554 P.I.F., and
suppressive effects were observed after the first of 45 megaunits. Treatment had to be abandoned because of side-effects, the severity of which may have been related to the combination of high-dosage P.I.F. and pre-existcourse
ing immunosuppression. The fact that leukopenia has been noted in patients treated with fibroblast’ or leucocyte derived interferon2.3 suggests that marrow suppression is a general and important side-effect of the preparations currently available. Details of this
case
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, 06105, U.S.A.
will be reported in full elsewhere.
Blood Transfusion Service,
Royal Infirmary, Edinburgh EH3 9HB Nuffield Transplantation Surgery Unit, Western General Hospital, Edinburgh Dermatology Department, Royal Infirmary, Edinburgh Department of Pathology, University of Edinburgh
S.
DAVID T. PURTILO
J. URBANIAK
I. M. HALLIDAY
G. W. BEVERIDGE
A. B. KAY
X-LINKED RECESSIVE LYMPHOPROLIFERATIVE SYNDROME StR,—Three excellent articlesl-3 on the X-linked recessive
lymphoproliferative syndrome4-9
receptors required for receiving messages of help from T cells may be lacking on the surface of defective B cells of the patients with the X-linked syndrome. While the clinicopathological and immunogenetic features of this devastating syndrome are being elucidated, the term "Duncan’s disease" should be avoided. "X-linked recessive lymphoproliferative syndrome" may not be simple, but meaning is conveyed. Students already have too many meaningless eponyms to learn.
have
speculated
on
the pro-
of and the mechanisms responsible for this provocaper tive syndrome. The generic name, "X-linked recessive lymphoproliferative syndrome"8 conveys information; "Duncan’s disease" does not. Regrettably, when we described the disease4 we attached the eponym "Duncan’s disease" to our cumbersome, but accurate "X-linked recessive progressive combined variable immunodeficiency". Alas, alliteration won out over science. Besides, Mr Duncan should not be blamed for this devastating disease-he could not have possessed the defective X-linked lymphoproliferative control locus. We chose to use the generic X-linked recessive lymphoproliferative syndrome8 because lymphoproliferation is the cardinal feature of this pleiotropic genetic disorder. Epstein-Barr virus (E.B.v.) infection is frequently lethal to males with the syndrome : approximately 40% have died after infection by E.B.v. as infectious mononucleosis, 40% developed B-cell lymphomas, and 20% have alymphoproliferative disorders such as hypogammaglobulinaemia.6-8 Thus the two essential elements of the syndrome are X-linked recessive inheritance and lymname
ABNORMALITIES OF CHROMOSOME NO. 1 IN HÆMATOLOGICAL MALIGNANCIES
SIR,-I read the letter by Dr Gahrton and colleagues (Jan. 14, p. 96) with interest because I have lately done a similar
analysis.l,2 Although both studies revealed that trisomy for the long arm of no. 1 invariably affected specific bands, the bands different in the two series. Gahrton et al. noted of lq23-25 in every one of 15 patients, whereas the adjacent bands lq25-32 were trisomic in all of the 34 patients on whom I reported (see figure). These bands (lq25-32) were trisomic in 14 of the 15 patients referred to by Gahrton et al.; on the other hand, 4 of the 34 patients in my report were not trisomic for lq23-25. In 3 of the 4 exceptions, bands lq25 to the end of the long arm were translocated to the short arm of no. 6 (bands 6q21-25); each patient also had two normal no. l’s. Thus, of the 35 patients studied in the two series, all except 1 were trisomic for lq25-1q32, and all except 4 were trisomic for lq21 to lq25, irrespective of the type ofhxmatological disorder. These bands are adjacent, and determination of break points in chromosomes, especially those involved in structural rearrangements, may be imprecise. Atkin and Baker3 called attention to abnormalities of chroinvolved
were
duplication
1.
