383 ANNOTATIONS all the more that those who control grants will appreciate the necessity for financial assistance and staff on a liberal scale and that they will not expect results to be produced rapidly. In this country, we are indeed fortunate in that the Medical Research Council has already done so much to support basic research on human nutrition. Annotations PLOUGHSHARES AT GENEVA THE International Conference on the Peaceful Uses of Atomic Energy, organised by the United Nations at Geneva, is now drawing to a close after nearly two weeks’ deliberation in which about a thousand scientific papers have been read or tabled. For the first time a good deal about the design of nuclear reactors and atomic power stations has been made public, and the machinery used in this work offered for international sale. Eco- nomically and industrially atomic energy has become important for national prestige, and it seems that at present Britain leads in the export of radio-isotopes. Part of the interest of the conference was to learn what Russia, the United States, and Canada were offering. Some of the medical papers, naturally enough, were on the health risks of radioactivity, which is where radiotherapy, genetics, and physics join hands. Others dealt with the biochemical and physiological results of using radio-isotopes in the investigation of intermediary metabolism, usually mammalian : a very great deal has already been published on such subjects as diabetes, the synthesis of hsemoglobin, and the metabolism of steroid hormones and proteins. In a third group of papers atomic energy was applied in medical practice-for example, to the detection of cerebral tumours, the invention of a highly portable X-ray apparatus requiring no electricity, the examination of thyroid activity, the spread of communicable diseases in the field-a miscel- laneous and ingenious group of fruitful applications. It is evident that many clinicians can hardly be aware of the enormous quantity of work that has been done, and mostly published, in the past ten years. Some of it is ready to affect clinical practice and research, but it is difficult for the medical worker to know what oppor- tunities atomic energy offers him, not because of any secrecy but because of the specialised language and specialist journals in which the work often appears. There is a need for simple reviews which explain the situation to the non-physicist, and perhaps for some kind of medical advisory service like that already offered to industry. At Geneva Dr. E. E. Pochin gave an excellent brief review of iodine metabolism. For examination of thyroid function he recommended a simple test in which an inoffensively small dose of radioactive iodide is injected, and two hours later the degree of absorption by the thyroid is estimated by a five-minute count at the patient’s neck and thigh. Normally the kidney clears the plasma of iodide at the rate of 2 litres per hour, while the thyroid works at only 1 litre per hour ; but the thyro- toxic thyroid clears at 15 litres per hour. The normal human thyroid (unlike that of rat and rabbit) discharges its iodine slowly, over six weeks or more. But the thyrotoxic gland discharges quickly (about four days), and so does carcinomatous thyroid, which has a poor uptake, however. A similar method for assay of thyroid function is in use in the U.S.S.R., according to Dr. M. N. Fateyeva ; but in Russia the chief interest has been to study thyroid activity in non-thyroid diseases. For instance, increased thyroid activity has been noted in stage-1 essential hypertension, in 50% of patients with rheumatic carditis at the height of the disease, and in acromegaly. The test is useful in the differential diagnosis of anxiety state from thyrotoxicosis, since function remains normal in the neurosis. Canadian workers advocated the measurement of radio-iodine in the saliva twenty-four hours after a test dose as a good guide to thyroid function. Urinary excretion of creatine in considerable amounts is one of the laboratory signs of thyrotoxicosis. Dr. DeWitt Stetten, jun., explained that creatine is normally made in the liver and taken up by the muscles, where as creatine phosphate it takes part in muscular con- traction. A fraction of it is converted there to creatinine and excreted constantly in the urine. Using isotope methods it has been possible to show that the creatinuria of thyrotoxicosis is due to overproduction by the liver under thyroid stimulation. In muscular dystrophies, on the other hand, liver production is normal but the diseased muscle does not take up its creatine ration, which consequently appears in the urine. In another illustration of isotope work Prof. A. B. Hastings described results in diabetic rats partly confirmed for human diabetics, which show that in dia-betes there is both an inability of muscles to use glucose and an overproduction of glucose by the liver, which contains twice the normal