114 mammals is governed by the size or appearance of the 2 upper incisors in their young. It is wiser to give guidance on the commencement and cessation of weaning-and indeed the value of breastfeeding in a developed country-on immunological and nutritional grounds. In the first week of life breast milk is of importance owing to the presence of large amounts of secretory IgA in the colostrum which protects the infant from Escherichia coli infections which are especially prevalent during this period of infancy. Thus even one week of breast-feeding is of great benefit to the baby. It is also advisable to continue breast-feeding for the first 4-6 months in order to provide the baby with a balanced diet, which is not provided by substitutes. If weaning begins at the age of 3-4 months, after which period breast milk alone is no longer sufficient for the nutritional requirements, and is completed after a further 1-2 months when the baby has settled down on the weaning diet-then the baby will be assured of the best start in life. Such advice, however, should never be given in a developing country, where it is to the baby’s advantage to prolong weaning by a year. In 1768 William Cadogan sent an Essay to the Committee of the Foundling Hospital in London: " ... and dry-nursing I look upon to be the most unnatural and dangerous method of all, and according to my observation not one in three survives it It is still advisable for all physicians and nurses in the developing countries to remember those words before advising the cessation of breast-feeding.
Liverpool School of Tropical Medicine, Pembroke Place,
Liverpool
L3
5QA.
FRANCIS M. SHATTOCK ANTHONY J. H. STEPHENS.
DIFFERENTIATION OF IRON DEFICIENCY FROM THALASSÆMIA TRAIT SIR,-England and Fraserproposed a function that could distinguish thalassasmia trait from other microcytic anxmias. Later, Mentzer2 claimed that a simpler index could be used with the same efficiency. On the other hand, Hamblin3 challenged the usefulness of England and Fraser’s function. More recently England et awl. have replied to the above objections. The D.F.’ of England and Fraser and the M.c.v./R.s.c. quotient proposed by Mentzer have been calculated for a group of 48 beta-thalasseemia-trait patients and 195 hypochromic sideropenic patients from our records. All the patients have been identified on the basis of the first work of England and Fraser (using an I.C.S.H. haemoglobin reference preparation). The results are summarised in the accompanying table.
14-5 °of the thalassxmia patients fall into the
uncertainty (from
zone
of
1 to
-1) applying D.F.’ compared to 39-5%for Mentzer’s index (11 to 13). Nevertheless, the actual failure in detecting thalassasmia is not very different (8-3 °and 12-5%, respectively). Both indices would have failed to detect 3 pregnant thalassxmia-trait patients, but these have been excluded from the group, following England and Fraser’s recommendations. With reference to iron-deficiency anaemia, 0-5% of all cases fall into the uncertainty zone using the D.F.’ and 10%
with Mentzer’s index. The percentage of failures is similar in both indices (0-5°° and 1 respectively). With regard to the thalassasmia failures in 3 patients, both indices fail to detect the trait, 3 other cases are detected 2. See Catchpole, B. N. Lancet, Dec. 7, 1974, p. 1392. 3. England, J. M., Fraser, P. M. ibid. 1973, i, 449. 4. Mentzer, W. C., Jr. ibid. p. 882. 5. Hamblin, T. J. ibid. p. 676. 6. England, J. M., Bain, B. J., Fraser, P. M. ibid. p. 1514.
