- Email: [email protected]
INSULIN AND GLUCOSE RESPONSE TO GLUCAGON IN DOWN'S SYNDROME
1093
paromomycin (’ Humatin ’), 500 mg. every 4 hours, through a Ryle’s tube, together with 15% glucose solution by intravenous drip transfusion, and parenteral vitamins. After 48 hours on this regimen the depth of coma was unchanged. At this stage (i.e., 60 hours after the onset of deep coma, and 108 hours after the onset of drowsiness) an exchange transfusion was performed with 10 pints of fresh heparinised blood. While making the skin incision and doing the dissection to identify the long saphenous vein, no local anxsthetic was needed because of deep coma; but as the transfusion was coming to an end, the patient seemed to have some awareness of pain in the groin. Twelve hours after the exchange transfusion the patient, who had been lying absolutely still, became extremely restless and was restrained in bed with great difficulty. Plantar response remained extensor on both sides. Later the depth of coma gradually lessened and 30 hours after the transfusion the patient complained of headache. At that time he was still confused and not fully orientated. His confused state gradually improved and 38 hours after the transfusion he was able to obey simple commands and answer simple questions. At this stage the plantar responses became flexor. Improvement was rapid during the next few hours and 50 hours after transfusion he was mentally alert and answered all questions rationally. Thereand
after his recovery was uneventful and he is now back at work, after a period of convalescence. Our experience is so far limited to this one case, but we feel that this form of treatment offers some hope in an otherwise hnmalPCe situation Dow Medical College and Civil Hospital, Karachi, Pakistan.
NAZIR A. CHAUDHARY NASEER AHMAD SHAIKH MUSHTAQ HASAN.
TRAINING IN MEDICAL LABORATORY TECHNOLOGY SIR The response in your correspondence columns to the statement from the Institute of Medical Laboratory Technology (Oct. 28, p. 935) reflects a widespread endeavour to maintain high standards of technology and efficiency. There is general agreement on a system of coordinated training conducted by experts and based on day or block release; and there should be close liaison between training institutes and working laboratories. However, laboratories must continue to function at all times as efficient working units, and the problem of providing full training facilities is linked with that of maintaining adequate work output of a high technical standard. Whether or not day release is made compulsory, there is little doubt that it is here to stay: it is also clear that the constraints imposed by regular staff absences can be overcome only by increases in technical establishments; but, because of present financial restrictions and shortage of labour, it is unlikely that early increases in senior establishments will come about or that, in any case, these would solve the immediate problem. In the recent correspondence, no account has been taken of those who are willing and capable of giving useful service in laboratories but who, for various reasons, have no wish to undergo training in depth or to acquire technological qualifications. Much of the work of medical laboratories-clinical, academic, or reference departments-is elementary or repetitive, and much of this can be carried out by people with comparatively little training. Is it not time, as a matter of national policy, to encourage employment of a quota of semiskilled labour in laboratories in order to permit greater flexibility in educational arrangements for those most suitable for advanced training ? Recruitment of such semiskilled labour should be based on recognised salary scales proportional to, but slightly less than, those of technicians in training; and increments could be based on age, length of service, and, possibly, degree of local responsibility. This suggestion in no way implies a lowering of technical standards. Most experienced laboratory workers are acquainted with technicians who are excellent at their daily work but pass examinations only with great difficulty, if at all.
Surely, employment and recognition of such workers would some of the obvious leaks in technical establishments, because many who are now deterred by academic handicaps would be encouraged to enter laboratory services. Contemporary proposals for technicians’ training are to be commended for their far-sighted aims and their optimism. But this optimism must be modified by the realities of the present situation. Only by paying due regard to the pressures on the
plug
lower echelons of laboratory workers will a future elite body of technologists be created. Department of Medical Microbiology, G. D. WASLEY St. Thomas’s Hospital Medical School, R. FRASER WILLIAMS. London S.E.1.
