1034

evident mischief. And there are no really safemethods, other than boredom, of rendering an

adversary unconscious. But perhaps it would not beasking too much if now and then the course of theplot were to suggest that a head injury is a seriousmatter, that any person who has been renderedunconscious in that way should be regarded as

potentially a very sick man, and that death or

permanent disability are quite possible after blowson the skull.

1. Report for 1956 of the Commonwealth Fund, Harkness House,1, East Seventy-Fifth Street, New York, 21.

2. See Lancet, Sept. 22, 1956, p. 612.

Annotations

REDISCOVERY OF THE PATIENT

IN the United States, as in this country, medicaleducation is the subject of discussion and concern, butwhen the representatives of our medical schools meet inLondon next week they may well speak with envy of the" unrestricted " grants, amounting to 121/2 million dollars,which nineteen American schools have lately receivedfrom the Commonwealth Fund to help them " in

strengthening and improving their programs of medicaleducation." As the annual report 1 explains, it is a

measure of the Fund’s conviction of the present urgentneeds and exceptional promise of medical education thatthis money has been largely found from capital. The

report also contains a valuable review of the trends ofmedical education in America during the past ten years.Many of these, including post-war interest in 1Jlentalhealth and in environmental medicine, lead directly tothe patient, and one of the lessons which the schoolsseem to be learning afresh is that " the patient is the

only reason for medicine." But it is perhaps truer tosay that the patient is being shown to the students froma new angle. He still comes to the doctor or the hospitalfor help with an injury, a lump, or a pain, but the studentsare now being taught to see his illness as an " aspect ofliving, not an isolated episode with a clear beginning orend." In practice this has meant that the students arebrought into earlier and closer contact with the patientand that the pattern of teaching is changing to givemore importance to the outpatient clinic as opposed tothe ward-round. The ambulant patient has led thestudents to his home and workshop and shown them theimportance of aftercare. These same ideas are also beingapplied to medical education in this country, and welately described their introduction, with the help of theRockefeller Foundation, in the university general-practice teaching unit at Edinburgh.2 sThe student, as well as the patient, the Fund’s report

suggests, has been regaining the place in the schoolsfrom which the " growth of research and the advanceof science " have tended to push him. Yet he is thecommon denominator of medical education, and research-workers are now, with profit, studying his attitudes andbehaviour and considering such questions as whether

early contact with patients reinforces or detracts fromthe student’s interest in preclinical science. The fundalso casts a sympathetic eye on the problems of themedical teacher " caught in a tight squeeze between thedemands of teaching, research, administration andoutside responsibilities." No-one can teach well who onlyteaches, and this is especially true in the medical facultywhere good teaching is often dependent on the stimulusof research. But the proper division of his time andinterest remains one of the teacher’s real problems.The question is sometimes asked today whether the

medical school should remain within the universities. By

its generous support to the universities the Fund has madeclear that it believes they should. The Fund sees the

university as a social institution, part of the community,and concerned with the affairs of man; and if the medicalschool ga,ins much from an academic setting it offers inreturn a<1equato and essential " equipment for the studyof the na.ture an<1 behaviour of man," and is in fact theuniversity’s potential laboratory of applied research.

1. Attinger, E. O., Goldstein, M. M., Segal, M. S. Amer. Rev.Tuberc. 1956, 74, 210.

2. Attinger, E. O., Goldstein, M. M., Segal, M. S. Ibid, p. 220.3. Fry, D. L., Ebert, R. V., Stead, W. W., Brown, C. C. Amer.

J. Med. 1954, 16, 80.4. Mead, J., Lindgren, I., Gaensler, E. A. J. clin. Invest. 1955,

34, 1005.

PRESSURE-VOLUME RECORDING IN EMPHYSEMA

IN two recent papers Attinger et al.1 deal with therelative merits of time-volume and pressure-volumeinvestigations in patients with pulmonary disease.Time-volume studies include the conventional functionaltests, such as vital capacity and maximal breathingcapacity, and other measurements such as timed vitalcapacity and maximal expiratory flow-rate. Attingeret al. point out that though these tests are a help to theclinician, they are often a poor reflection of the patient’sactual incapacity. Pressure-volume recordings, on theother hand, allow measurement of pulmonary com.pliance and flow-resistance and of the work involved inbreathing.

Attinger et al. are concerned with the changes inviscous-elastic properties in the lungs in chronic emphy-sema, and they have measured intracesophageal pressuresand air-flow rates by the pneumotachograph to examinepulmonary pressure-volume relations in this disease.With characteristic unequal distribution of ventilationin the emphysematous lung the distension of differentareas of lung varies ; with high respiratory rates onlynormal alveoli are ventilated, while with low respiratoryrates there is more time per breath for equilibrationthroughout the lung and the passage of respiratory air intoand out of the diseased alveoli. Because of the increasedtime for air passage, the effective lung-volume increasesat slower respiratory rates, and the compliance (measuredas change in lung-volume divided by intracesophagealpressure difference between instants of zero tracheal