RESULTS OF APPLICATION OF INDICES TO
243 PATIENTS
by the D.F.’ but not by Mentzer’s index, and only 1 case is detected by Mentzer’s index alone. In the iron-deficiency group failures, the D.F.’ fails to detect only 1 case (this is a one-year-old child) and Mentzer’s index fails to detect 2 other cases (one a child of three years). 8 thalasssemia-trait patients in whom both indices fit well with the diagnosis had a degree of iron deficiency. The indices remained more or less constant throughout sound and well-controlled iron treatment. England and Fraser’s discriminant function (D.F.) seems to be able to screen the great majority ofthalasssemiatrait cases (using only three laboratory measurements). As soon as its usefulness has been throughtly proved, we believe the substituting of the D.F.’ for the present M.H.c. in automated laboratory instruments should be recommended. ENRIQUE GIMFERRER Servicio de Hematología, GEMMA MARIGO Hospital de la Santa Cruz y San MIGUEL L. RUTLLANT Pablo, JOSE VIÑAS. Barcelona, Spain. ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY WITH DYSPROTEINÆMIA
SiR,—The paper by Frizzera et al.l evoked a response in case-reports,2-5 which suggests that angio-immunoblastic lymphadenopathy with dysproteinsemia (A.I.L.D.) is not uncommon. Discussion of the same lesion by Dorfman and Warnkeunder the title " immunoblastic lymphadenopathy refers to personal communications by Rappaport and by Lukes. We have seen a case similar in many ways to those described by Frizzera et a1.l and exemplifying the diagnostic and therapeutic problems which will persist until A.I.L.D. is more clearly defined. the form of several
"
A 66-year-old woman had sudden onset of increasing tiredness and shortness of breath, with loss of weight and appetite. Lymphnodes were palpable in the cervical, axillary, and inguinal regions. The spleen was 3 cm. below the left costal margin. On admission there were no petechial haemorrhages or bruises, and retinal examination was normal. A blood-film showed normocytic and normochromic anasmia with prominent rouleaux formation. White blood-count was 11,300 per c.mm. with absolute lymphopenia (678 per c.mm.) and 2% plasmacytosis. Erythrocyte sedimentation-rate was raised (120 mm. in 1 hour). A sternal marrow aspirate was hypercellular with a 16% plasmacytosis. Serum-uric-acid was high (18-9 mg. per 100 ml.). There was a moderate increase in alkaline phosphatase (96 units), serum-creatinine (1-5 mg. per 100 ml.), blood-urea nitrogen (40 mg. per 100 ml.), and bromsulphalein retention after 45 minutes (10%). Other investigations included normal serum bilirubin, transaminases, calcium, and
phosphorous. Serum-protein electrophoresis showed a polygammopathy and hypoalbuminaemia (albumin 1-7 g. per 100 ml. and globulins 5-7 g. per 100 ml.). Radial immunodiffusion showed all classes of immunoglobulins to be raised (IgG 5795 mg., IgA 1245 mg., 1. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. 2. Horne, C. H. W., Fraser, R. A., Petrie, J. C. ibid. 1974, ii, 291. 3. Nomanbhoy, Y. T., Prager, P. R. ibid. p. 409. 4. Twomey, J. J. ibid. 1974, i, 1345. 5. Tangun, Y., Saracbasi, Z., Pekcelen, Y., Inceman, S. ibid. p. 1345. 6. Dorfman, R. F., Warnke, R. Hum. Path. 1974, 5, 519.
115 and IgM 420 mg. per 100 ml.). There was Bence-Jones proteinuria with both K and X light chains in the serum. Protein electrophoresis of a 24-hour urine showed a diffuse band at the and
(albumin
1-1 g. and
Obituary
2-4 g. per 24 hours). Quantitative immunoglobulins in a concentrated urine sample showed that only IgG (88 mg. per 100 ml.) and IgA (trace) were y zones
globulin
VINCENT ZACHARY COPE Kt., M.D., M.S.Lond., F.R.C.S.
present.
Hepatosplenomegaly was confirmed by scanning. Lymphangiogram failed to show contrast material in the retroperitoneal
lymph-nodes, although lymphatics
were
easily displayed. Lytic
were absent in a skeletal survey. Cervical and axillary lymph-node biopsy (kindly confirmed by
Zachary Cope, consulting surgeon to St. Mary’s Hospital, Paddington, died on Dec. 28 at the age Sir
lesions
of 93.