DERMATOGLYPHICS IN ECTODERMAL DYSPLASIA
SIR,—I wish to report briefly my dermatoglyphic analyses of families with hereditary anhydrotic ectodermal dysplasia, since there seem to be findings common to affected individuals two
and carriers. In this X-linked disorder there are decreased numbers of sweat-glands in the skin, hypotrichosis, and anodontia. The carrier female usually has symptoms. Since the skin is involved, one might expect to find characteristic dermatoglyphic changes, as in this short series. In family1 the father was clinically normal; the mother had thin hair, decreased sweating, and poor teeth; three sons were all severely affected. In family 2 the father was clinically normal; the mother had decreased sweating; three sons were severely involved and one son was normal. The dermatoglyphics of all these people were analysed; the affected ones had striking ridge disruption in all areas of palms and soles. There was also a tendency for the patterns to be vestigial, particularly in the third and fourth interdigital and plantar hallucal areas. The c and d digital triradii tended to be absent, vestigial, or displaced, and the C and D palmar lines were impossible to trace or stopped without going anywhere. The hypothenar patterns were usually too complex to describe by a single pattern name, and in addition the palmar axial triradius tended to be distal. The carriers (mothers) had some but not all of these patterns. The complex hypothenar patterns were present in both mothers. The normal people in this series had none of these findings. Thus dermatoglyphics may prove to be another clinical measure for diagnosis of patients with anhydrotic ectodermal dysplasia and of the carrier or less affected female. This work was aided by a grant from the National Foundation. Departments of Pathology and Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220. JEAN H. PRIEST.
INSULIN AND GLUCOSE RESPONSE TO GLUCAGON IN DOWN’S SYNDROME
SIR,-Abnormal glucose tolerance has been reported 1-3 in patients with Down’s syndrome (D.S.). In children with D.S., other mentally retarded children, and normal children, we have found that the mean rise in plasma-immunoreactiveinsulin level after oral glucose is only about half that observed in adults.4 Since glucagon has been shown to promote insulin secretion in adults,5 6 we decided to measure the response to it of these children. 16 children (aged 20 months to 6 years 4 months) were studied: 6 had D.s., 5 were mentally retarded from other causes, and 5 were normal. All were taking a high-carbohydrate diet containing 1000-2000 calories per day. After an overnight fast 0-5 mg. glucagon was given intravenously during 1-2 1. O’Leary, W. D. Am. J. Dis. Child. 1931, 41, 544. Runge, G. H. Am. J. ment. Defic. 1959, 63, 822. Benda, C. E. The Child with Mongolism; p. 175. New York, 1960. Milunsky, A., Rubenstein, A. H., Lowy, C., Wright, A. D. Devl Med. Child Neurol (in the press). 5. Yalow, R. S., Black, H., Villazon, M., Berson, A. A. Diabetes, 1960, 9, 356. 6. Samols, E., Marri, G., Marks, V. Lancet, 1965, ii, 415. 2. 3. 4.
1094 INSULIN AND GLUCOSE BLOOD-LEVELS DURING GLUCAGON-TOLERANCE TESTS IN CHILDREN WITH D.S. AND MENTALLY RETARDED AND NORMAL CHILDREN
that the maximal rise of plasma-insulin level after glucagon administration may have occurred before the 10-minute sample. We have speculated9 whether the failure of plasmainsulin level to rise in response to glucagon under these circumstances is due to reduction of intra-&bgr;-cell glycogen, breakdown of which may be an essential step in the activation of insulin secretion by this agent. It is possible that in children their 10-14-hour fast before their test had the same results as more prolonged fasting in adults. Our thanks are due to Dr. B. H. Kirman, Dr. V. Cowie, and Dr. D. N. Lawson for allowing us to study their patients; and to Dr. J. Stern for the blood-sugar estimations. Departments of Pædiatrics and Psychiatry, Queen Mary’s Hospital, Carshalton, Surrey. AUBREY MILUNSKY. Department of Chemical Pathology, Area Laboratory, VINCENT MARKS. West Park Hospital, Epsom, Surrey. Department of Medicine, Royal Free Hospital, London W.C.1.
