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THE PATIENT'S COMPLAINT
1162 TABLE II-PLASMA-INSULIN 1U!SPONSE TO GLUCOSE BY MOUTH g. per kg. BODY-WEIGHT) IN TYPICAL GALACTOSMIA HEREDITARY FRUCTOSE INTOLERANCE
(1-75 AND
et aU and Richardson et al. The presence of methaemalbumin in the serum of patients can be explained only by accepting a mechanism that is more complex than simple release of haemoglobin. This could consist in oxidation and eventually proteolytic cleavage. We are thus strongly in favour of the views expressed by Northam et al.
Laboratory of the Medical Clinic, Academic Hospital, Ghent, Belgium.
G == galactosasmia.
H.F.I.
=hereditary fructose intolerance.
These results indicate that the hyperinsulinism in 3, 4, and 2 is not primarily the result of the patients’ inability to metabolise galactose and fructose normally. (Conversely, the hyperinsulinism of patients with islet-cell tumours, which tends to be independent of blood-glucose levels, does not cause fructose or galactose intolerance.) Hyperinsulinism without hypoglycaemia may be associwith early diabetes mellitus, ated lipoatrophic diabetes, and acromegaly; but in these conditions both insulin response and glucose tolerance is different. The finding by Froesch et al. of normal fasting I.L.A. in 2 adults with hereditary fructose intolerance suggests that age or the duration of the disease is not a determining factor. Although both galactosaemia and hereditary fructose intolerance are caused by specific single-enzyme defects, clinical mimicry is possible.It may also be difficult to disentangle primary defects from manifestations of secondary enzyme inhibitions.’ It is at present impossible to pin down the fructose and galactose intolerance and the hyperinsulinism in cases 3, 4, and 2 to a single known enzyme defect. The insulin-bioassay results suggest that the mechanism which allows these patients to produce, tolerate, or indeed require extraordinarily high concentrations of circulating insulin may reflect some metabolic abnormality at tissue level. Such cases of metabolic non-conformity may shed light on normal pathways. We are grateful to our colleagues mentioned in the subscript to table I for carrying out the various insulin assays. cases
Department of Medicine, Royal Free Hospital, London, W.C.1. Department of Experimental Medicine, Guy’s Hospital, London, S.E.1.
ELLIS SAMOLS.
T. L. DORMANDY.
METHÆMALBUMIN IN THE DIAGNOSIS OF PANCREATITIS SIR,-When freshly prepared haemoglobin is added in
large amounts to normal human serum and is submitted to electrophoresis, peroxidase activity can be detected only at the level of the haptoglobins and the free hxmoglobins. It is to be noted that under these conditions hxmoglobin does not become bound to albumin. When older haemoglobin solutions are used in this experiment, however, peroxidase activity may be manifest at the albumin level. This can be traced to the presence of an oxidation product of haemoglobin: methaemoglobin, which has affinity for albumin. A split product of methaemoglobin, haematin, has still higher affinity and forms methaemalbumin, which also has peroxidase activity. These facts help to explain the observations of Northam 6. Schwarz, W., Wells, A. Genet. 1961, 25, 179. 7.
Lancet, 1962, ii,
764.
R., Holzel, A., Komrower, G.
R. J. WIEME.
VACCINIA GANGRENOSA SiR,-The well-known association of vaccinia gangrenosa with hypogammaglobulinaemia is to most of us something of a mystery. Dr. White (May 4) mentions that humoral-antibody deficiency ought not to affect the response to vaccination, but she then adds that " it is therefore not surprising that in some cases [of hypogammaglobulinæmia] vaccinia gangrenosa should follow
vaccination ". It would be interesting to know how Dr. White has resolved this apparent anomaly. Bacteriology Department, University of Edinburgh.
*** We showed Dr. Selwyn’s reply follows.-ED. L.
S. SELWYN. letter
to
Dr. White, and
her
SIR,-Iapologise for failing to make my meaning clear. to convey that, though the humoral antibody factor was lacking, and though a cellular defence mechanism was possibly the essential one against vaccinia virus, that mechanism alone was not infallible or certain, and in some cases of hypogammaglobulinaemia, vaccinia gangrenosa might follow vaccination. I intended
St. Helier Hospital,
CATHERINE M. WHITE.
Carshalton, Surrey.
