogen and had not been found positive in spite of later development of embolism or iliofemoral thrombosis. we continue to use the 125I-fibrinogen test diagnose calf-vein thrombosis as a test of three main prophylactic methods in patients undergoing hip replacements. Finally, we shall find which patients have a pul-
In Exeter
to
or die as a result of it. This will be the crucial test of these prophylactic methods, and this will also tell us whether calf-vein thrombosis as diagnosed by 125I-tagged fibrinogen is associated with pulmonary embolism.
monary embolism
Princess Elizabeth Orthopædic Exeter EX2 4UE.
Hospital,
D. S. HALPIN C. D. JEFFERISS R. S. M. LING.
SIR,-The report of Mr. Mavor and colleagues is Their conclusions are certain to provoke controversy. based on a study of 76 cases of pulmonary embolism and 50 cases of iliofemoral thrombophlebitis. It is unwarranted and misleading to deprecate the validity of 1251-labelled fibrinogen leg scanning for the detection of early disease in asymptomatic subjects on the basis of a study restricted, as was theirs, to late, even far-advanced, thromboembolism. Authors cited in this article, and others, have confirmed with phlebograms that the radioisotope technique sensitively detects the earliest form of the disease in the areas which appear to be involved first-the soleal veins and other deep veins of the leg.l-3 It is not contested that the Negus, D., Pinto, D. J., Le Quesne, L. P., Brown, N., Chapman, M. Br. J. Surg. 1968, 55, 835. 2. Bonnar, J., Walsh, J. Lancet, March 18, 1972, i, 614. 3. Tsapogas, M. J., et al. Archs Surg. 1970, 101, 149. 1.
iliofemoral segment is the source of major pulmonary embolism. It is regrettable, on the other hand, that the authors minimise the importance of venous thrombosis arising in more peripheral sites. There is every reason to believe that effective prevention at this level in patients at risk will protect against thrombosis in the iliofemoral area at the same time. Our own experience with 1251labelled fibrinogen in a controlled trial of postoperative prophylaxis clearly shows that neither physical examination, ultrasound, nor electrical impedance techniques are superior to radioisotope leg scanning for early detection. Phlebograms confirmed that venous thrombosis could be demonstrated in 10 of the 12 patients with positive leg scans among 50 patients who had had total hip replacement. None of these incurred embolism or developed occlusion in the iliofemoral segment. We hold that the efficacy of prevention should be judged by criteria reflecting the earliest form of the disease. It must be assumed that the deposition of fibrin in the leg, even though often selflimiting, represents one stage of the same disease process which in more fulminant form gives rise to iliofemoral thrombosis and pulmonary embolism. Prophylaxis should quite properly be evaluated by criteria which indicate that the disease has been affected at its onset, for reasons of both efficacy and ethics. No technique now available approaches 125I_labelled fibrinogen for this purpose. Lemuel Shattuck Hospital, 170 Morton Street, Boston, Massachusetts 02130, U.S.A.
MICHAEL HUME VICTOR GUREWICH.
"
SIR,-Mr. Mavor and his colleagues seek to discount the impression which is rapidly gaining ground that peripheral scanning is the new early-warning system for deep-vein thrombosis and its subsequent treatment ". We cannot agree statement.
that their
study lends
much support
to
this
Their report suffers from a number of omissions. There no description of the methodology of the 25I_labelled fibrinogen uptake test used in the study, nor of the criteria for the diagnosis of venous thrombosis. It would have been interesting to know the age and sex distribution of the patients studied and also why only iliac-femoral is
phlebography was performed. Peripheral phlebography was clearly indicated in those 26 patients in whom both iliofemoral phlebography and peripheral scanning were negative. Of course, phlebography is the best single diagnostic procedure in the investigation of a patient presenting with pulmonary embolism of unknown origin; and, of course, the 125I-fibrinogen-uptake technique is useless in the groin and above the inguinal ligament, 1,2where a number of major thromboses are known to arise, 3,4 and is also unlikely to detect peripheral thrombi more than 5 or 6 days old
or
in the presence of lower limb oedema.5
These
recognised deficiencies of the test in no way detract from its proven value as a prospective method for the detection of early (e.g., before embolism has occurred) calf and femoral thromboses, 1,6 and used in this way it has a useful place in patient screening and in research. Admittedly, many peripheral thrombi are of little significance but they are phlebographically demonstrable thrombi none the less.s The established method for screening and for early detection of thrombosis in the femoral and iliac veins is 1. 2. 3. 4. 5.