Rowley, J. D.
in Molecular Human Cytogenetics: ICN-UCLA Symposium on Molecular and Cellular Biology; vol. III (edited by R. S. Sparkes, D. Comings, and C. F. Fox); p. 457. New York, 1977. 2. Rowley, J. D. Proc. natn. Acad. Sci. U.S.A. 1977, 74, 5729. 3. Atkin, N. B., Baker, M. Lancet, 1977, ii, 984.
phoproliferation. You3 claim that "The absence of any previous susceptibility candidiasis or other infections which typically occur in patients with defective cell-mediated immunity is evidence to
a pre-existing generalised defect of T cells in the boys with Duncan’s disease". This is not true: neonatal thrush, disseminated vaccinia after smallpox vaccination, and extraordinary measles infections have preceded fatal E.B.v. infections in affected males.4-9 The adjective, "subtle" could have reasonably been added to our report in The Lancet.4 The syndrome is not "limited"; it can be deadly when E.B.v. infection occurs. Failure of appropriate immune response to E.B.v. in boys with the defective X-linked lymphoproliferative control locus is responsible for the development of diverse disorders.1-9 The molecular defect responsible for this anergy to E.B.v. may result from a failure of the defective B cells to express E.B.v. antigens on the surface of E.B.v.-infected B cells.2.3Alternatively, as in the X-linked immunodeficient CBA/N mouse,2.3.10
against
Epstein, M. A., Achong, B. G. Lancet, 1977, ii, 1270. Rosen, R. S. New Engl. J. Med. 1977, 297, 1120. 3. Lancet, 1978, i, 132. 4. Purtilo, D. T., and others ibid. 1975, i, 935. 5. Purtilo, D. T. ibid. 1976, ii, 882. 1. 2.
6. Purtilo, D. T., and others Am. J. Med. 1977, 62, 225. 7. Purtilo, D. T. Sem. Oncol. 1977, 4, 335. 8. Purtilo, D. T., and others New Engl. J. Med. 1977, 297, 1077. 9. Purtilo, D. T., and others Clin. Immun. Immunopath. 1978, 9, 147. 10. Cone, R. F., Huber, B., Cantor, H., Gershon, H. Personal communication.
trisomic for chromosome no. 1 in 34 patients. Part of chromosome no. 1 that is trisomic in each patient is represented by vertical line. Detailed karyotypes are listed in ref. 1; the first nine patients have been studied in my laboratory. Dashed vertical lines indicate uncertain break points. A short horizontal bar indicates the end(s) of the chromosome. The dashed horizontal lines enclose the segment that is trisomic in every one of the 34 patients. (Reprinted from the Proceedings of the National Academy of Sciences of the United States of America.)
Region
555 a variety of human cancers affecting ovary, bladder, breast, and cervix; it is clear that (contrary to their statement) abnormalities of no. 1 occur in heematologic disorders as well. The observations reflect our increasing precision in defining not only the chromosome affected but also the critical portion of the chromosome. As I have suggested,2 correlation of these regions with the human gene map will provide insights into the role of chromosome changes in neoplasia.
mosome no.
1 in
,
Department of Medicine, Franklin McLean Memorial Research Institute
University of Chicago Chicago, Illinois 60637, U.S.A.
JANET D. ROWLEY
cannot be prescribed by general practibe obtained from a hospital consultant in exceptional circumstances. I suggest they are unnecessary if the British Diabetic Association recommendations on syringe sterilisation are followed. The case described by Mr Goldberg (Feb. 11, p. 331) is unusual and shows that better education of diabetics is needed, not disposable syringes. Disposable needles are more satisfactory and many patients purchase these in bulk to reduce cost. They can be prescribed from hospital at the consultant’s discretion. Many patients find that one needle is serviceable for several injections.
Disposable syringes
tioners but
can
Diabetic Clinic, Department of Child Health, Alder Hey Children’s Hospital, Liverpool L12 2AP
C. S. SMITH
SiR,--Gahrton mosome no.
q23-25
was
et al., summarising abnormalities of chromyeloproliferative diseases, note that region duplicated in all cases. Oshimura et aI.4 have
1 in
reviewed abnormalities of chromosome no. 1 in various tumour types; and the significance of involvement of chromosome no. 1, particularly region q21-25, has been pointed by Kakati et al. I found trisomy or partial trisomy of chromo-
Duplicated parts of chromosome no.
1 in
primary cancers.
1 in 5 breast cancers, 4 colonic cancers, and a primary, recurrent, and metastatic undifferentiated tumour of unknown origin studied by banding techniques.6 I found i(lq) in 3 breast cancers and 1 colonic cancer. Several parts of chro.mosome no. 1 were duplicated, but only q21-25 was duplicated in all cases (see figure). These findings suggest that region q21-25 of chromosome no. 1 is important for development of different tumour types, and that q21 is a vulnerable point on human chromosome no. 1. some no.
