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TERMINAL-DEOXYNUCLEOTIDYL-TRANSFERASE POSITIVE ACUTE LYMPHOBLASTIC LEUKÆMIA WITH AUER RODS
1042 itance of bone fragility without blue sclerse and dentinogenesis but no history of presenile hearing loss. Other reports confirm the existence of a dominantly inherited form of bone fragility in patients with normal sclerae.s.6 Levin et al. suggest that there are two distinct clinical syndromes associated with the dominantly inherited triad of bone fragility, blue sclerae, and presenile deafness (0.1. type i), one
imperfecta,
with and one without dentinogenesis imperfecta. However, there is no evidence that these two syndromes are biochemically distinct. Perhaps both syndromes should be called 0.1. type I and distinguished by the label with (or without) dentinogenesis imperfecta until the biochemical defect(s) is elucidated. Undoubtedly, other 0.1. syndromes exist. An autosomal recessive syndrome of bone fragility, normal sclerae, and joint hypermobility7 may well prove to be 0.1. type v. Only when biochemical characterisation of these syndromes is complete will the full heterogeneity be recognised, permitting confident classification of sporadic cases. Division of Medical Genetics, U.C.L.A. School of Medicine, Harbor General Hospital Campus, Torrance, California 90509, U.S.A.
DAVID O. SILLENCE DAVID L. RIMOIN
TREATMENT OF PAROXYSMAL ATRIAL TACHYCARDIA BY DIVING REFLEX
SIR,-Dr Mathew’s observation (March 4, p. 510) that
patients are less responsive than younger patients to the diving reflex is interesting. The difference between the two agegroups may be related to a general decline in cardiovascular reflex responsiveness with ageing.’ Since the original report of our experience with the diving reflex2 we, like Mathew, have encountered occasional patients of all ages who fail to convert to normal rhythm with carotid-sinus massage or with diving. In several of these patients, we accomplished a successful conversion by combining the two procedures: massage of a carotid sinus for 5-10 s during the course of a dive resulted in a return to normal rhythm in over one-third of the patients who were resistant to each procedure when it was used alone. older
that ascorbic acid might be helpful to these analogy with its reputed benefit in prickly heat. It is certainly helpful in some cases. One girl whom I treated achieved complete control of sweating on a dose as small as 50 mg daily but the sweating recurred whenever she stopped the drug or lowered the dose further. It would be interesting to
suggested
children,
to me
on an
know whether this treatment is ever successful in children with non-thalidomide reduction deformities. Department of Paediatrics and Child Health, University of Leeds, Leeds LS1 3ET
TERMINAL-DEOXYNUCLEOTIDYL-TRANSFERASE POSITIVE ACUTE LYMPHOBLASTIC LEUKÆMIA WITH AUER RODS
SiR,—Terminal deoxynucleotidyl transferase (TdT) is a valuable marker for lymphoblastic leukaemias.1.2 The possibility that this enzyme is present in a primitive haEmatopoeitic stem cell has been considered.3 Evidence for this theory is the transformation of rare cases of chronic myelogenous leukaemia into blast crisis with TdT-positive cells.4 We have seen a case of TdT-positive acute lymphoblastic leukxmia with rare Auer rods. This supports the theory of a stem-cell localisation for TdT with resultant differentiation into a predominantly lymphoblastic cell line with insignificant differentiation into the myeloblastic cell line. A 28-year-old female with acute leukaemia had 80% blast cells in the bone-marrow without peripheral-blood involvement. The morphology of the blasts suggested a lymphoid origin. However, rare cells contained definite Auer rods (see figure)’) which were peroxidase and sudan-black B positive. Less than 5% of the cells were positive for these stains. Tartrate-sensitive 1.
Coleman, M. S., Greenwood, M. F., Hutton, J. J., Bollum, F. J., Lampkin, B., Holland, P. Cancer Res. 1976, 36, 120 2. Hutton, J. J., Coleman, M. S. Br.J. Hœmat. 1976, 34, 447. 3. Coleman, M. S., Hutton, J. J., DeSimone, P., Bollum, F. J. Proc. natn. Acad. Sci. U.S.A. 1976, 71, 4404. 4. Sarin, P. S., Anderson, P. N., Gallo, R. C. Blood, 1976, 47, 11.
Department of Internal Medicine and Physiology, University of Texas Health Science Center
at
Dallas,
KERN WILDENTHAL
Dallas, Texas 75235, U.S.A.