6.
Negus, D., Pinto, D. J., Le Quesne, L. P., Brown, N., Chapman, M. Br. J. Surg. 1968, 55, 835. Evans, D. S., Negus, D. Br. J. Hosp. Med. 1971, 6, 729. Sevitt, S., Gallagher, N. G. Lancet, 1959, ii, 981. Negus, D., Evans, D. S. ibid. 1971, ii, 763. Browse, N. L., Clapham, W. F., Croft, D., Jones, D. J., Lea Thomas, M., Williams, J. O. Br. med. J. 1971, iv, 325. Flanc, C., Kakkar, V. V., Clarke, M. B. Br. J. Surg. 1968, 55, 742.
Radcliffe Infirmary, Oxford.
dissociation, with due allowance K. G. M. M. ALBERTI PAULINE M. EMERSON J. H. DARLEY T. D. R. HOCKADAY.
THE SINGLE-HANDED PRACTITIONER
SiR,—The urban single-handed general practitioner can same (increasingly appreciated) advantages to his patients, and suffers the same disadvantages as those rural doctors described by Dr. Bowden (April 1, p. 755). Moreover, living expenses in the centre of a large city, especially "Reversal of London, are disproportionately heavy. justice " is too high-sounding. The sordid reality is that there is a deliberate policy to squeeze out those who are presently seen as untidy anachronisms. -offer the
8 Orange Street, Haymarket, London W.C.2.
BENJAMIN LEE.
THE WIEDEMANN-BECKWITH SYNDROME: GENETIC CONSIDERATIONS AND A DIAGNOSTIC SIGN
SiR,—There have been several reports of familial occurof the Wiedemann-Beckwith syndrome (w.B.S.).l-6 It has been suggested 7-9 that the W.B.S. is determined by -the homozygous state of an autosomal recessive mutation. We have studied a family (fig. 1) in which the syndrome occurred in two pairs of sibs who are second cousins. Two rence
sib-first cousins once removed died neonatally, and at least of them had omphalocele. The parents of the affected children were not known to be consanguineous, and trans-
one
1. 2. 3. 4. 5. 6. 7.
8. 9.
Wiedemann, H.-R. J. Génét. hum. 1964, 13, 223. Irving, I. M. J. pediat. Surg. 1967, 2, 499. Borit, A., Kosek, J. Archs Path. 1969, 88, 58. Chambionnat, D. Thèse, Faculté de Médecine, Paris, 1969. Rossier, A., Lustosa, M. L. Ann. Pediat. 1970, 17, 452. Bohlmann, H.-G., Havers, W. Arch. Kinderheilk, 1971, 183, 175. Beckwith, J. B. Birth Defects: Original Article Series; vol. v, p. 188. New York, 1969. Fillippi, G., McKusick, V. A. Medicine, 1970, 49, 279. McKusick, V. A. Mendelian Inheritance in Man; p. 275. Baltimore, 1971.
Fig. 2-Indented
ear
lesions
on
the
posterior
rim of the helix
of IV-26.
mission of the w.B.s. in this family is not consistent with recessive inheritance. Similarly, the hypothesis of recessive inheritance is not supported by the famiiy reported by Irving2 in which two brothers, their second cousin, and possibly a first cousin were affected with the w.B.s. In addition to the previously described malformations, we have found an ear anomaly in all five of the WiedemannBeckwith patients we have examined. It consists of one or more bilateral, focal, well-demarcated, indented areas on the posterior rim of the helix measuring 1-2 mm. in diameter (fig. 2). We have not seen this lesion in other syndromes. Though probably not pathognomonic of and obligatory in the w.B.s., we think that it is very helpful in the diagnosis of that condition. Departments of Pediatrics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53706, U.S.A.