Department of Pathology, County Hospital, Kecskemét, Hungary
GYULA KOVACS
DISPOSABLE SYRINGES AND NEEDLES FOR DIABETICS
SIR,-Iwas surprised to read that Fiona Toal (Jan. 7, p. 45) found that 66% of diabetic patients did not sterilise their needles and syringes as recommended by the hospital. This suggests some deficiency in the educational programme for diabetic patients and a continuing need to educate diabetics about their condition and its management. The views of the British Diabetic Association are clearly set out in a leaflet (Insulin Treatment, DH 104) which should be issued to all new diabetic patients. Replacing needles and syr-
PROTEASE AS ENDOGENOUS ACTIVATOR OF INACTIVE RENIN
SIR,-The data presented by Dr Osmond and Dr Loh (Jan. 14, p. 102) accord with our repon1 that cryoactivation of inac-
plasma renin (D.F.P.). However,
tive
is inhibited by diisopropylfluorophosphate do not believe their conclusions entirely accord with the available evidence. They state that acid-activation of inactive renin "cannot prove that endogenous activation exists" but suggest that D.F.P.-inhibitable cryoactivation and activation by exogenous trypsin "bring us closer" to that proof. We have shown’ that acid-activation and cryoactivation involve similar enzymatic reactions. Acid-activation is a two-step process, 70% of the observed activation of inactive renin occurring not at pH 3.33 but during dialysis from pH 3.3to pH 7.4. This activation during dialysis at 40C to pH 7.4 requires previous exposure to pH 3.3, is inhibited completely by unacidified plasma, and can also be inhibited by D.F.P.1 Thus we have postulated that invitro activation of inactive plasma renin largely proceeds by the action of a neutral serine protease which is inhibited in native plasma by an acid-labile protease inhibitor.’ To explain cryoactivation-i.e., an enzymatic reaction whose apparent rate increases as the temperature is lowered towards freezing2-we suggested that cold either reversibly denatures or promotes the dissociation of a similar protease inhibitor. This might explain why Osmond and Loh found that the polypeptide aprotinin (’Trasylol’) is a less effective inhibitor of cryoactivation than is D.F.P. Thus both cryoactivation , and acid-activation of inactive plasma renin each involve an enzymatic reaction which can occur at a physiological pH. But neither process is "physiological" since, at least in vitro, one cannot occur without an unphysiological temperature and the other without prior acidification. Since exogenous trypsin can cause activation3-5 and since certain of the serine proteases in plasma are "trypsinlike", it is difficult to postulate that one of these is the "endogenous activator" of inactive renin merely because cold treatment or acidification permits its action in vitro. Although this type of protease might be involved in the physiological conversion of inactive to active renin in vivo, it is highly improbable, as Osmond and Loh appear to assume, that it could act in the systemic circulation, where naturally occurring inhibitors are we
in excess. Cardiovascular Center, New York Hospital-Cornell Medical Center, New York, N.Y. 10021, U.S.A.
STEVEN A. ATLAS JEAN E. SEALEY JOHN H. LARAGH
inge in industrial methylated spirit
contained in a spirit-proof case-both spirit and case are available on prescriptionremoves the need for daily boiling. 4. Oshimura, M., Kakati, S., Sandberg, A. A. Cancer Res. 1977, 37, 5. Kakati, S., Song, S. Y., Sandberg, A. A. Cancer, 1977, 40, 1173. 6. Kovacs, Gy. Int. J. Cancer (in the press).
3501.
1. Atlas, S. A., Sealey, J. E., Laragh, J. H. Kid. Int. 1977, 12, 495. 2. Sealey, J. E., Moon, C., Laragh, J. H., Alderman, M. Am. J. Med. 1976, 61, 731. 3. Morris, B. J., Lumbers, E. R. Biochim. biophys. acta 1972, 289, 385. 4. Day, R. P., Luetscher, J. A. J. clin. Endocr. Metab. 1975, 40, 1085. 5. Cooper, R. M., Murray, G. E., Osmond, D. H. Circulation Res. 1977, 40,
suppl. I, 171.
suppressive effects were observed after the first of 45 megaunits. Treatment had to be abandoned because of side-effects, the severity of which may have been related to the combination of high-dosage P.I.F. and pre-existcourse
ing immunosuppression. The fact that leukopenia has been noted in patients treated with fibroblast’ or leucocyte derived interferon2.3 suggests that marrow suppression is a general and important side-effect of the preparations currently available. Details of this
case
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, 06105, U.S.A.
will be reported in full elsewhere.