THALIDOMIDE, ABSENT APPENDIX, AND SWEATING
SIR,-Mr Bremner and Dr Mooney (April 15, p. 826) call attention to appendicular agenesis as a feature of thalidomide children. This defect was referred to in the original letter of Lenz3 in 1962 and has been described many times since. It should therefore perhaps not be reported as "a further thalidomide anomaly", although the reminder is helpful. Dr McBride, in the same issue, refers to the problem of excessive sweating in children with reduction deformities of the limbs. This is a common problem amongst thalidomide children, and I share his impression that the severity of this symptom is not necessarily proportional to the loss of body-surface area and cannot be explained entirely on this basis. The sweating can be a very troublesome symptom, causing intense irritation and sweat rash. Many years ago Dr Philip Quibell 6. Holcomb, D. Y.J. Hered. 1931, 22, 105. 7. Meigel, W. N., Müller, P. K., Pontz, B. F., Sörensen, N., Spranger, J. Klin. 1. 2.
schr. 1974, 52, 906. Gribbin, B., Pickering, T. G., Sleight, P., Peto, R. Circulation Res. 1971, 29, 424. Wildenthal, K., Atkins, J. M., Leshin, S. J., Skelton, C. L. Lancet, 1975, i,
12. 3. Lenz, W. Lancet, 1962, i, 45.
R. W. SMITHELLS
Blast with Auer rod in
cytoplasm (arrowed). (Wright-Giemsa; x 320).
1043 acid phosphatase, p-glucuronidase, and periodic-acid/Schiff stains were positive, indicating lymphoid cells. TdT done by indirect immunofluorescence of air-dried bone-marrow smears demonstrated 100% positive blasts, supporting the predominant lymphoblastic differentiation of the cells. Cytogenetics was negative for a Philadelphia chromosome. Through rare cases of acute myeloblastic leukaemia without Auer rods and positive TdT have been reported by enzyme assay,S we know of no other case of TdT-positive acute lymphoblastic leukaemia with Auer rods. Additional studies are being done on this patient and will be described in detail elsewhere. This case seems to demonstrate the presence of a stemin acute leukaemia which can differentiate into cell lymphoblastic and myeloblastic cell lines.
populaiftn
We thank Mrs Sondra Gandler Getz for editorial assistance and
Wendy Smith for the photography.
National Naval Medical Center, Bethesda, Maryland 20014, U.S.A. Uniformed Services University of the Health Sciences,
Bethesda, Maryland
S. A. STASS S. VEACH S. M. PASQUALE H. R. SCHUMACHER T. P. KENEKLIS F. J. BOLLUM
BIOASSAY OF CHOLECYSTOKININ-PANCREOZYMIN IN DUODENAL MUCOSA
SIR,-Radioimmunoassays of cholecystokinin-pancreozy(C.C.K.-P.Z.) have run into methodological difficulties and problems with differences in antibodies. To elucidate the pathophysiological significance of C.C.K.-P.Z. in gastrointestinal diseases, we have assessed c.c.K.-like activity in the duodenal mucosa according to the method of Ljungberg, using the gallbladder of the guineapig in situ (Svesk. Farm. Tidsk. 1961, 68,351). After an overnight fast samples of duodenal mucosa of patients with gallstones (8 cases), duodenal ulcer (9), gastric ulcer (4), ulcerative colitis (3), Crohn’s disease (1), or chronic pancreatitis (2) and from 10 healthy controls were obtained by endoscopic biopsy and immersed in 0-43 ml of 10 mmol/1 hydrochloric acid (HCI). The samples were boiled for 3 min at 100°C, 50 1 of 1 mol/1 HCI was added, exposed to ultrasound for 6 min, and centrifuged for 20 min. The supernatant was used for the bioassay. A standard dose curve of caerulein was obtained and the c.c.K.-like activity was expressed by the dose of cserulein was converted into Ivy dog units (1 mg cxrulein is equivalent to 15 400 Ivy units in our laboratory). Almost all specimens were assayed in duplicate and the average value of min
activities was calculated. The mean c.c.K-like activity of the duodenal mucosa in the patients with gallstone and duodenal ulcer was 0-38 and 0.49 vy units/mg dry weight of the duodenal mucosa, respectively. Both these figures are significantly higher than the normal 0.21 units/mg (P<0.005, P<0.01, respectively) (see figure). No significant differences were found for the other patients studied. We do not know why c.c.K.-like activity in the duodenal mucosa was raided in patients with gallstones. One possibility is a feedback mechanism-i.e., decrease of bile concentration and impaired contraction of the gallbladder might have induced hyperplasia and/or hypertrophy of C.C.K.-P.Z. producing cells in the duodenal mucosa. Qualitative changes in the bile and hepatic enzymes might also have contributed to the increase.
c.c.K.-like activity of the duodenal mucosa was also increased in patients with duodenal ulcers, raising questions about the role of C.C.K.-P.Z. in the large cast of gastrointestinal hormones related to duodenal ulcer. Hyperacidity in duodenal 5. Srivastava, B. I., Khan, S. A., Henderson, E. S. Cancer Res. 1976, 36, 3847.