ELLIS SAMOLS.
ACTIVITY OF ENDOGENOUS GROWTH HORMONE SIR,-Radioimmunoassays for protein hormones-’ are based on the immunological properties; they do not express biological activity. The need for a method of bioassay of the activity of growth hormone which has been measured by radioimmunoassay, became evident when I and my colleagues found a syndrome characterised by the clinical signs and symptoms of growth-hormone deficiency but high serum concentrations of immunoreacting human growth hormone.4b We assume that this syndrome is due to an inherited defect of growth-hormone synthesis which results in an immuno-
minutes. Venous blood was collected fasting, and 10, 20, and 30 minutes after glucagon administration, and capillary blood also at 60 and 120 minutes. Blood-sugar levels were measured by the reductiometric method,’ and insulin by immunoassay,8 on heparinised plasma stored at -20°C. In patients with D.S. the rise in blood-glucose was delayed, reaching its peak at 60 minutes instead of at 20 minutes as in the other two groups (see accompanying table). This delay reflects the high blood-sugar levels at 60 minutes in cases 2 and 6, a difference which would probably be resolved in a larger study. The rise in plasma-insulin was not significantly different in the three groups of subjects studied but was lower than in non-diabetic adults treated similarly.In 4 of the children (2 with D.s. and 2 normal) plasma-insulin levels did not rise significantly after intravenous glucagon. The results again confirm that glucagon promotes insulin secretion, an action shown to be independent of its effect on blood-glucose,9 and suggest that such action is less effective in all these classes of children than in adults. This is consistent with previous evidence that oral glucose seemed less effective in stimulating insulin secretion in these children than in adults.4 10 In 1 child with D.s. and 2 other retarded children we studied, intravenously administered tolbutamide produced low plasma-insulin levels. The reason for this decreased insulin secretion in response to both natural and pharmacological agents in children is not known, but it may be related to their decreased tolerance to fasting. In the present study, 2 children had good increments in plasma-insulin level (cases 10 and 12), while 4 children failed to show a rise in this level, after intravenous glucagon administration. Such failure has not been observed in nondiabetic adult subjects treated similarly, except during prolonged fasting-e.g., 72 hours without food, or during anabolic steroid therapy with methandienone.9 It is possible, however, 7. 8. 9. 10.
King, E. J., Wootton, I. D. P. Microanalysis in Medical Biochemistry. London, 1956. Samols, E., Bilkus, D. Proc. Soc. exp. Biol. Med. 1964, 115, 79. Samols, E., Marri, G., Marks, V. Diabetes, 1966, 15, 855. Slone, D., Soeldner, J. S., Steinke, J., Crigler, J. F. New Engl. J. Med. 1966, 274, 820.
Plasma-insulin change after arginine infusion (0.5 g. per kg.) in normal children (*), children with pituitary insufficiency and growth-hormone lack (0), and children with the syndrome of genetic pituitary dwarfism with high serum-growth-hormone (X).
logically active, but biologically inactive, hormone. While we were testing the regulation of growth-hormone secretion in several of the 20 patients with this syndrome under our care, observed that their insulin response to the infusion of was less than that in normal children and that it resembled that seen in patients with pituitary-growthhormone insufficiency (see figure). Rimoin and others (Sept. 9, p. 523) made similar observations in African pygmies
we
arginine
S. M., Roth, J., Yalow, R. S., Berson, S. A. Nature, Lond. 1963, 199, 784. 2. Hunter, W. M., Greenwood, F. C. Biochem. J. 1964, 91, 43. 3. Laron, Z., Mannheimer, S. Israel J. med. Sci. 1966, 2, 115. 4. Laron, Z., Pertzelan, A., Mannheimer, S. ibid. p. 152. 5. Laron, Z., Pertzelan, A., Doron, M. Excerpta med. int. Congr. Ser. 1967, no. 142, p. 43. 1.