THE PATIENT’S COMPLAINT must know of people who feel not been properly treated in
SIR,-Every doctor
that
their relations have general hospitals either through what they regard as indifference or through lack of proper direction of the staff. Indeed they sometimes feel that death need not have occurred. Relations who believe that these things are true may make a complaint, but to whom do they make it ? It must be to the individual who they believe to be responsible. It is small wonder, therefore, that reforms do not occur. Who should receive such complaints? It could be the chairman of the medical staff committee or the surgeon or physician who for the time being is regarded as being in charge of the particular department concerned, but their names will not be widely known and indeed how can these individuals be expected to deal firmly with colleagues who have erred when perhaps in the next year or so this particular colleague will, by popular acclaim, be occupying their own position. There is no reason why complaints should not be made to the management committee, but the management committee has to seek advice from someone, and the doctor to whom it turns will be almost certainly one in the vulnerable positions I have mentioned if it is not the individual against whom the complaint is levelled. There is therefore, as Dr. Shillitoe very sensibly says in his letter of May 11, every reason to have a medical administrator who can deal with complaints from a position of some
authority. 1.
M. Ann. hum. 2.
Northam, B. E., Rowe, D. S., Winstone, N. E. Lancet, Feb. 16, 1963, p. 348. Richardson, R. W., Glick, S., Bates, A., Shinton, N. K. ibid. March 16, 1963, p. 608.
1163
If general hospitals are to have medical administrators, most doctors would think desirable for their efficient running, then an adequate salary must be paid to those who undertake such posts, -and more than this, the administrators must be assured of the support of their regional hospital boards, and particularly be aware that once the hospital is running efficiently the regional hospital board will tend to lose interest in their efforts and will commonly fail to afford the support which is as
essential. Hospital, Willerby, Hull.
De La Pole
THE TRANSMISSION OF G/G TRANSLOCATION SiR,-The translocation between chromosomes in group G (nos. 21 and 22) found in Down’s syndrome cannot be
identified by microscopy alone, since the chromosomes
resulting from reciprocal translocation of 21/21, 21/22, or the 21-isochromosome are similar in length and form. The offspring of individuals with a balanced karyotype (21/21 or 21-isochromosome) evidently consist of mongoloid children exclusively, monosomy of chromosome 21 presumably being lethal. Thus the chromosomal anomaly will be found only in 2 generations. If a G/G translocation is traced in more than 2 generations or if children with a normal or balanced karyotype are born, one could conclude that the translocation is of type 21/22. Reciprocal translocation of the two chromosomes no. 22 in one parent results in unbalanced gametes and may be lethal. Forssman and Lehmann1 recently reported a family in which translocation 21/22 could not be excluded, though the clinical and cytological diagnosis could only be made in 2 generations. Zellweger2 cited " a familial G/G translocation in 2 sibships with 2 mongoloid and eight normal children " investigated by Shaw. We report here a relevant family (fig. 1). The propositus is female mongol (iv 10). Chromosomal analysis showed 46 chromosomes, with five chromosomes in group F (19-20) and three in group G (21-22) (fig. 2). She is the first living child of a 21-year-old healthy mother (ill 16) who has 45 chromosomes, with five in group F and two in group G. The father, aged 23, is healthy and has a normal chromosome complement. Three earlier pregnancies miscarried. a
1. 2.
Fig. 2-Chromosomes of
J. A. R. BICKFORD.
Forssman, H., Lehmann, O. Acta pœsdiat., Stockh. 1962, 51, Zellweger, H. Lancer, 1962, ii, 660.
180.
groups F and G.
Chromosomal analyses were performed on ten members of the mother’s family who agreed to venepuncture, and five had the same abnormality with 45 chromosomes. It will be seen that the maternal grandfather (lia) is a carrier, that in his sibship of seven three died in infancy, and all of the remainder except one have been tested and found to be carriers, and that all three proved carriers in this sibship have transmitted the carrier state. No member of this family except the propositus is known to be a mongol or to have any obvious congenital defect. These findings may be interpreted as a result of translocation of the chromosomes 21 and 22. The gametes produced by a carrier of this anomaly contain the chromosomes 21 and 22 of the translocated chromosome 21/22. Hence the relation of normal to balanced zygotes is 1:1. The trisomic state of chromosome 21 as the cause of mongolism results from nondisjunction in the carrier of the translocated chromsome 21/22 or in the normal parent, and may not be more frequent than in the general population. The pedigree shows that the translocated chromosomes are transmitted from mother to son (n/5-IIIIB), father to son (II/8-III/B), and father to daughter (II I 9-III I 16). The only transmission from mother to daughter is accompanied by nondisjunction. The question arises whether these mechanisms are linked. The unusually high number of miscarriages and the young age of the mother (m/16) are remarkable.
Our observation accords with that of Walker and Harris,3 who described a family with transmission of translocated chromosomes of group D (nos. 13-15). Their arguments apply equally to our case. The study is supported by the Deutsche Forschungsgemeinschaft. I am greatly indebted to Prof. H. Mai for helpful advice. Universitäts-Kinderklinik, RUDOLF A. PFEIFFER. Münster, Germany. 3.