Dr H. Rappaport) showed destruction of the normal architecture of the nodes with proliferation of both reticular and lymphocytic cells. The reticulum cells were irregular with prominent mitotic activity. There was also heavy diffuse infiltration by plasma cells, and methyl-green pyronin stains showed a striking pyroninophilia in many cells throughout the nodes. Thickened capillaries with prominent endothelial linings were increased throughout all sections examined. While in hospital the patient had petechial haemorrhages over the legs, which later evolved into a hasmorrhagic macular rash on the face and trunk. Initial platelet count was normal, but mild thrombocytopenia developed later (88,000 per c.mm.). She was given combination chemotherapy, including cyclophosphamide 800 mg. intravenously, vincristine 2 mg. intravenously, and prednisone 50 mg. orally twice daily. Two days later, she became febrile, and bronchial breathing was heard at the base of the left lung posteriorly. She died on the third day after treatment started. At necropsy, the cause of death was bilateral bronchoThere was generalised lymphadenopathy and pneumonia. splenomegaly, the spleen weighing 825 g. There were also multiple ulcers in the oesophageal mucosa, which were demonstrated to be of herpetic type. Sections of lymph-nodes showed similar appearances to those of the biopsy material, and the same changes were seen in spleen and bone-marrow. Focal infiltration by plasma cells and lymphocytes was noted in subcutaneous tissue, pericardium, liver, and kidneys.
He was born in 1881, the son of a Nonconformist minister, and he lived almost all his life in London. His association with St. Mary’s Hospital was a long and most fruitful one, beginning with a scholarship entrance to the medical school and ending not many days ago, after a Christmas which he had marked, as was increasingly his custom in later years, with a greetings verse in rhyme that will shortly be published in St. Mary’s Hospital Gazette. He was early associated with
The close clinical and pathological similarities between this case and those of Frizzera et al.l are evident. The histological identity has been confirmed by Dr Rappaport, who did, however, point out two rather unusual features, namely, the degree of mitotic activity and the massive involvement of the spleen. The active cellular proliferation probably also explains the remarkably high serum-uric-acid and the very high levels of all classes of immunoglobulins. The presence of light chains in the serum has been reported by Tangun et al.5 The original diagnosis in our case was malignant lymphoma of mixed type with pronounced immunological reaction to the tumour. This sort of immunological to is tumour response commonplace in minor degrees and may be marked in such neoplasms as medullary carcinoma of breast. However, we found Dr Rappaport’s arguments convincing and we were particularly impressed by the
pyroninophilia. is in fact a graft-v.-host reaction rather than then there are, as suggested by Frizzera et al.,l neoplasm, obvious implications for treatment. Our patient was given immunosuppressive therapy on the basis of a diagnosis of malignant lymphoma. She died soon after treatment began, as happened in other reported cases, and it certainly seems desirable to use only supportive therapy in future to determine whether the disease runs a more prolonged course. In our patient, however, the alarming clinical deterioration from the outset, even before therapy, suggests a rapidly progressive disease. If
A.LL.D.
Ontario Cancer Foundation, Windsor Clinic, 2220 Kildare Road, Windsor, Ontario N8W 2X3, Canada. Department of Pathology, Hotel Dieu Hospital, 1030 Ouellette Avenue, Windsor, Ontario N9A 1E1, Canada.
H. T. ABU-ZAHRA D. B. MCDONALD.
of the contemporary great and others, his classmates,
many
who, like him, were in the future to
achieve
wide
fame
and
Among his teachers Augustus Waller, who
success.
were
made the first electrocardiograph, and Almroth Wright, the pioneer of bacteriology and Student colimmunology. leagues included Alexander Fleming, Charles Pannett, and In such an Aleck Bourne. at a time of swift environment, advance on many surgical fronts, Cope found rapid promUHUH———JU
JUilU
mc
LC1U.
hospital in 1911 just two years after becoming F.R.C.S. His reputation as a clinical teacher at the bedside brought a large attendance at his rounds. He was able to express his own response as a Christian gentleman to the suffering of others while at the same time putting across the wise and practical inferences that his excellently inductive mind could so readily distil for the assimilation of his pupils. It must have been this felicitous grasp of clinical essentials combined with a deep compassion for the victims of unhappy surgical circumstances that led him to write one of the most successful books in surgery, The Early Diagnosis of the Acute Abdomen, which was first published in 1921, when mistakes of this kind were far less easily rectified than today. The recent fourteenth edition is still selling all over the world. Later in his career Zachary Cope showed his full literary bent in studies on subjects as diverse as actinomycosis and the surgery of modern war-with personal contributions on blast injury, burns, and the
of his
own
results of the atomic bomb. After retirement, his undiminished energies were applied to the wide and rewarding field of medical history. He was generally to be seen in the library of the Royal Society of Medicine, researching for his next book. During these years he wrote the histories of the Royal College of Surgeons to whose council he had been elected in 1940, and of St. Mary’s Hospital, as well as the life of Cheselden. These and other written works will ensure him a lasting place in medical history, but those whose good fortune it has been to know him will above all remember his kindness, honesty, and modest greatness. He
was
twice
widowed, and is survived by his only
daughter. H. H. G. E. The
W. I. HORNE.
drawing
of Sir
Zachary Cope
is
by Juliet Pannett, and is
duced from St. Mary’s Hospital Gazette.