Glick,
paromomycin (’ Humatin ’), 500 mg. every 4 hours, through a Ryle’s tube, together with 15% glucose solution by intravenous drip transfusion, and parenteral vitamins. After 48 hours on this regimen the depth of coma was unchanged. At this stage (i.e., 60 hours after the onset of deep coma, and 108 hours after the onset of drowsiness) an exchange transfusion was performed with 10 pints of fresh heparinised blood. While making the skin incision and doing the dissection to identify the long saphenous vein, no local anxsthetic was needed because of deep coma; but as the transfusion was coming to an end, the patient seemed to have some awareness of pain in the groin. Twelve hours after the exchange transfusion the patient, who had been lying absolutely still, became extremely restless and was restrained in bed with great difficulty. Plantar response remained extensor on both sides. Later the depth of coma gradually lessened and 30 hours after the transfusion the patient complained of headache. At that time he was still confused and not fully orientated. His confused state gradually improved and 38 hours after the transfusion he was able to obey simple commands and answer simple questions. At this stage the plantar responses became flexor. Improvement was rapid during the next few hours and 50 hours after transfusion he was mentally alert and answered all questions rationally. Thereand
after his recovery was uneventful and he is now back at work, after a period of convalescence. Our experience is so far limited to this one case, but we feel that this form of treatment offers some hope in an otherwise hnmalPCe situation Dow Medical College and Civil Hospital, Karachi, Pakistan.
NAZIR A. CHAUDHARY NASEER AHMAD SHAIKH MUSHTAQ HASAN.
TRAINING IN MEDICAL LABORATORY TECHNOLOGY SIR The response in your correspondence columns to the statement from the Institute of Medical Laboratory Technology (Oct. 28, p. 935) reflects a widespread endeavour to maintain high standards of technology and efficiency. There is general agreement on a system of coordinated training conducted by experts and based on day or block release; and there should be close liaison between training institutes and working laboratories. However, laboratories must continue to function at all times as efficient working units, and the problem of providing full training facilities is linked with that of maintaining adequate work output of a high technical standard. Whether or not day release is made compulsory, there is little doubt that it is here to stay: it is also clear that the constraints imposed by regular staff absences can be overcome only by increases in technical establishments; but, because of present financial restrictions and shortage of labour, it is unlikely that early increases in senior establishments will come about or that, in any case, these would solve the immediate problem. In the recent correspondence, no account has been taken of those who are willing and capable of giving useful service in laboratories but who, for various reasons, have no wish to undergo training in depth or to acquire technological qualifications. Much of the work of medical laboratories-clinical, academic, or reference departments-is elementary or repetitive, and much of this can be carried out by people with comparatively little training. Is it not time, as a matter of national policy, to encourage employment of a quota of semiskilled labour in laboratories in order to permit greater flexibility in educational arrangements for those most suitable for advanced training ? Recruitment of such semiskilled labour should be based on recognised salary scales proportional to, but slightly less than, those of technicians in training; and increments could be based on age, length of service, and, possibly, degree of local responsibility. This suggestion in no way implies a lowering of technical standards. Most experienced laboratory workers are acquainted with technicians who are excellent at their daily work but pass examinations only with great difficulty, if at all.
Surely, employment and recognition of such workers would some of the obvious leaks in technical establishments, because many who are now deterred by academic handicaps would be encouraged to enter laboratory services. Contemporary proposals for technicians’ training are to be commended for their far-sighted aims and their optimism. But this optimism must be modified by the realities of the present situation. Only by paying due regard to the pressures on the
plug
lower echelons of laboratory workers will a future elite body of technologists be created. Department of Medical Microbiology, G. D. WASLEY St. Thomas’s Hospital Medical School, R. FRASER WILLIAMS. London S.E.1.