amount of the enzyme glucose-6-phosphatase. When insulin is given, the muscle failure is corrected almost at once whereas the liver abnormality takes some hours to put right. In an equally interesting report, Dr. Dale W. Jenkins described the labelling of mosquitoes and flies to determine their spread from a release point, their life-span, their predators (which also become radioactive), and the total natural population (by dilution). In the same way, many viruses and bacteria can be made radioactive, and their survival in and dissemination by their hosts followed. And in man erythrocytes can be labelled by contact with sodium chromate (Cr51), and serum-albumin with radio- active iodine, as Prof. W. V. Mayneord mentioned in a useful review of other isotope methods. He described how xenon 133 can be adsorbed on carbon and used to take radiographs without any source of electricity or large apparatus : a radiograph of the ankle needed a ten-second exposure. Professor Mayneord also referred to the use of radioactive isotopes selectively absorbed by cerebral tumours, as did Dr. G. L. Brownell and Dr. W. H. Sweet, who have devised an ingenious way of displaying the tumours without opening the skull. They inject arsenic 74 intravenously, and this concen- trates about ten times more in tumour tissue than in normal cerebrum. The many papers on the health effects of radiation combined to emphasise the impossibility of being sure that so-called safe exposure limits are neither too high nor too low. Dr. D. E. Clark reported 15 cases of carcinoma of thyroid in children under 16, all of whom had at some time had X-ray treatment for benign con- ditions of the head, neck, or chest. Dr. R. J. Hasterlik and Dr. L. D. Marinelli described 4 patients who got neutron and gamma-ray overdoses from an accident at work. None of them had symptoms of radiation sickness, and only 1 showed a (transient) skin erythema. Haemato- logical investigation did not show a great deal either, but there was a high and abnormal urinary amino-acid excretion within twelve hours of exposure and this continued for five months ; and sperm counts on the men showed diminution or aspermia maximal at the tenth month, with subsequent recovery. As for genetic effects produced by the increased rate of mutation, we , really know nothing good or ill. As Dr. J. F. Loutit said, " New mutations are merely repetitions of the old v which Nature has tried before. When the environment L changes, a mutation once deleterious may in fact be L favourable."
Transcript
383ANNOTATIONS
all the more that those who control grants will
appreciate the necessity for financial assistance andstaff on a liberal scale and that they will not expectresults to be produced rapidly. In this country, weare indeed fortunate in that the Medical ResearchCouncil has already done so much to support basicresearch on human nutrition.
Annotations
PLOUGHSHARES AT GENEVA
THE International Conference on the Peaceful Usesof Atomic Energy, organised by the United Nations atGeneva, is now drawing to a close after nearly two weeks’deliberation in which about a thousand scientific papershave been read or tabled. For the first time a gooddeal about the design of nuclear reactors and atomic
power stations has been made public, and the machineryused in this work offered for international sale. Eco-
nomically and industrially atomic energy has becomeimportant for national prestige, and it seems that at
present Britain leads in the export of radio-isotopes.Part of the interest of the conference was to learn whatRussia, the United States, and Canada were offering.Some of the medical papers, naturally enough, were
on the health risks of radioactivity, which is where
radiotherapy, genetics, and physics join hands. Othersdealt with the biochemical and physiological results ofusing radio-isotopes in the investigation of intermediarymetabolism, usually mammalian : a very great deal hasalready been published on such subjects as diabetes, thesynthesis of hsemoglobin, and the metabolism of steroidhormones and proteins. In a third group of papersatomic energy was applied in medical practice-forexample, to the detection of cerebral tumours, theinvention of a highly portable X-ray apparatus requiringno electricity, the examination of thyroid activity, thespread of communicable diseases in the field-a miscel-laneous and ingenious group of fruitful applications. Itis evident that many clinicians can hardly be aware ofthe enormous quantity of work that has been done, andmostly published, in the past ten years. Some of it isready to affect clinical practice and research, but it isdifficult for the medical worker to know what oppor-tunities atomic energy offers him, not because of anysecrecy but because of the specialised language andspecialist journals in which the work often appears.There is a need for simple reviews which explain thesituation to the non-physicist, and perhaps for some kindof medical advisory service like that already offeredto industry.At Geneva Dr. E. E. Pochin gave an excellent brief