C.C.K.-like activity in duodenal mucosa. Means and individual values shown.
levels in the duodenal mucosa by continuously stimulating producing cells. Or the increased mucosal level could be the result of inhibition of C.C.K.-P.Z. release. Some workers have found that administration of extrinsic C.C.K.-P.Z. prevents gastric acid secretion while not stimulating pepsin secretion, so C.C.K.-P.Z. may be more effective than secretin as an antagonist of gastrin and might act physiologically for the cure of duodenal ulcer. ulcer may raise
C.C.K.-P.Z.
C.C.K.-P.Z.
We thank Dr S. Tachibana of Eisai Co. for his advice and for supplying pure C.C.K.P.Z. 2nd
Department of Medicine, Yamagata University School of Medicine, Yamagata, Japan
on
bioassay
S. KATAOKA T. KAMEI M. ISHIKAWA
COMPLICATION OF THE INFUSION PUMP
SIR,-Unfortunately, Dr Ayalon and colleagues (April 22, p. 853) do not describe their technique for insertion of the central venous line in the two case-reports given. Clearly neither line was in a major vein, so precautions to ensure this had not been taken. In 1973 we stressed the importance of making absolutely sure that central venous lines were in a major vein before any infusion was started.’ With the increase in use of this technique, not only for resuscitation but also for intrafeeding, free back-flow of blood must be achieved and the position of the line must be confirmed by chest X-ray before the central venous line is used. If there is any doubt, the line must be removed and the procedure repeated using another central vein. If extravasations do occur the patient should be tipped head down and the line connected to drainage, thereby removing the fluid from pleural cavity, or mediastinum. venous
Department of Surgery, Guy’s Hospital, London SE1 9RT
M. BEWICK C. J. RUDGE
Dr Ayalon and colleagues is misleadthe central venous cannulx were misplaced. The distal end of one was in the mediastinum and the other was in either the mediastinum or the pleural cavity. Extravasation would have occurred whether or not an infusion pump was used. These complications are well known. The position of a central venous cannula can be checked immediately by lowering the infusion set below the level of the patient and opening the control clip. Free back-flow of blood into the infusion set
SIR,—The report by
ing. Surely,
1.
Rudge, C. J., Bewick, M., McColl, I. Br. med.J. 1973, iii, 22.
imperfecta,
with and one without dentinogenesis imperfecta. However, there is no evidence that these two syndromes are biochemically distinct. Perhaps both syndromes should be called 0.1. type I and distinguished by the label with (or without) dentinogenesis imperfecta until the biochemical defect(s) is elucidated. Undoubtedly, other 0.1. syndromes exist. An autosomal recessive syndrome of bone fragility, normal sclerae, and joint hypermobility7 may well prove to be 0.1. type v. Only when biochemical characterisation of these syndromes is complete will the full heterogeneity be recognised, permitting confident classification of sporadic cases. Division of Medical Genetics, U.C.L.A. School of Medicine, Harbor General Hospital Campus, Torrance, California 90509, U.S.A.
DAVID O. SILLENCE DAVID L. RIMOIN
TREATMENT OF PAROXYSMAL ATRIAL TACHYCARDIA BY DIVING REFLEX
SIR,-Dr Mathew’s observation (March 4, p. 510) that
patients are less responsive than younger patients to the diving reflex is interesting. The difference between the two agegroups may be related to a general decline in cardiovascular reflex responsiveness with ageing.’ Since the original report of our experience with the diving reflex2 we, like Mathew, have encountered occasional patients of all ages who fail to convert to normal rhythm with carotid-sinus massage or with diving. In several of these patients, we accomplished a successful conversion by combining the two procedures: massage of a carotid sinus for 5-10 s during the course of a dive resulted in a return to normal rhythm in over one-third of the patients who were resistant to each procedure when it was used alone. older
that ascorbic acid might be helpful to these analogy with its reputed benefit in prickly heat. It is certainly helpful in some cases. One girl whom I treated achieved complete control of sweating on a dose as small as 50 mg daily but the sweating recurred whenever she stopped the drug or lowered the dose further. It would be interesting to
suggested
children,
to me
on an
know whether this treatment is ever successful in children with non-thalidomide reduction deformities. Department of Paediatrics and Child Health, University of Leeds, Leeds LS1 3ET
TERMINAL-DEOXYNUCLEOTIDYL-TRANSFERASE POSITIVE ACUTE LYMPHOBLASTIC LEUKÆMIA WITH AUER RODS
SiR,—Terminal deoxynucleotidyl transferase (TdT) is a valuable marker for lymphoblastic leukaemias.1.2 The possibility that this enzyme is present in a primitive haEmatopoeitic stem cell has been considered.3 Evidence for this theory is the transformation of rare cases of chronic myelogenous leukaemia into blast crisis with TdT-positive cells.4 We have seen a case of TdT-positive acute lymphoblastic leukxmia with rare Auer rods. This supports the theory of a stem-cell localisation for TdT with resultant differentiation into a predominantly lymphoblastic cell line with insignificant differentiation into the myeloblastic cell line. A 28-year-old female with acute leukaemia had 80% blast cells in the bone-marrow without peripheral-blood involvement. The morphology of the blasts suggested a lymphoid origin. However, rare cells contained definite Auer rods (see figure)’) which were peroxidase and sudan-black B positive. Less than 5% of the cells were positive for these stains. Tartrate-sensitive 1.