Walker, H., Harris, R. Ann. hum. Genet. 1962, 26, 151.
Fig. 1-Pedigree. Translocation of chromosomes 21/22.
(1-75 AND
et aU and Richardson et al. The presence of methaemalbumin in the serum of patients can be explained only by accepting a mechanism that is more complex than simple release of haemoglobin. This could consist in oxidation and eventually proteolytic cleavage. We are thus strongly in favour of the views expressed by Northam et al.
Laboratory of the Medical Clinic, Academic Hospital, Ghent, Belgium.
G == galactosasmia.
H.F.I.
=hereditary fructose intolerance.
These results indicate that the hyperinsulinism in 3, 4, and 2 is not primarily the result of the patients’ inability to metabolise galactose and fructose normally. (Conversely, the hyperinsulinism of patients with islet-cell tumours, which tends to be independent of blood-glucose levels, does not cause fructose or galactose intolerance.) Hyperinsulinism without hypoglycaemia may be associwith early diabetes mellitus, ated lipoatrophic diabetes, and acromegaly; but in these conditions both insulin response and glucose tolerance is different. The finding by Froesch et al. of normal fasting I.L.A. in 2 adults with hereditary fructose intolerance suggests that age or the duration of the disease is not a determining factor. Although both galactosaemia and hereditary fructose intolerance are caused by specific single-enzyme defects, clinical mimicry is possible.It may also be difficult to disentangle primary defects from manifestations of secondary enzyme inhibitions.’ It is at present impossible to pin down the fructose and galactose intolerance and the hyperinsulinism in cases 3, 4, and 2 to a single known enzyme defect. The insulin-bioassay results suggest that the mechanism which allows these patients to produce, tolerate, or indeed require extraordinarily high concentrations of circulating insulin may reflect some metabolic abnormality at tissue level. Such cases of metabolic non-conformity may shed light on normal pathways. We are grateful to our colleagues mentioned in the subscript to table I for carrying out the various insulin assays. cases
Department of Medicine, Royal Free Hospital, London, W.C.1. Department of Experimental Medicine, Guy’s Hospital, London, S.E.1.
ELLIS SAMOLS.
T. L. DORMANDY.
METHÆMALBUMIN IN THE DIAGNOSIS OF PANCREATITIS SIR,-When freshly prepared haemoglobin is added in
large amounts to normal human serum and is submitted to electrophoresis, peroxidase activity can be detected only at the level of the haptoglobins and the free hxmoglobins. It is to be noted that under these conditions hxmoglobin does not become bound to albumin. When older haemoglobin solutions are used in this experiment, however, peroxidase activity may be manifest at the albumin level. This can be traced to the presence of an oxidation product of haemoglobin: methaemoglobin, which has affinity for albumin. A split product of methaemoglobin, haematin, has still higher affinity and forms methaemalbumin, which also has peroxidase activity. These facts help to explain the observations of Northam 6. Schwarz, W., Wells, A. Genet. 1961, 25, 179. 7.
Lancet, 1962, ii,
764.
R., Holzel, A., Komrower, G.
R. J. WIEME.
VACCINIA GANGRENOSA SiR,-The well-known association of vaccinia gangrenosa with hypogammaglobulinaemia is to most of us something of a mystery. Dr. White (May 4) mentions that humoral-antibody deficiency ought not to affect the response to vaccination, but she then adds that " it is therefore not surprising that in some cases [of hypogammaglobulinæmia] vaccinia gangrenosa should follow
vaccination ". It would be interesting to know how Dr. White has resolved this apparent anomaly. Bacteriology Department, University of Edinburgh.
*** We showed Dr. Selwyn’s reply follows.-ED. L.
S. SELWYN. letter
to
Dr. White, and
her
SIR,-Iapologise for failing to make my meaning clear. to convey that, though the humoral antibody factor was lacking, and though a cellular defence mechanism was possibly the essential one against vaccinia virus, that mechanism alone was not infallible or certain, and in some cases of hypogammaglobulinaemia, vaccinia gangrenosa might follow vaccination. I intended
St. Helier Hospital,
CATHERINE M. WHITE.
Carshalton, Surrey.
THE PATIENT’S COMPLAINT must know of people who feel not been properly treated in
SIR,-Every doctor
that
their relations have general hospitals either through what they regard as indifference or through lack of proper direction of the staff. Indeed they sometimes feel that death need not have occurred. Relations who believe that these things are true may make a complaint, but to whom do they make it ? It must be to the individual who they believe to be responsible. It is small wonder, therefore, that reforms do not occur. Who should receive such complaints? It could be the chairman of the medical staff committee or the surgeon or physician who for the time being is regarded as being in charge of the particular department concerned, but their names will not be widely known and indeed how can these individuals be expected to deal firmly with colleagues who have erred when perhaps in the next year or so this particular colleague will, by popular acclaim, be occupying their own position. There is no reason why complaints should not be made to the management committee, but the management committee has to seek advice from someone, and the doctor to whom it turns will be almost certainly one in the vulnerable positions I have mentioned if it is not the individual against whom the complaint is levelled. There is therefore, as Dr. Shillitoe very sensibly says in his letter of May 11, every reason to have a medical administrator who can deal with complaints from a position of some
authority. 1.