review of iodine metabolism. For examination of thyroidfunction he recommended a simple test in which an
inoffensively small dose of radioactive iodide is injected,and two hours later the degree of absorption by thethyroid is estimated by a five-minute count at thepatient’s neck and thigh. Normally the kidney clearsthe plasma of iodide at the rate of 2 litres per hour, whilethe thyroid works at only 1 litre per hour ; but the thyro-toxic thyroid clears at 15 litres per hour. The normalhuman thyroid (unlike that of rat and rabbit) dischargesits iodine slowly, over six weeks or more. But thethyrotoxic gland discharges quickly (about four days),and so does carcinomatous thyroid, which has a pooruptake, however. A similar method for assay of thyroidfunction is in use in the U.S.S.R., according to Dr. M. N.Fateyeva ; but in Russia the chief interest has been tostudy thyroid activity in non-thyroid diseases. Forinstance, increased thyroid activity has been noted instage-1 essential hypertension, in 50% of patients with
rheumatic carditis at the height of the disease, and inacromegaly. The test is useful in the differential diagnosisof anxiety state from thyrotoxicosis, since functionremains normal in the neurosis. Canadian workersadvocated the measurement of radio-iodine in the salivatwenty-four hours after a test dose as a good guide tothyroid function.
Urinary excretion of creatine in considerable amountsis one of the laboratory signs of thyrotoxicosis. Dr.DeWitt Stetten, jun., explained that creatine is normallymade in the liver and taken up by the muscles, whereas creatine phosphate it takes part in muscular con-traction. A fraction of it is converted there to creatinineand excreted constantly in the urine. Using isotopemethods it has been possible to show that the creatinuriaof thyrotoxicosis is due to overproduction by the liverunder thyroid stimulation. In muscular dystrophies, onthe other hand, liver production is normal but thediseased muscle does not take up its creatine ration,which consequently appears in the urine. In anotherillustration of isotope work Prof. A. B. Hastings describedresults in diabetic rats partly confirmed for humandiabetics, which show that in dia-betes there is both aninability of muscles to use glucose and an overproductionof glucose by the liver, which contains twice the normalamount of the enzyme glucose-6-phosphatase. Wheninsulin is given, the muscle failure is corrected almost atonce whereas the liver abnormality takes some hours toput right.
In an equally interesting report, Dr. Dale W. Jenkinsdescribed the labelling of mosquitoes and flies to determinetheir spread from a release point, their life-span, theirpredators (which also become radioactive), and the totalnatural population (by dilution). In the same way,many viruses and bacteria can be made radioactive, andtheir survival in and dissemination by their hosts followed.And in man erythrocytes can be labelled by contact withsodium chromate (Cr51), and serum-albumin with radio-active iodine, as Prof. W. V. Mayneord mentioned in auseful review of other isotope methods. He describedhow xenon 133 can be adsorbed on carbon and used totake radiographs without any source of electricity orlarge apparatus : a radiograph of the ankle needed aten-second exposure. Professor Mayneord also referredto the use of radioactive isotopes selectively absorbedby cerebral tumours, as did Dr. G. L. Brownell andDr. W. H. Sweet, who have devised an ingenious wayof displaying the tumours without opening the skull.
They inject arsenic 74 intravenously, and this concen-trates about ten times more in tumour tissue thanin normal cerebrum.The many papers on the health effects of radiation
combined to emphasise the impossibility of being surethat so-called safe exposure limits are neither too highnor too low. Dr. D. E. Clark reported 15 cases ofcarcinoma of thyroid in children under 16, all of whomhad at some time had X-ray treatment for benign con-ditions of the head, neck, or chest. Dr. R. J. Hasterlikand Dr. L. D. Marinelli described 4 patients who gotneutron and gamma-ray overdoses from an accident atwork. None of them had symptoms of radiation sickness,and only 1 showed a (transient) skin erythema. Haemato-logical investigation did not show a great deal either,
but there was a high and abnormal urinary amino-acidexcretion within twelve hours of exposure and thiscontinued for five months ; and sperm counts on themen showed diminution or aspermia maximal at thetenth month, with subsequent recovery. As for genetic
. effects produced by the increased rate of mutation, we, really know nothing good or ill. As Dr. J. F. Loutit
said, " New mutations are merely repetitions of the oldv which Nature has tried before. When the environmentL changes, a mutation once deleterious may in fact beL favourable."