repro-
Liverpool School of Tropical Medicine, Pembroke Place,
Liverpool
L3
5QA.
FRANCIS M. SHATTOCK ANTHONY J. H. STEPHENS.
DIFFERENTIATION OF IRON DEFICIENCY FROM THALASSÆMIA TRAIT SIR,-England and Fraserproposed a function that could distinguish thalassasmia trait from other microcytic anxmias. Later, Mentzer2 claimed that a simpler index could be used with the same efficiency. On the other hand, Hamblin3 challenged the usefulness of England and Fraser’s function. More recently England et awl. have replied to the above objections. The D.F.’ of England and Fraser and the M.c.v./R.s.c. quotient proposed by Mentzer have been calculated for a group of 48 beta-thalasseemia-trait patients and 195 hypochromic sideropenic patients from our records. All the patients have been identified on the basis of the first work of England and Fraser (using an I.C.S.H. haemoglobin reference preparation). The results are summarised in the accompanying table.
14-5 °of the thalassxmia patients fall into the
uncertainty (from
zone
of
1 to
-1) applying D.F.’ compared to 39-5%for Mentzer’s index (11 to 13). Nevertheless, the actual failure in detecting thalassasmia is not very different (8-3 °and 12-5%, respectively). Both indices would have failed to detect 3 pregnant thalassxmia-trait patients, but these have been excluded from the group, following England and Fraser’s recommendations. With reference to iron-deficiency anaemia, 0-5% of all cases fall into the uncertainty zone using the D.F.’ and 10%
with Mentzer’s index. The percentage of failures is similar in both indices (0-5°° and 1 respectively). With regard to the thalassasmia failures in 3 patients, both indices fail to detect the trait, 3 other cases are detected 2. See Catchpole, B. N. Lancet, Dec. 7, 1974, p. 1392. 3. England, J. M., Fraser, P. M. ibid. 1973, i, 449. 4. Mentzer, W. C., Jr. ibid. p. 882. 5. Hamblin, T. J. ibid. p. 676. 6. England, J. M., Bain, B. J., Fraser, P. M. ibid. p. 1514.
RESULTS OF APPLICATION OF INDICES TO
243 PATIENTS
by the D.F.’ but not by Mentzer’s index, and only 1 case is detected by Mentzer’s index alone. In the iron-deficiency group failures, the D.F.’ fails to detect only 1 case (this is a one-year-old child) and Mentzer’s index fails to detect 2 other cases (one a child of three years). 8 thalasssemia-trait patients in whom both indices fit well with the diagnosis had a degree of iron deficiency. The indices remained more or less constant throughout sound and well-controlled iron treatment. England and Fraser’s discriminant function (D.F.) seems to be able to screen the great majority ofthalasssemiatrait cases (using only three laboratory measurements). As soon as its usefulness has been throughtly proved, we believe the substituting of the D.F.’ for the present M.H.c. in automated laboratory instruments should be recommended. ENRIQUE GIMFERRER Servicio de Hematología, GEMMA MARIGO Hospital de la Santa Cruz y San MIGUEL L. RUTLLANT Pablo, JOSE VIÑAS. Barcelona, Spain. ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY WITH DYSPROTEINÆMIA
SiR,—The paper by Frizzera et al.l evoked a response in case-reports,2-5 which suggests that angio-immunoblastic lymphadenopathy with dysproteinsemia (A.I.L.D.) is not uncommon. Discussion of the same lesion by Dorfman and Warnkeunder the title " immunoblastic lymphadenopathy refers to personal communications by Rappaport and by Lukes. We have seen a case similar in many ways to those described by Frizzera et a1.l and exemplifying the diagnostic and therapeutic problems which will persist until A.I.L.D. is more clearly defined. the form of several
"
