superoxide dismutase in down syndrome
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Ftt. 2—Negativety stained in- Fig. 3—Negativety stained in-8uenza-like virus ( 130,000). fluenza-like filament
( 130,000).
Fig. 4—Elongated structures in nucleus and cytoplasm ( 65,000).
Electron microscopy revealed myxovirus-like bodies inuncentrifuged fluid harvests (figs. 2 and 3). The viralparticles in thin sections averaged 85 nm. in diameter asdid the negatively stained viral filaments. Surface spikeswere present on both forms. Nucleocapsid strands wereabundant in the cytoplasm, and elongated structures50-70 nm. in diameter occurred frequently in the nucleusbut only rarely in the cytoplasm (fig. 4).The cytopathic changes seen in cultures stained with
hæmatoxylin and eosin were quite unlike those of knownparamyxoviruses inoculated by us into simian kidney cells.In 1966 Harwin et al. recorded the presence of cytoplasmicbasophilic inclusions and nuclear eosinophilic masses invervet monkey kidney cells infected with strains of influenzaB virus. These workers did not describe nucleolar changes,but review of stained vervet kidney cultures infected withinfluenza B virus recovered from one of us (H. M.) anumber of years ago showed that eosinophilic changes inthe nucleoli, similar to those now described, were presentalthough to a lesser extent.
Further characterisation studies are in progress, but onthe basis of the distinctive cytopathology and the electron-microscopy findings, the baboon isolate appears to belongto the myxovirus group.We thank Ms A. Golston for technical assistance. This study
was funded in part by U.S. Pubhc Health Service grantsRROO361 and RR05519, and W.H.O. grants Z2 181 27 andV4 181 38. This laboratory serves as the N.I.H. W.H.O. Colla-borating Centre for Reference and Research in Sinnao Viruses.
Southwest Foundation forResearch and Education,
P.O Box 28147, San Antonio,Texas 78284, U S.A.
H. MALHERBEM. STRICKLAND-
CHOLMLEYG. C. SMITH.
1. Harwin, R M , Joesting, A , Gear, J H S Lancet, 1966, i, 1218.
DAY-TRANSFUSION CENTRE FORTHALASSÆMICS
SIR,—The paper by Dr Vance (April 26, p. 967) pin-pointing loss of school-time in thalassaemics undergoingregular blood-transfusions is exceedingly important.I should like to report our own method for combatingthis problem.The Whittington Hospital currently treats nineteen
thalassaemic children, transfusing them at approximately6-weekly intervals (8 transfusions per year). It was realisedmany years ago that this could significantly encroach onschool and home life unless streamlined for the benefit ofthe patients. Consequently, the children are seen in aspecial outpatient clinic, 3 or 4 each Monday morningbetween 9 and 10 A.M. The haematology laboratory kindlymeasures haemoglobin before they are seen by the pa:diatri-cian, who then examines them and cross-matches bloodas necessary. They are back at school between 9.30 and10.30 A.M. Transfusion is carried out on Friday or Saturdaynights starting at about 8 P.M., the children thus sleepingthrough the major part of the transfusion. They go homefirst thing in the morning, thus missing no further schoolingand little weekend home life. The following evening theycome to the ward to have a post-transfusion h2emoglobinestimation by the s.H.o. on duty. This regimen is possibleas all our patients live within a few miles of the hospital.With 8 transfusions a year they will miss, hopefully, nomore than 8 hours of school-time for their routine visits.The rest of our treatment is similar to that of the Victoria
group, though our chelation is more intensive-3 g. ofdesferrioxamine per pint of blood transfused and 750-1000mg. desferrioxamine intramuscularly per day. With thisregimen our eldest children are in negative iron balance. 1
Pædiatric Unit,Whittington Hospital,London N19 5NF. NEIL MCINTOSH.
BLOOD-PRESSURE READING
SIR,—The measurement of blood-pressure is one of themost important parts of clinical examination, and it isessential that a standard procedure is followed. Thevarious technical details of blood-pressure reading are
clearly laid down. However, it is less well known thatthe reading of blood-pressure in the right arm is oftenslightly higher than in the left, and differences of 2 mm. to10 mm. Hg mercury are seen. It is even more importantthat the endpoint of the diastolic reading is often clearerand more easily recognised on the left side. The reasonfor this must be the difference in the origins of the sub-elavian arteries. It is therefore recommended that theblood-pressure is always taken in the left arm.Wanstead Hospital,
London E11. ERIC FRANKEL.
SUPEROXIDE DISMUTASE IN DOWNSYNDROME
SIR,—Your editorial on metabolic disorders in Down
syndrome I suggests that a convincing gene-dosage effectin trisomy 21 has never been reported. Later, however,Sinet et al.’ demonstrated that cytoplasmic superoxide-dismutase activity (S.O.D.A.) was increased in the erythrocytesof 10 trisomy-21 children compared with 10 controls.*
1. Modell, C. B., Beek, J. Ann. N.Y. Acad. Sci. 1974, 232, 201.2. Lancet, 1974, ii, 1554.3. Sinet, P.-M., Allard, D., Lejeune, J., Jérôme, H. ibid. 1975, i, 276.4. Sinet, P.-M., Allard, D., Lejeune, J., Jérôme, H. C. r. Acad. Sci.
Paris, 1974, 278, 3267.
43
0 20 40 60 80 100 120 140 160 180 200
RELATIVE S.O.D. CONCENTRATION
Relative erythrocyte (cytoplasmic) superoxide-dismutase concentration in Down syndrome patients and two control groups.