384 ANNOTATIONS
SKELETAL MATURITY
Tm degree of maturity of the skeleton is of interestoccasionally to the clinician and constantly to those
investigating growth and development. Such workersare increasingly aware of the shortcomings of presentmethods, which are four in number :
(1) Comparison of radiographs of the hand and wrist withstandard films typical of different ages. An " atlas " of such
‘
films was published as long ago as 1902 by Wilms.l(2) Measurement of the size of the bone images on a radio-
graph.2-,’ This method is little used because it is inaccurateand time-consuming.
(3) Radiography of all the joints on one side of the body,counting the ossified centres.6 7 This is expensive and is
impracticable as a routine procedure.(4) A method, based on (1), in which the equilibrium of
bone maturation is determined by recording the individualrange in various bones. This is known as the red graphmethod. 8 It is complex and does not take into considerationstructural changes in epiphyses.
Investigations by these methods have yielded one vjtalpiece of information : there are sometimes considerabledifferences between the stage of maturation of differentareas of the body. Maresh 9 has shown that the longbones do not all grow at the same rates, nor fully matureat the same end-point. The cause of these differences isnot clear.
Today the inspectional technique is most commonlyused. It is based on the fundamental work of Todd, owho published an atlas and standard of reference in 1937after discussions with Hellman 11 and Flory.12 Todddescribed the exact image changes in the radiographsof the growing ends of long bones. His publicationconcerned the hand and wrist, but he prepared excellentunpublished descriptions and standards for the elbow,shoulder, hip, knee, and foot. In 1950 Greulich and
Pyle 13 revised the atlas and added descriptions of thematuring round bones of the carpus. This atlas is at
present the standard work of reference. In additionthere is an atlas of standards of Dutch children bySpeijer,14 and a report by Mackay,l5 relating to EastAfrican children, which reveals another difficulty-thepart played by racial, nutritional, and other influences.
Acheson16 has pointed to the shortcomings of the
inspectional technique. These are :
(a) A fixed pattern of first appearance and subsequentdevelopment of centres is presupposed. The order in whichcertain centres appear is known normally to vary widely,and thus comparison of films with the standards is difficult anda large subjective error inevitable.
(b) The time interval between the standard films is too long.Coarse grouping is an essential of the method, but this intro-duces further subjective errors.
(c) Two sets of standard films are needed since the two sexesmature at different rates.
(d) Acheson points out that bone cannot decrease in sizeduring growth ; so, he argues, skeletal maturity should notbe measured with time as a. yardstick, but should have unitsof its own.
Acheson writes : " To speak of the mean skeletal
maturity status of a group of children aged 21/2 years as’ skeletal age 30 months,’ is no more reasonable than tospeak of their mean weight as being ’ ponderal age 301. Wilms, M. Fortschr. Röntgenstr. 1902, Ergänzungsband 9.2. Carter, T. M. J. educ. Psychol. 1926, 17, 237.3. Baldwin, B. T. Univ. Ia Stud. Child Welf. 1928, 4, 1.4. Sawtell, R. O. Amer. J. Dis. Child. 1929, 37, 61.5. West, E. D. Harv. Teach. Res. 1936, 6, 162.6. Sontag, L. W., Lipford, J. J. Pediat. 1943, 23, 391.7. Lurie, L., Levy, S., Lurie, M. L. Ibid, p. 131.8. Pyle, S. I. Ibid, 1948, 32, 125.9. Maresh, M. M. Personal communication.