Coleman, M. S., Greenwood, M. F., Hutton, J. J., Bollum, F. J., Lampkin, B., Holland, P. Cancer Res. 1976, 36, 120 2. Hutton, J. J., Coleman, M. S. Br.J. Hœmat. 1976, 34, 447. 3. Coleman, M. S., Hutton, J. J., DeSimone, P., Bollum, F. J. Proc. natn. Acad. Sci. U.S.A. 1976, 71, 4404. 4. Sarin, P. S., Anderson, P. N., Gallo, R. C. Blood, 1976, 47, 11.
Department of Internal Medicine and Physiology, University of Texas Health Science Center
at
Dallas,
KERN WILDENTHAL
Dallas, Texas 75235, U.S.A.
THALIDOMIDE, ABSENT APPENDIX, AND SWEATING
SIR,-Mr Bremner and Dr Mooney (April 15, p. 826) call attention to appendicular agenesis as a feature of thalidomide children. This defect was referred to in the original letter of Lenz3 in 1962 and has been described many times since. It should therefore perhaps not be reported as "a further thalidomide anomaly", although the reminder is helpful. Dr McBride, in the same issue, refers to the problem of excessive sweating in children with reduction deformities of the limbs. This is a common problem amongst thalidomide children, and I share his impression that the severity of this symptom is not necessarily proportional to the loss of body-surface area and cannot be explained entirely on this basis. The sweating can be a very troublesome symptom, causing intense irritation and sweat rash. Many years ago Dr Philip Quibell 6. Holcomb, D. Y.J. Hered. 1931, 22, 105. 7. Meigel, W. N., Müller, P. K., Pontz, B. F., Sörensen, N., Spranger, J. Klin. 1. 2.
schr. 1974, 52, 906. Gribbin, B., Pickering, T. G., Sleight, P., Peto, R. Circulation Res. 1971, 29, 424. Wildenthal, K., Atkins, J. M., Leshin, S. J., Skelton, C. L. Lancet, 1975, i,
12. 3. Lenz, W. Lancet, 1962, i, 45.
R. W. SMITHELLS
Blast with Auer rod in
cytoplasm (arrowed). (Wright-Giemsa; x 320).
1043 acid phosphatase, p-glucuronidase, and periodic-acid/Schiff stains were positive, indicating lymphoid cells. TdT done by indirect immunofluorescence of air-dried bone-marrow smears demonstrated 100% positive blasts, supporting the predominant lymphoblastic differentiation of the cells. Cytogenetics was negative for a Philadelphia chromosome. Through rare cases of acute myeloblastic leukaemia without Auer rods and positive TdT have been reported by enzyme assay,S we know of no other case of TdT-positive acute lymphoblastic leukaemia with Auer rods. Additional studies are being done on this patient and will be described in detail elsewhere. This case seems to demonstrate the presence of a stemin acute leukaemia which can differentiate into cell lymphoblastic and myeloblastic cell lines.
populaiftn
We thank Mrs Sondra Gandler Getz for editorial assistance and
Wendy Smith for the photography.