Blood Transfusion Service,
Royal Infirmary, Edinburgh EH3 9HB Nuffield Transplantation Surgery Unit, Western General Hospital, Edinburgh Dermatology Department, Royal Infirmary, Edinburgh Department of Pathology, University of Edinburgh
S.
DAVID T. PURTILO
J. URBANIAK
I. M. HALLIDAY
G. W. BEVERIDGE
A. B. KAY
X-LINKED RECESSIVE LYMPHOPROLIFERATIVE SYNDROME StR,—Three excellent articlesl-3 on the X-linked recessive
lymphoproliferative syndrome4-9
receptors required for receiving messages of help from T cells may be lacking on the surface of defective B cells of the patients with the X-linked syndrome. While the clinicopathological and immunogenetic features of this devastating syndrome are being elucidated, the term "Duncan’s disease" should be avoided. "X-linked recessive lymphoproliferative syndrome" may not be simple, but meaning is conveyed. Students already have too many meaningless eponyms to learn.
have
speculated
on
the pro-
of and the mechanisms responsible for this provocaper tive syndrome. The generic name, "X-linked recessive lymphoproliferative syndrome"8 conveys information; "Duncan’s disease" does not. Regrettably, when we described the disease4 we attached the eponym "Duncan’s disease" to our cumbersome, but accurate "X-linked recessive progressive combined variable immunodeficiency". Alas, alliteration won out over science. Besides, Mr Duncan should not be blamed for this devastating disease-he could not have possessed the defective X-linked lymphoproliferative control locus. We chose to use the generic X-linked recessive lymphoproliferative syndrome8 because lymphoproliferation is the cardinal feature of this pleiotropic genetic disorder. Epstein-Barr virus (E.B.v.) infection is frequently lethal to males with the syndrome : approximately 40% have died after infection by E.B.v. as infectious mononucleosis, 40% developed B-cell lymphomas, and 20% have alymphoproliferative disorders such as hypogammaglobulinaemia.6-8 Thus the two essential elements of the syndrome are X-linked recessive inheritance and lymname
ABNORMALITIES OF CHROMOSOME NO. 1 IN HÆMATOLOGICAL MALIGNANCIES
SIR,-I read the letter by Dr Gahrton and colleagues (Jan. 14, p. 96) with interest because I have lately done a similar
analysis.l,2 Although both studies revealed that trisomy for the long arm of no. 1 invariably affected specific bands, the bands different in the two series. Gahrton et al. noted of lq23-25 in every one of 15 patients, whereas the adjacent bands lq25-32 were trisomic in all of the 34 patients on whom I reported (see figure). These bands (lq25-32) were trisomic in 14 of the 15 patients referred to by Gahrton et al.; on the other hand, 4 of the 34 patients in my report were not trisomic for lq23-25. In 3 of the 4 exceptions, bands lq25 to the end of the long arm were translocated to the short arm of no. 6 (bands 6q21-25); each patient also had two normal no. l’s. Thus, of the 35 patients studied in the two series, all except 1 were trisomic for lq25-1q32, and all except 4 were trisomic for lq21 to lq25, irrespective of the type ofhxmatological disorder. These bands are adjacent, and determination of break points in chromosomes, especially those involved in structural rearrangements, may be imprecise. Atkin and Baker3 called attention to abnormalities of chroinvolved
were
duplication
1.