10. Todd, T. W. Atlas of Skeletal Maturation. Part I : TheHand. St. Louis. 1937.
11. Hellman, M. Amer. J. phys. Anthrop. 1928, 11, 223.12. Flory, C. D. Monog. Soc. Res. Child. Developm. 1936, 1, 3.13. Greulich, W. W., Pyle, S. I. Atlas of Skeletal Development of
the Hand and Wrist. Stanford, 1950.14. Speijer, B. Beteknis en Bepaling van de skeletleestijd Sijthoff.
Leiden, 1950.15. Mackay, D. H. Trans. R. Soc. trop. Med. Hyg. 1952, 46, 135.16. Acheson, R. M. J. Anat. 1954, 88, 488.
months.’ " Both processes are correlated with time, butnot closely ; and he describes a new method of assessingmaturity in which each round bone and epiphysis isconsidered regardless of the ossification pattern ; smallincreases of maturity are recorded ; the same standardsare used for both sexes ; and finally maturation is given ayardstick of its own, the units being termed Oxford
maturity units.This method was used in a pilot study of 97 children
from the Oxford child health surveyY Since thenAcheson et al.18 have applied it to some 600children from birth to 5 years of age. Scores are given tobones in the hand and wrist-joint for each definite changein shape, maturity indicators described by workers alreadymentioned being used. The principle is that the sum totalof the units scored by any bone will indicate its degreeof maturity. The knee is also used, and indicators aresuggested on the basis of 1200 serial films of this joint.(Sick’s 19 account of this joint was not sufficientlydetailed.) Stuart 20 and his co-workers in Boston, findingthe wrist unsatisfactory, are analysing their compre-hensive data with a view to producing information onthe maturation of the knee ; and we understand thatanother group in the U.S.A. have just completed anatlas on this joint.Acheson is careful to emphasise that his method of
computation is experimental. At present it is uncertainwhether we can legitimately assume that round-boneand epiphyseal development proceed at a parallel rate.Again, different bone areas of the body may mature atdifferent rates ; so should " maturity indicators " forone area be added to those for another in order to givea truer picture of the total maturity ?As Krogman 21.has said, a 100% level of morphological
maturity is inevitable in the healthy human, and accord-ingly Acheson suggests that when the whole age-rangeof the growing human is investigated it would be logicalto express skeletal maturity as a percentage. (Someworkers hold that final adult height can be predicted byassessing skeletal maturity during growth.22) Acheson’swork shows the need for considering skeletal maturityin terms other than time ; and it clearly points the wayout of the present unsatisfactory situation.
NO SOVEREIGN REMEDY
IT can be harder work to ameliorate symptoms than toprescribe a complete and perfect remedy. Problemfamilies, according to the fourth Southampton survey 23on the subject, have no single cause, and there is no
single remedy for them ; nevertheless, the authors ofthe survey-Mr. E. T. Ashton, Mr. C. J. Thomas, andProf. P. Ford (all of the department of economics of theUniversity of Southampton)-do not suggest that theamelioration of symptoms need be given up. They wereasked by Dr. H. C. Maurice Williams, medical officer ofhealth for Southampton, to study the problem family" in the administrator’s sense "-in the sense, that is, of the-problems requiring solution they present from day to day.The survey team have analysed all the cases brought
up to, and accepted by, the Southampton social rehabili-tation committee as problem families between Jan. 1,1952, and Dec. 31, 1953. There were 104 such families,but, as is pointed out, behind this " accepted " groupis a much larger group of marginal cases. Many of thedifficulties of these families can be traced to the character,initial endowment, and emotional and educationalhistory, of family members, and to the emotional rela-tions between them : and such intricate personal matterscannot easily be expressed in averages, and the truth17. Stewart, A. M., Russell, W. T. Med. Offr, 1952, 88, 5.18. Acheson, R. M., Kemp, F. H., Parfit, J. Lancet, 1955, i, 691.19. Sick, C. Fortschr. Röntgenstr. 1902, Ergänzungsband 9.20. Stuart, H. C. Personal communication.21. Krogman, W. M. Child Developm. 1950, 21, 25.22. See Lancet, 1952, ii, 328.23. Problem Families. Oxford: Blackwell. Pp. 51. 4s.