A 66-year-old woman had sudden onset of increasing tiredness and shortness of breath, with loss of weight and appetite. Lymphnodes were palpable in the cervical, axillary, and inguinal regions. The spleen was 3 cm. below the left costal margin. On admission there were no petechial haemorrhages or bruises, and retinal examination was normal. A blood-film showed normocytic and normochromic anasmia with prominent rouleaux formation. White blood-count was 11,300 per c.mm. with absolute lymphopenia (678 per c.mm.) and 2% plasmacytosis. Erythrocyte sedimentation-rate was raised (120 mm. in 1 hour). A sternal marrow aspirate was hypercellular with a 16% plasmacytosis. Serum-uric-acid was high (18-9 mg. per 100 ml.). There was a moderate increase in alkaline phosphatase (96 units), serum-creatinine (1-5 mg. per 100 ml.), blood-urea nitrogen (40 mg. per 100 ml.), and bromsulphalein retention after 45 minutes (10%). Other investigations included normal serum bilirubin, transaminases, calcium, and
phosphorous. Serum-protein electrophoresis showed a polygammopathy and hypoalbuminaemia (albumin 1-7 g. per 100 ml. and globulins 5-7 g. per 100 ml.). Radial immunodiffusion showed all classes of immunoglobulins to be raised (IgG 5795 mg., IgA 1245 mg., 1. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. 2. Horne, C. H. W., Fraser, R. A., Petrie, J. C. ibid. 1974, ii, 291. 3. Nomanbhoy, Y. T., Prager, P. R. ibid. p. 409. 4. Twomey, J. J. ibid. 1974, i, 1345. 5. Tangun, Y., Saracbasi, Z., Pekcelen, Y., Inceman, S. ibid. p. 1345. 6. Dorfman, R. F., Warnke, R. Hum. Path. 1974, 5, 519.
115 and IgM 420 mg. per 100 ml.). There was Bence-Jones proteinuria with both K and X light chains in the serum. Protein electrophoresis of a 24-hour urine showed a diffuse band at the and
(albumin
1-1 g. and
Obituary
2-4 g. per 24 hours). Quantitative immunoglobulins in a concentrated urine sample showed that only IgG (88 mg. per 100 ml.) and IgA (trace) were y zones
globulin
VINCENT ZACHARY COPE Kt., M.D., M.S.Lond., F.R.C.S.
present.
Hepatosplenomegaly was confirmed by scanning. Lymphangiogram failed to show contrast material in the retroperitoneal
lymph-nodes, although lymphatics
were
easily displayed. Lytic
were absent in a skeletal survey. Cervical and axillary lymph-node biopsy (kindly confirmed by
Zachary Cope, consulting surgeon to St. Mary’s Hospital, Paddington, died on Dec. 28 at the age Sir
lesions
of 93.
Dr H. Rappaport) showed destruction of the normal architecture of the nodes with proliferation of both reticular and lymphocytic cells. The reticulum cells were irregular with prominent mitotic activity. There was also heavy diffuse infiltration by plasma cells, and methyl-green pyronin stains showed a striking pyroninophilia in many cells throughout the nodes. Thickened capillaries with prominent endothelial linings were increased throughout all sections examined. While in hospital the patient had petechial haemorrhages over the legs, which later evolved into a hasmorrhagic macular rash on the face and trunk. Initial platelet count was normal, but mild thrombocytopenia developed later (88,000 per c.mm.). She was given combination chemotherapy, including cyclophosphamide 800 mg. intravenously, vincristine 2 mg. intravenously, and prednisone 50 mg. orally twice daily. Two days later, she became febrile, and bronchial breathing was heard at the base of the left lung posteriorly. She died on the third day after treatment started. At necropsy, the cause of death was bilateral bronchoThere was generalised lymphadenopathy and pneumonia. splenomegaly, the spleen weighing 825 g. There were also multiple ulcers in the oesophageal mucosa, which were demonstrated to be of herpetic type. Sections of lymph-nodes showed similar appearances to those of the biopsy material, and the same changes were seen in spleen and bone-marrow. Focal infiltration by plasma cells and lymphocytes was noted in subcutaneous tissue, pericardium, liver, and kidneys.