DERMATOGLYPHICS IN ECTODERMAL DYSPLASIA
SIR,—I wish to report briefly my dermatoglyphic analyses of families with hereditary anhydrotic ectodermal dysplasia, since there seem to be findings common to affected individuals two
and carriers. In this X-linked disorder there are decreased numbers of sweat-glands in the skin, hypotrichosis, and anodontia. The carrier female usually has symptoms. Since the skin is involved, one might expect to find characteristic dermatoglyphic changes, as in this short series. In family1 the father was clinically normal; the mother had thin hair, decreased sweating, and poor teeth; three sons were all severely affected. In family 2 the father was clinically normal; the mother had decreased sweating; three sons were severely involved and one son was normal. The dermatoglyphics of all these people were analysed; the affected ones had striking ridge disruption in all areas of palms and soles. There was also a tendency for the patterns to be vestigial, particularly in the third and fourth interdigital and plantar hallucal areas. The c and d digital triradii tended to be absent, vestigial, or displaced, and the C and D palmar lines were impossible to trace or stopped without going anywhere. The hypothenar patterns were usually too complex to describe by a single pattern name, and in addition the palmar axial triradius tended to be distal. The carriers (mothers) had some but not all of these patterns. The complex hypothenar patterns were present in both mothers. The normal people in this series had none of these findings. Thus dermatoglyphics may prove to be another clinical measure for diagnosis of patients with anhydrotic ectodermal dysplasia and of the carrier or less affected female. This work was aided by a grant from the National Foundation. Departments of Pathology and Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220. JEAN H. PRIEST.
INSULIN AND GLUCOSE RESPONSE TO GLUCAGON IN DOWN’S SYNDROME
SIR,-Abnormal glucose tolerance has been reported 1-3 in patients with Down’s syndrome (D.S.). In children with D.S., other mentally retarded children, and normal children, we have found that the mean rise in plasma-immunoreactiveinsulin level after oral glucose is only about half that observed in adults.4 Since glucagon has been shown to promote insulin secretion in adults,5 6 we decided to measure the response to it of these children. 16 children (aged 20 months to 6 years 4 months) were studied: 6 had D.s., 5 were mentally retarded from other causes, and 5 were normal. All were taking a high-carbohydrate diet containing 1000-2000 calories per day. After an overnight fast 0-5 mg. glucagon was given intravenously during 1-2 1. O’Leary, W. D. Am. J. Dis. Child. 1931, 41, 544. Runge, G. H. Am. J. ment. Defic. 1959, 63, 822. Benda, C. E. The Child with Mongolism; p. 175. New York, 1960. Milunsky, A., Rubenstein, A. H., Lowy, C., Wright, A. D. Devl Med. Child Neurol (in the press). 5. Yalow, R. S., Black, H., Villazon, M., Berson, A. A. Diabetes, 1960, 9, 356. 6. Samols, E., Marri, G., Marks, V. Lancet, 1965, ii, 415. 2. 3. 4.
1094 INSULIN AND GLUCOSE BLOOD-LEVELS DURING GLUCAGON-TOLERANCE TESTS IN CHILDREN WITH D.S. AND MENTALLY RETARDED AND NORMAL CHILDREN
that the maximal rise of plasma-insulin level after glucagon administration may have occurred before the 10-minute sample. We have speculated9 whether the failure of plasmainsulin level to rise in response to glucagon under these circumstances is due to reduction of intra-&bgr;-cell glycogen, breakdown of which may be an essential step in the activation of insulin secretion by this agent. It is possible that in children their 10-14-hour fast before their test had the same results as more prolonged fasting in adults. Our thanks are due to Dr. B. H. Kirman, Dr. V. Cowie, and Dr. D. N. Lawson for allowing us to study their patients; and to Dr. J. Stern for the blood-sugar estimations. Departments of Pædiatrics and Psychiatry, Queen Mary’s Hospital, Carshalton, Surrey. AUBREY MILUNSKY. Department of Chemical Pathology, Area Laboratory, VINCENT MARKS. West Park Hospital, Epsom, Surrey. Department of Medicine, Royal Free Hospital, London W.C.1.