ANDREW L. KOSSEFF JÜRGEN HERRMANN JOHN M. OPITZ.
CHRONIC CARRIAGE OF AUSTRALIA ANTIGEN SIR,-We reportedtwo apparent types of chronic carriage of Australia antigen associated with hepatitis, namely, (a) patients recovering from hepatitis showing high stable c.F. titres (1024-2048) in whom the antigen was " free ", and (b) patients with low c.F. titres (4-16) in whom antigen was " bound " and could be detected only
Fig. 1-Dominant inheritance in W.B.S. Note transmission through apparently normal individuals. Blackened symbols indicate cases of w.B.s. Bar over symbol :indicates family members examined by us. III-1 died neonatally and had omphalocele. III-3 died neonatally. IV-11 -died at nine months of age with multiple congenital anomalies.
by heating the serum at 85’C for 1 hour before testing. We suggested that these low titres of " bound " antigen were probably liberated from antigen-antibody complexes. We have now circumstantial evidence that a male nurse, aged 28, showing persistent hepatitis with stable high c.F. titres of free antigen for 1 year, acquired his initial acute hepatitis infection while nursing a man age 53 with chronic active hepatitis who, at the time of probable infection of the nurse and during the subsequent year, had low titres of " bound " antigen. This suggests that cross-infection with the virus bound in antigen-antibody complexes may result in persistent infection. Two possible mechanisms may be involved in such persistence-namely, inhibition of the patient’s own antibody response, and slow release of virus from such 1. Ross, C. A. C.,
Pringle,
R. C.
Lancet, 1971, ii, 434.
complexes. In individuals with normal immunological responses, infection with an Australia antigen-antibody complex may therefore be more likely to result in a symptomless infection and prolonged carriage of Australia antigen than infection with " free " virus. Virus Laboratory, Ruchill Hospital, Glasgow G20 9NB.
Regional Ayrshire
Central
CONSTANCE A. C. ROSS.
Hospital,
Irvine,
Ayrshire KA12 8SS. Ballochmyle Hospital, Mauchline, Ayrshire.
W. S. ROBERTS. A. SLESSOR.
PERIPHERAL VENOUS SCANNING WITH 125I-TAGGED FIBRINOGEN
SIR,-Mr. Mavor and his colleagues (March 25, p. 661) rightly question some extravagant claims made for the 125I-fibrinogen test in peripheral venous scanning,
particularly
when it is used
coagulant therapy.
as an
index of need for anti-
However, they have chosen
weapon for debate. We take their description of method to
a
poor
mean
that
125I-tagged fibrinogen was given to patients after the diagnosis of pulmonary embolism or iliofemoral thrombosis. Administration of tagged fibrinogen subsequent to established thrombosis or embolism is bound to be relatively useless since (a) thrombolysis is likely to be taking place and the tagged fibrinogen will find no thrombus in which to be incorporated; (b) in those patients with embolism the clot may have left the periphery entirely. (Shown in their paper by the 36% of patients with negative phlebography.) Their arguments would have gained validity only if their patients had undergone peripheral venous scanning using 125I-fibrinogen and had not been found positive in spite of later development of embolism or iliofemoral thrombosis. we continue to use the 125I-fibrinogen test diagnose calf-vein thrombosis as a test of three main prophylactic methods in patients undergoing hip replacements. Finally, we shall find which patients have a pul-
In Exeter
to
or die as a result of it. This will be the crucial test of these prophylactic methods, and this will also tell us whether calf-vein thrombosis as diagnosed by 125I-tagged fibrinogen is associated with pulmonary embolism.
monary embolism
Princess Elizabeth Orthopædic Exeter EX2 4UE.