M. Ann. hum. 2.
Northam, B. E., Rowe, D. S., Winstone, N. E. Lancet, Feb. 16, 1963, p. 348. Richardson, R. W., Glick, S., Bates, A., Shinton, N. K. ibid. March 16, 1963, p. 608.
1163
If general hospitals are to have medical administrators, most doctors would think desirable for their efficient running, then an adequate salary must be paid to those who undertake such posts, -and more than this, the administrators must be assured of the support of their regional hospital boards, and particularly be aware that once the hospital is running efficiently the regional hospital board will tend to lose interest in their efforts and will commonly fail to afford the support which is as
essential. Hospital, Willerby, Hull.
De La Pole
THE TRANSMISSION OF G/G TRANSLOCATION SiR,-The translocation between chromosomes in group G (nos. 21 and 22) found in Down’s syndrome cannot be
identified by microscopy alone, since the chromosomes
resulting from reciprocal translocation of 21/21, 21/22, or the 21-isochromosome are similar in length and form. The offspring of individuals with a balanced karyotype (21/21 or 21-isochromosome) evidently consist of mongoloid children exclusively, monosomy of chromosome 21 presumably being lethal. Thus the chromosomal anomaly will be found only in 2 generations. If a G/G translocation is traced in more than 2 generations or if children with a normal or balanced karyotype are born, one could conclude that the translocation is of type 21/22. Reciprocal translocation of the two chromosomes no. 22 in one parent results in unbalanced gametes and may be lethal. Forssman and Lehmann1 recently reported a family in which translocation 21/22 could not be excluded, though the clinical and cytological diagnosis could only be made in 2 generations. Zellweger2 cited " a familial G/G translocation in 2 sibships with 2 mongoloid and eight normal children " investigated by Shaw. We report here a relevant family (fig. 1). The propositus is female mongol (iv 10). Chromosomal analysis showed 46 chromosomes, with five chromosomes in group F (19-20) and three in group G (21-22) (fig. 2). She is the first living child of a 21-year-old healthy mother (ill 16) who has 45 chromosomes, with five in group F and two in group G. The father, aged 23, is healthy and has a normal chromosome complement. Three earlier pregnancies miscarried. a
1. 2.
Fig. 2-Chromosomes of
J. A. R. BICKFORD.
Forssman, H., Lehmann, O. Acta pœsdiat., Stockh. 1962, 51, Zellweger, H. Lancer, 1962, ii, 660.
180.
groups F and G.
Chromosomal analyses were performed on ten members of the mother’s family who agreed to venepuncture, and five had the same abnormality with 45 chromosomes. It will be seen that the maternal grandfather (lia) is a carrier, that in his sibship of seven three died in infancy, and all of the remainder except one have been tested and found to be carriers, and that all three proved carriers in this sibship have transmitted the carrier state. No member of this family except the propositus is known to be a mongol or to have any obvious congenital defect. These findings may be interpreted as a result of translocation of the chromosomes 21 and 22. The gametes produced by a carrier of this anomaly contain the chromosomes 21 and 22 of the translocated chromosome 21/22. Hence the relation of normal to balanced zygotes is 1:1. The trisomic state of chromosome 21 as the cause of mongolism results from nondisjunction in the carrier of the translocated chromsome 21/22 or in the normal parent, and may not be more frequent than in the general population. The pedigree shows that the translocated chromosomes are transmitted from mother to son (n/5-IIIIB), father to son (II/8-III/B), and father to daughter (II I 9-III I 16). The only transmission from mother to daughter is accompanied by nondisjunction. The question arises whether these mechanisms are linked. The unusually high number of miscarriages and the young age of the mother (m/16) are remarkable.
Our observation accords with that of Walker and Harris,3 who described a family with transmission of translocated chromosomes of group D (nos. 13-15). Their arguments apply equally to our case. The study is supported by the Deutsche Forschungsgemeinschaft. I am greatly indebted to Prof. H. Mai for helpful advice. Universitäts-Kinderklinik, RUDOLF A. PFEIFFER. Münster, Germany. 3.
Walker, H., Harris, R. Ann. hum. Genet. 1962, 26, 151.
Fig. 1-Pedigree. Translocation of chromosomes 21/22.