He was born in 1881, the son of a Nonconformist minister, and he lived almost all his life in London. His association with St. Mary’s Hospital was a long and most fruitful one, beginning with a scholarship entrance to the medical school and ending not many days ago, after a Christmas which he had marked, as was increasingly his custom in later years, with a greetings verse in rhyme that will shortly be published in St. Mary’s Hospital Gazette. He was early associated with
The close clinical and pathological similarities between this case and those of Frizzera et al.l are evident. The histological identity has been confirmed by Dr Rappaport, who did, however, point out two rather unusual features, namely, the degree of mitotic activity and the massive involvement of the spleen. The active cellular proliferation probably also explains the remarkably high serum-uric-acid and the very high levels of all classes of immunoglobulins. The presence of light chains in the serum has been reported by Tangun et al.5 The original diagnosis in our case was malignant lymphoma of mixed type with pronounced immunological reaction to the tumour. This sort of immunological to is tumour response commonplace in minor degrees and may be marked in such neoplasms as medullary carcinoma of breast. However, we found Dr Rappaport’s arguments convincing and we were particularly impressed by the
pyroninophilia. is in fact a graft-v.-host reaction rather than then there are, as suggested by Frizzera et al.,l neoplasm, obvious implications for treatment. Our patient was given immunosuppressive therapy on the basis of a diagnosis of malignant lymphoma. She died soon after treatment began, as happened in other reported cases, and it certainly seems desirable to use only supportive therapy in future to determine whether the disease runs a more prolonged course. In our patient, however, the alarming clinical deterioration from the outset, even before therapy, suggests a rapidly progressive disease. If
A.LL.D.
Ontario Cancer Foundation, Windsor Clinic, 2220 Kildare Road, Windsor, Ontario N8W 2X3, Canada. Department of Pathology, Hotel Dieu Hospital, 1030 Ouellette Avenue, Windsor, Ontario N9A 1E1, Canada.
H. T. ABU-ZAHRA D. B. MCDONALD.
of the contemporary great and others, his classmates,
many
who, like him, were in the future to
achieve
wide
fame
and
Among his teachers Augustus Waller, who
success.
were
made the first electrocardiograph, and Almroth Wright, the pioneer of bacteriology and Student colimmunology. leagues included Alexander Fleming, Charles Pannett, and In such an Aleck Bourne. at a time of swift environment, advance on many surgical fronts, Cope found rapid promUHUH———JU
JUilU
mc
LC1U.
hospital in 1911 just two years after becoming F.R.C.S. His reputation as a clinical teacher at the bedside brought a large attendance at his rounds. He was able to express his own response as a Christian gentleman to the suffering of others while at the same time putting across the wise and practical inferences that his excellently inductive mind could so readily distil for the assimilation of his pupils. It must have been this felicitous grasp of clinical essentials combined with a deep compassion for the victims of unhappy surgical circumstances that led him to write one of the most successful books in surgery, The Early Diagnosis of the Acute Abdomen, which was first published in 1921, when mistakes of this kind were far less easily rectified than today. The recent fourteenth edition is still selling all over the world. Later in his career Zachary Cope showed his full literary bent in studies on subjects as diverse as actinomycosis and the surgery of modern war-with personal contributions on blast injury, burns, and the
of his
own
results of the atomic bomb. After retirement, his undiminished energies were applied to the wide and rewarding field of medical history. He was generally to be seen in the library of the Royal Society of Medicine, researching for his next book. During these years he wrote the histories of the Royal College of Surgeons to whose council he had been elected in 1940, and of St. Mary’s Hospital, as well as the life of Cheselden. These and other written works will ensure him a lasting place in medical history, but those whose good fortune it has been to know him will above all remember his kindness, honesty, and modest greatness. He
was
twice
widowed, and is survived by his only
daughter. H. H. G. E. The
W. I. HORNE.
drawing
of Sir
Zachary Cope
is
by Juliet Pannett, and is
duced from St. Mary’s Hospital Gazette.
repro-