Hospital,
D. S. HALPIN C. D. JEFFERISS R. S. M. LING.
SIR,-The report of Mr. Mavor and colleagues is Their conclusions are certain to provoke controversy. based on a study of 76 cases of pulmonary embolism and 50 cases of iliofemoral thrombophlebitis. It is unwarranted and misleading to deprecate the validity of 1251-labelled fibrinogen leg scanning for the detection of early disease in asymptomatic subjects on the basis of a study restricted, as was theirs, to late, even far-advanced, thromboembolism. Authors cited in this article, and others, have confirmed with phlebograms that the radioisotope technique sensitively detects the earliest form of the disease in the areas which appear to be involved first-the soleal veins and other deep veins of the leg.l-3 It is not contested that the Negus, D., Pinto, D. J., Le Quesne, L. P., Brown, N., Chapman, M. Br. J. Surg. 1968, 55, 835. 2. Bonnar, J., Walsh, J. Lancet, March 18, 1972, i, 614. 3. Tsapogas, M. J., et al. Archs Surg. 1970, 101, 149. 1.
iliofemoral segment is the source of major pulmonary embolism. It is regrettable, on the other hand, that the authors minimise the importance of venous thrombosis arising in more peripheral sites. There is every reason to believe that effective prevention at this level in patients at risk will protect against thrombosis in the iliofemoral area at the same time. Our own experience with 1251labelled fibrinogen in a controlled trial of postoperative prophylaxis clearly shows that neither physical examination, ultrasound, nor electrical impedance techniques are superior to radioisotope leg scanning for early detection. Phlebograms confirmed that venous thrombosis could be demonstrated in 10 of the 12 patients with positive leg scans among 50 patients who had had total hip replacement. None of these incurred embolism or developed occlusion in the iliofemoral segment. We hold that the efficacy of prevention should be judged by criteria reflecting the earliest form of the disease. It must be assumed that the deposition of fibrin in the leg, even though often selflimiting, represents one stage of the same disease process which in more fulminant form gives rise to iliofemoral thrombosis and pulmonary embolism. Prophylaxis should quite properly be evaluated by criteria which indicate that the disease has been affected at its onset, for reasons of both efficacy and ethics. No technique now available approaches 125I_labelled fibrinogen for this purpose. Lemuel Shattuck Hospital, 170 Morton Street, Boston, Massachusetts 02130, U.S.A.
MICHAEL HUME VICTOR GUREWICH.
"
SIR,-Mr. Mavor and his colleagues seek to discount the impression which is rapidly gaining ground that peripheral scanning is the new early-warning system for deep-vein thrombosis and its subsequent treatment ". We cannot agree statement.
that their
study lends
much support
to
this
Their report suffers from a number of omissions. There no description of the methodology of the 25I_labelled fibrinogen uptake test used in the study, nor of the criteria for the diagnosis of venous thrombosis. It would have been interesting to know the age and sex distribution of the patients studied and also why only iliac-femoral is
phlebography was performed. Peripheral phlebography was clearly indicated in those 26 patients in whom both iliofemoral phlebography and peripheral scanning were negative. Of course, phlebography is the best single diagnostic procedure in the investigation of a patient presenting with pulmonary embolism of unknown origin; and, of course, the 125I-fibrinogen-uptake technique is useless in the groin and above the inguinal ligament, 1,2where a number of major thromboses are known to arise, 3,4 and is also unlikely to detect peripheral thrombi more than 5 or 6 days old
or
in the presence of lower limb oedema.5
These
recognised deficiencies of the test in no way detract from its proven value as a prospective method for the detection of early (e.g., before embolism has occurred) calf and femoral thromboses, 1,6 and used in this way it has a useful place in patient screening and in research. Admittedly, many peripheral thrombi are of little significance but they are phlebographically demonstrable thrombi none the less.s The established method for screening and for early detection of thrombosis in the femoral and iliac veins is 1. 2. 3. 4. 5.
6.
Negus, D., Pinto, D. J., Le Quesne, L. P., Brown, N., Chapman, M. Br. J. Surg. 1968, 55, 835. Evans, D. S., Negus, D. Br. J. Hosp. Med. 1971, 6, 729. Sevitt, S., Gallagher, N. G. Lancet, 1959, ii, 981. Negus, D., Evans, D. S. ibid. 1971, ii, 763. Browse, N. L., Clapham, W. F., Croft, D., Jones, D. J., Lea Thomas, M., Williams, J. O. Br. med. J. 1971, iv, 325. Flanc, C., Kakkar, V. V., Clarke, M. B. Br. J. Surg. 1968, 55, 742.