Rowley, J. D.
in Molecular Human Cytogenetics: ICN-UCLA Symposium on Molecular and Cellular Biology; vol. III (edited by R. S. Sparkes, D. Comings, and C. F. Fox); p. 457. New York, 1977. 2. Rowley, J. D. Proc. natn. Acad. Sci. U.S.A. 1977, 74, 5729. 3. Atkin, N. B., Baker, M. Lancet, 1977, ii, 984.
phoproliferation. You3 claim that "The absence of any previous susceptibility candidiasis or other infections which typically occur in patients with defective cell-mediated immunity is evidence to
a pre-existing generalised defect of T cells in the boys with Duncan’s disease". This is not true: neonatal thrush, disseminated vaccinia after smallpox vaccination, and extraordinary measles infections have preceded fatal E.B.v. infections in affected males.4-9 The adjective, "subtle" could have reasonably been added to our report in The Lancet.4 The syndrome is not "limited"; it can be deadly when E.B.v. infection occurs. Failure of appropriate immune response to E.B.v. in boys with the defective X-linked lymphoproliferative control locus is responsible for the development of diverse disorders.1-9 The molecular defect responsible for this anergy to E.B.v. may result from a failure of the defective B cells to express E.B.v. antigens on the surface of E.B.v.-infected B cells.2.3Alternatively, as in the X-linked immunodeficient CBA/N mouse,2.3.10
against
Epstein, M. A., Achong, B. G. Lancet, 1977, ii, 1270. Rosen, R. S. New Engl. J. Med. 1977, 297, 1120. 3. Lancet, 1978, i, 132. 4. Purtilo, D. T., and others ibid. 1975, i, 935. 5. Purtilo, D. T. ibid. 1976, ii, 882. 1. 2.
6. Purtilo, D. T., and others Am. J. Med. 1977, 62, 225. 7. Purtilo, D. T. Sem. Oncol. 1977, 4, 335. 8. Purtilo, D. T., and others New Engl. J. Med. 1977, 297, 1077. 9. Purtilo, D. T., and others Clin. Immun. Immunopath. 1978, 9, 147. 10. Cone, R. F., Huber, B., Cantor, H., Gershon, H. Personal communication.
trisomic for chromosome no. 1 in 34 patients. Part of chromosome no. 1 that is trisomic in each patient is represented by vertical line. Detailed karyotypes are listed in ref. 1; the first nine patients have been studied in my laboratory. Dashed vertical lines indicate uncertain break points. A short horizontal bar indicates the end(s) of the chromosome. The dashed horizontal lines enclose the segment that is trisomic in every one of the 34 patients. (Reprinted from the Proceedings of the National Academy of Sciences of the United States of America.)
Region
555 a variety of human cancers affecting ovary, bladder, breast, and cervix; it is clear that (contrary to their statement) abnormalities of no. 1 occur in heematologic disorders as well. The observations reflect our increasing precision in defining not only the chromosome affected but also the critical portion of the chromosome. As I have suggested,2 correlation of these regions with the human gene map will provide insights into the role of chromosome changes in neoplasia.
mosome no.
1 in
,
Department of Medicine, Franklin McLean Memorial Research Institute
University of Chicago Chicago, Illinois 60637, U.S.A.
JANET D. ROWLEY
cannot be prescribed by general practibe obtained from a hospital consultant in exceptional circumstances. I suggest they are unnecessary if the British Diabetic Association recommendations on syringe sterilisation are followed. The case described by Mr Goldberg (Feb. 11, p. 331) is unusual and shows that better education of diabetics is needed, not disposable syringes. Disposable needles are more satisfactory and many patients purchase these in bulk to reduce cost. They can be prescribed from hospital at the consultant’s discretion. Many patients find that one needle is serviceable for several injections.
Disposable syringes
tioners but
can
Diabetic Clinic, Department of Child Health, Alder Hey Children’s Hospital, Liverpool L12 2AP
C. S. SMITH
SiR,--Gahrton mosome no.
q23-25
was
et al., summarising abnormalities of chromyeloproliferative diseases, note that region duplicated in all cases. Oshimura et aI.4 have
1 in
reviewed abnormalities of chromosome no. 1 in various tumour types; and the significance of involvement of chromosome no. 1, particularly region q21-25, has been pointed by Kakati et al. I found trisomy or partial trisomy of chromo-
Duplicated parts of chromosome no.
1 in
primary cancers.
1 in 5 breast cancers, 4 colonic cancers, and a primary, recurrent, and metastatic undifferentiated tumour of unknown origin studied by banding techniques.6 I found i(lq) in 3 breast cancers and 1 colonic cancer. Several parts of chro.mosome no. 1 were duplicated, but only q21-25 was duplicated in all cases (see figure). These findings suggest that region q21-25 of chromosome no. 1 is important for development of different tumour types, and that q21 is a vulnerable point on human chromosome no. 1. some no.