ELLIS SAMOLS.
ACTIVITY OF ENDOGENOUS GROWTH HORMONE SIR,-Radioimmunoassays for protein hormones-’ are based on the immunological properties; they do not express biological activity. The need for a method of bioassay of the activity of growth hormone which has been measured by radioimmunoassay, became evident when I and my colleagues found a syndrome characterised by the clinical signs and symptoms of growth-hormone deficiency but high serum concentrations of immunoreacting human growth hormone.4b We assume that this syndrome is due to an inherited defect of growth-hormone synthesis which results in an immuno-
minutes. Venous blood was collected fasting, and 10, 20, and 30 minutes after glucagon administration, and capillary blood also at 60 and 120 minutes. Blood-sugar levels were measured by the reductiometric method,’ and insulin by immunoassay,8 on heparinised plasma stored at -20°C. In patients with D.S. the rise in blood-glucose was delayed, reaching its peak at 60 minutes instead of at 20 minutes as in the other two groups (see accompanying table). This delay reflects the high blood-sugar levels at 60 minutes in cases 2 and 6, a difference which would probably be resolved in a larger study. The rise in plasma-insulin was not significantly different in the three groups of subjects studied but was lower than in non-diabetic adults treated similarly.In 4 of the children (2 with D.s. and 2 normal) plasma-insulin levels did not rise significantly after intravenous glucagon. The results again confirm that glucagon promotes insulin secretion, an action shown to be independent of its effect on blood-glucose,9 and suggest that such action is less effective in all these classes of children than in adults. This is consistent with previous evidence that oral glucose seemed less effective in stimulating insulin secretion in these children than in adults.4 10 In 1 child with D.s. and 2 other retarded children we studied, intravenously administered tolbutamide produced low plasma-insulin levels. The reason for this decreased insulin secretion in response to both natural and pharmacological agents in children is not known, but it may be related to their decreased tolerance to fasting. In the present study, 2 children had good increments in plasma-insulin level (cases 10 and 12), while 4 children failed to show a rise in this level, after intravenous glucagon administration. Such failure has not been observed in nondiabetic adult subjects treated similarly, except during prolonged fasting-e.g., 72 hours without food, or during anabolic steroid therapy with methandienone.9 It is possible, however, 7. 8. 9. 10.
King, E. J., Wootton, I. D. P. Microanalysis in Medical Biochemistry. London, 1956. Samols, E., Bilkus, D. Proc. Soc. exp. Biol. Med. 1964, 115, 79. Samols, E., Marri, G., Marks, V. Diabetes, 1966, 15, 855. Slone, D., Soeldner, J. S., Steinke, J., Crigler, J. F. New Engl. J. Med. 1966, 274, 820.
Plasma-insulin change after arginine infusion (0.5 g. per kg.) in normal children (*), children with pituitary insufficiency and growth-hormone lack (0), and children with the syndrome of genetic pituitary dwarfism with high serum-growth-hormone (X).
logically active, but biologically inactive, hormone. While we were testing the regulation of growth-hormone secretion in several of the 20 patients with this syndrome under our care, observed that their insulin response to the infusion of was less than that in normal children and that it resembled that seen in patients with pituitary-growthhormone insufficiency (see figure). Rimoin and others (Sept. 9, p. 523) made similar observations in African pygmies
we
arginine
S. M., Roth, J., Yalow, R. S., Berson, S. A. Nature, Lond. 1963, 199, 784. 2. Hunter, W. M., Greenwood, F. C. Biochem. J. 1964, 91, 43. 3. Laron, Z., Mannheimer, S. Israel J. med. Sci. 1966, 2, 115. 4. Laron, Z., Pertzelan, A., Mannheimer, S. ibid. p. 152. 5. Laron, Z., Pertzelan, A., Doron, M. Excerpta med. int. Congr. Ser. 1967, no. 142, p. 43. 1.
Glick,