National Naval Medical Center, Bethesda, Maryland 20014, U.S.A. Uniformed Services University of the Health Sciences,
Bethesda, Maryland
S. A. STASS S. VEACH S. M. PASQUALE H. R. SCHUMACHER T. P. KENEKLIS F. J. BOLLUM
BIOASSAY OF CHOLECYSTOKININ-PANCREOZYMIN IN DUODENAL MUCOSA
SIR,-Radioimmunoassays of cholecystokinin-pancreozy(C.C.K.-P.Z.) have run into methodological difficulties and problems with differences in antibodies. To elucidate the pathophysiological significance of C.C.K.-P.Z. in gastrointestinal diseases, we have assessed c.c.K.-like activity in the duodenal mucosa according to the method of Ljungberg, using the gallbladder of the guineapig in situ (Svesk. Farm. Tidsk. 1961, 68,351). After an overnight fast samples of duodenal mucosa of patients with gallstones (8 cases), duodenal ulcer (9), gastric ulcer (4), ulcerative colitis (3), Crohn’s disease (1), or chronic pancreatitis (2) and from 10 healthy controls were obtained by endoscopic biopsy and immersed in 0-43 ml of 10 mmol/1 hydrochloric acid (HCI). The samples were boiled for 3 min at 100°C, 50 1 of 1 mol/1 HCI was added, exposed to ultrasound for 6 min, and centrifuged for 20 min. The supernatant was used for the bioassay. A standard dose curve of caerulein was obtained and the c.c.K.-like activity was expressed by the dose of cserulein was converted into Ivy dog units (1 mg cxrulein is equivalent to 15 400 Ivy units in our laboratory). Almost all specimens were assayed in duplicate and the average value of min
activities was calculated. The mean c.c.K-like activity of the duodenal mucosa in the patients with gallstone and duodenal ulcer was 0-38 and 0.49 vy units/mg dry weight of the duodenal mucosa, respectively. Both these figures are significantly higher than the normal 0.21 units/mg (P<0.005, P<0.01, respectively) (see figure). No significant differences were found for the other patients studied. We do not know why c.c.K.-like activity in the duodenal mucosa was raided in patients with gallstones. One possibility is a feedback mechanism-i.e., decrease of bile concentration and impaired contraction of the gallbladder might have induced hyperplasia and/or hypertrophy of C.C.K.-P.Z. producing cells in the duodenal mucosa. Qualitative changes in the bile and hepatic enzymes might also have contributed to the increase.
c.c.K.-like activity of the duodenal mucosa was also increased in patients with duodenal ulcers, raising questions about the role of C.C.K.-P.Z. in the large cast of gastrointestinal hormones related to duodenal ulcer. Hyperacidity in duodenal 5. Srivastava, B. I., Khan, S. A., Henderson, E. S. Cancer Res. 1976, 36, 3847.
C.C.K.-like activity in duodenal mucosa. Means and individual values shown.
levels in the duodenal mucosa by continuously stimulating producing cells. Or the increased mucosal level could be the result of inhibition of C.C.K.-P.Z. release. Some workers have found that administration of extrinsic C.C.K.-P.Z. prevents gastric acid secretion while not stimulating pepsin secretion, so C.C.K.-P.Z. may be more effective than secretin as an antagonist of gastrin and might act physiologically for the cure of duodenal ulcer. ulcer may raise
C.C.K.-P.Z.
C.C.K.-P.Z.
We thank Dr S. Tachibana of Eisai Co. for his advice and for supplying pure C.C.K.P.Z. 2nd
Department of Medicine, Yamagata University School of Medicine, Yamagata, Japan
on
bioassay
S. KATAOKA T. KAMEI M. ISHIKAWA
COMPLICATION OF THE INFUSION PUMP
SIR,-Unfortunately, Dr Ayalon and colleagues (April 22, p. 853) do not describe their technique for insertion of the central venous line in the two case-reports given. Clearly neither line was in a major vein, so precautions to ensure this had not been taken. In 1973 we stressed the importance of making absolutely sure that central venous lines were in a major vein before any infusion was started.’ With the increase in use of this technique, not only for resuscitation but also for intrafeeding, free back-flow of blood must be achieved and the position of the line must be confirmed by chest X-ray before the central venous line is used. If there is any doubt, the line must be removed and the procedure repeated using another central vein. If extravasations do occur the patient should be tipped head down and the line connected to drainage, thereby removing the fluid from pleural cavity, or mediastinum. venous
Department of Surgery, Guy’s Hospital, London SE1 9RT
M. BEWICK C. J. RUDGE
Dr Ayalon and colleagues is misleadthe central venous cannulx were misplaced. The distal end of one was in the mediastinum and the other was in either the mediastinum or the pleural cavity. Extravasation would have occurred whether or not an infusion pump was used. These complications are well known. The position of a central venous cannula can be checked immediately by lowering the infusion set below the level of the patient and opening the control clip. Free back-flow of blood into the infusion set
SIR,—The report by
ing. Surely,
1.
Rudge, C. J., Bewick, M., McColl, I. Br. med.J. 1973, iii, 22.