They concluded that the increase in S.O.D.A. is the resultof a gene-dosage effect. Benson 4 calls this interpretationinto question. He concludes that enhancement of enzymeactivity in erythrocytes and leucocytes is not convincingevidence of a gene-dosage effect in trisomic conditions.We have developed a quantitative immunological
technique (Mancini) to determine the amount of S.O.D.protein in human material, including red cells. Thes.o.D. concentration was correlated with haemoglobin, with ahaemolysate pool from laboratory personnel as standard.5,6 sWe have investigated 33 institutionalised Down syndromepatients aged 4-29. So far 22 of them have been karyotypedand were found to be regularly trisomic 21. Two controlgroups were studied. The first consisted of mentallyretarded but chromosomally normal patients from thesame wards, matched for age and sex. As a second control
group, staff from the same wards was investigated.Down syndrome patients have, on average, 40% more
S.O.D.A. in the erythrocytes than both control groups (seeaccompanying figure). The accordance with the results ofSinet et awl. is obvious, although it has to be borne in mindthat they used a colorimetric technique measuring thecapacity of s.o.D. to inhibit superoxide radical-mediatedreduction of a synthetic acceptor, whereas we are deter-mining the s.o.D. protein concentration.
In trisomy 21 an elevation has been found in the activityof many other enzymes-e.g., leucocyte-alkaline-phosphatase,’’ whole-blood galactose-1-phosphate-uridyl-transferase 8 red-cell phosphohexokinase,9,10 and red-cellcatechol-0-methyl-transferase." i The elevation inalkaline phosphatase is non-specific, occurring also inother trisomies and in infections.12 Furthermore, thereis no real evidence that the gene for any of these enzymesis localised on chromosome 21, and the excess in enzymeactivity cannot be explained directly on the basis of gene-dosage effect. However, the gene for S.O.D. has been
assigned to chromosome 21 by linkage analysis usingsomatic-cell!hybrids.13 Thus, the most tempting conclusionis that the high S.O.D.A. in trisomy 21 is the consequence of agene-dosage effect.
4. Benson, P. F. Lancet, 1975, i, 584.5. Frants, R. R., Eriksson, A. W. 16th Dutch Federative Meeting 1975,
p. 208.6. Frants, R. R. Unpublished.7. Alter, A. A., Lee, S. L., Pourfar, M., Dobkin, G. J. clin. Invest.
1962, 41, 1341.8. Brandt, N. J., Frøland, A., Mikkelsen, M., Nielsen, A., Tolstrup, N.
Lancet, 1963, ii, 700.9. Baikie, A. G., Loder, P. B., deGruchy, G. C., Pitt, D. B. ibid.
1965, i, 412.10. Bartels, H., Kruse, K. Humangenetik, 1968, 6, 305.11. Gustavson, K.-H., Wetterberg, L., Bäckström, M., Ross, S. B.
Clin. Genet. 1973, 4, 279.12. Trubowitz, S., Kirman, D., Masek, B. Lancet, 1962, ii, 486.13. Tan, Y. H., Tischfield, J., Ruddle, F. H.J. exp. Med. 1973, 137, 317.
A physiological role of S.O.D. is to dismutate the reactivesuperoxide radicals. Such radicals have been shown to beinvolved in defence against bacteria. Increased S.O.D.A.could lower the concentration of superoxide radicals,resulting in the increased susceptibility to bacterial andviral infections 6 frequently encountered in Down syndrome.
Further studies will show whether the S.O.D. concentrationis influenced by a triple-gene dosage effect or by secondaryfactors, such as a generally disturbed protein synthesis or ayounger mean cell-age, reflected in a slight macrocytosisin a number of our Down syndrome subjects.
Institute of Human Genetics,Free University of Amsterdam,
The Netherlands.
R. R. FRANTSA. W. ERIKSSON.
Huize " Maria Roepaan ",Institute for Observation and
Treatment of Mentally Retarded,Ottersum, The Netherlands.
P. H. JONGBLOETA. J. HAMERS.
Obituary
WILLIAM STUART McRAE CRAIGM.D.Edin., B.Sc.Glasg., F.R.C.P., F.R.C.P.E., F.R.S.E.
Prof. W. S. M. Craig, professor emeritus of paedi-atrics and child health in the University of Leeds,died on June 21 at the age of 72.He came by an unusual path to the chair in Leeds.
He was the son of a much-loved general practitioner inBingley, Yorkshire, and after obtaining his B.sc. (in navalarchitecture) at Glasgow University in 1924, he worked fora time in a Clydeside shipyard. He turned later to medicineand made rapid progress after graduating M.B. in 1930 atEdinburgh University. By 1936 he had published severalvaluable papers, and was an assistant paediatrician in
Edinburgh under Prof. Charles McNeil; but there waslittle hope of early advancement, and young paediatricianshad small incomes in those days. He joined the Ministryof Health in 1936, and spent 10 years there, chiefly as ahospital medical officer. In 1946 he published Child andAdolescent Life in Health and Disease. This was the firstbook of its kind on social pxdiatrics and was soon consideredessential reading for budding paediatricians.When he was appointed to the chair at Leeds University
in 1946, he had a tiny room in the General Infirmary andplenty of patients in four hospitals, but no department ofpxdiatrics in the modern sense, so he had to make a startfrom very little, in a city without a children’s hospital.