Department of Pathology, County Hospital, Kecskemét, Hungary
GYULA KOVACS
DISPOSABLE SYRINGES AND NEEDLES FOR DIABETICS
SIR,-Iwas surprised to read that Fiona Toal (Jan. 7, p. 45) found that 66% of diabetic patients did not sterilise their needles and syringes as recommended by the hospital. This suggests some deficiency in the educational programme for diabetic patients and a continuing need to educate diabetics about their condition and its management. The views of the British Diabetic Association are clearly set out in a leaflet (Insulin Treatment, DH 104) which should be issued to all new diabetic patients. Replacing needles and syr-
PROTEASE AS ENDOGENOUS ACTIVATOR OF INACTIVE RENIN
SIR,-The data presented by Dr Osmond and Dr Loh (Jan. 14, p. 102) accord with our repon1 that cryoactivation of inac-
plasma renin (D.F.P.). However,
tive
is inhibited by diisopropylfluorophosphate do not believe their conclusions entirely accord with the available evidence. They state that acid-activation of inactive renin "cannot prove that endogenous activation exists" but suggest that D.F.P.-inhibitable cryoactivation and activation by exogenous trypsin "bring us closer" to that proof. We have shown’ that acid-activation and cryoactivation involve similar enzymatic reactions. Acid-activation is a two-step process, 70% of the observed activation of inactive renin occurring not at pH 3.33 but during dialysis from pH 3.3to pH 7.4. This activation during dialysis at 40C to pH 7.4 requires previous exposure to pH 3.3, is inhibited completely by unacidified plasma, and can also be inhibited by D.F.P.1 Thus we have postulated that invitro activation of inactive plasma renin largely proceeds by the action of a neutral serine protease which is inhibited in native plasma by an acid-labile protease inhibitor.’ To explain cryoactivation-i.e., an enzymatic reaction whose apparent rate increases as the temperature is lowered towards freezing2-we suggested that cold either reversibly denatures or promotes the dissociation of a similar protease inhibitor. This might explain why Osmond and Loh found that the polypeptide aprotinin (’Trasylol’) is a less effective inhibitor of cryoactivation than is D.F.P. Thus both cryoactivation , and acid-activation of inactive plasma renin each involve an enzymatic reaction which can occur at a physiological pH. But neither process is "physiological" since, at least in vitro, one cannot occur without an unphysiological temperature and the other without prior acidification. Since exogenous trypsin can cause activation3-5 and since certain of the serine proteases in plasma are "trypsinlike", it is difficult to postulate that one of these is the "endogenous activator" of inactive renin merely because cold treatment or acidification permits its action in vitro. Although this type of protease might be involved in the physiological conversion of inactive to active renin in vivo, it is highly improbable, as Osmond and Loh appear to assume, that it could act in the systemic circulation, where naturally occurring inhibitors are we
in excess. Cardiovascular Center, New York Hospital-Cornell Medical Center, New York, N.Y. 10021, U.S.A.
STEVEN A. ATLAS JEAN E. SEALEY JOHN H. LARAGH
inge in industrial methylated spirit
contained in a spirit-proof case-both spirit and case are available on prescriptionremoves the need for daily boiling. 4. Oshimura, M., Kakati, S., Sandberg, A. A. Cancer Res. 1977, 37, 5. Kakati, S., Song, S. Y., Sandberg, A. A. Cancer, 1977, 40, 1173. 6. Kovacs, Gy. Int. J. Cancer (in the press).
3501.
1. Atlas, S. A., Sealey, J. E., Laragh, J. H. Kid. Int. 1977, 12, 495. 2. Sealey, J. E., Moon, C., Laragh, J. H., Alderman, M. Am. J. Med. 1976, 61, 731. 3. Morris, B. J., Lumbers, E. R. Biochim. biophys. acta 1972, 289, 385. 4. Day, R. P., Luetscher, J. A. J. clin. Endocr. Metab. 1975, 40, 1085. 5. Cooper, R. M., Murray, G. E., Osmond, D. H. Circulation Res. 1977, 40,
suppl. I, 171.