air-flow) also increases. The loss of elasticity andincreased mechanical resistance in the emphysematouslung lead to an active expiratory effort, which produceshigh positive intrapulmonary pressures, which in tunicause the collapse of airways ; air-flow then decreasesuntil intrabronchial pressure rises high enough to over-come the intrapulmonary pressure, when air-flow startsagain. This type of cycle resulting from this check-valvemechanism is common in emphysema and may not alwaysbe recognised from time-volume lung tests. Pressure-volume measurements, on the other hand, show up thegreatly increased work/cycle (as an increased area enclosedby the pressure-volume trace) resulting from a highmechanical resistance in the emphysematous lung.Approximate values show an inspiratory resistance offour times normal and an expiratory resistance of seventimes normal; and there is a considerable drop in

compliance when the respiratory rate is increased. These

findings are in accordance with those of Fry et al.3 andMead et awl. 4 Pressure-volume diagrams show that mostof the work of breathing goes toward overcomingmechanical resistance and only a small part toward over-coming elastic forces ; further, the pressure necessaryto obtain a given flow-rate increases progressively during Z)

expiration. In consequence, a large part of the patient’senergy and oxygen uptake are spent on the breathingprocess alone, and the work of breathing helps todetermine the incapacity of the emphysematouspatient.

1035

Attinger and his colleagues have performed a usefulservice in underlining the importance of making simul-taneous records of pressure and volume in order to gainaccurate knowledge of changes in lung characteristics.Those who support the conventional time-volume

pulmonary tests could no doubt make a case- to showTheir advantages on such grounds as little disturbanceto the patient and simple apparatus ; but Attinger et al.find that measurements of compliance and mechanicalresistance reveal abnormalities when the usual pulmonaryfunction tests are still within the normal range. More-over, the simultaneous measurement of pressure has the

unquestionable advantage over time-volume measure-

ments alone that the work involved in respiration maybe computed. Attinger et al. declare that " the clinicianshould realize that an evaluation of ventilatory functionon the basis of volume measurements or volume-timerelationships alone may be as incomplete and as mis-leading as evaluating cardiac function on the basis ofcardiac output without taking into consideration bloodpressures and vascular resistance."

1. Lancet, Sept. 22, 1956, p. 611.2. Stanbury, J. B., Eassenaar, A. A. H., Meijer, J. W. A., Terpstra, J.

J. clin. Endocrin. 1955, 15, 1216.3. Stanbury, J. B., Meijer, J. W. A., Kasseuaar, A. A. H. Ibid,

1956, 16, 848.4. Querido, A., Stanbury, J. B., Kassenaar, A. A. H., Meijer, J. W. A.

Ibid, p. 1096.5. McGirr, E. M., Hutehison, J. H., Clement, W. E. Lancet, Nov. 3,

1956, p. 906.6. McGirr, E. M., Hutohison, J. H. Ibid, 1953, i, 1117.7. Hutchison, J. H., McGirr, E. M. J. clin. Endocrin. 1954, 14, 869.

ONE GENE:ONE ENZYME ?

WE lately discussed some interesting observations byStanbury and his colleagues 2 3 relating to the metabolismof iodotyrosines in certain patients with goitrous cretin-ism. These observations showed that the blood of these

patients contained mono- and di-iodotyrosine ; and thatlabelled mono- and di-iodotyrosine, injected intraven-ously, were largely excreted unchanged in the urine. Itseemed likely that these patients did not have the

deiodinating enzyme which is normally present both inthe thyroid and in other tissues. Querido, Stanbury,and their colleagues 4 have now obtained direct connrma-tion of the absence of this enzyme. They showed thatslices of sheep or ox thyroid, or of human nodular goitres,were able to deiodinate diiodotyrosine. Slices from the

goitre of one of their patients with familial goitrouscretinism, however, left the diiodotyrosine unchanged.As the experiments were done under identical conditionsthere seems no doubt that the cretin’s thyroid containedno deiodinase. The presumed result is a life-long leak ofiodotyrosines from the thyroid into the blood and thenthe urine, of sufficient magnitude to cause serious iodinedeficiency; and both goitre and cretinism can be

explained on a basis of iodine deficiency.McGirr et a1.5 have provided more information about

the genetics of this biochemical lesion. They have madeextensive studies,6 both biochemical and genetic, of anintriguing family of itinerant tinkers living in South-WestScotland. No less than 10 members of this family aregoitrous cretins. From this inquiry it was concludedthat the defect was determined by the presence or absenceof a single autosomal recessive gene. In their latestpaper McGirr et al. have been able to demonstrate bothmono- and di-iodotyrosine in the blood and urine of someof the affected members. This means in all probabilitythat the defect in the tinker family is the same as thatstudied by Stanbury and Querido in their goitrous cretins.By combining the work of both groups we can surmisethat a single recessive gene controls the presence or

absence of a single deiodinating enzyme ; and that theabsence of this enzyme explains all the clinical featuresobserved in these particular goitrous cretins. McGirr

I et al.5 are careful to point out, however, that this gene-

and-enzyme defect accounts for only one group of non-endemic goitrous cretins ; at least two other apparentlyunrelated biochemical lesions have been demonstrated in

clinically similar cases.

1. Upton, A. C., Furth, J. Proc. Soc. exp. Biol., N.Y. 1953, 84, 255.2. Upton, A. C., Furth, J. J. nat. Cancer Inst. 1955, 15, 1005.3. Furth, J., Gadsden, E. L., Clifton, K. H., Anderson, E. Cancer

Res. 1956, 16, 600.4. Furth, J., Clifton, K. H., Gadsden, E. L., Buffett, R.’F. Ibid,

p. 608.

MAMMATROPHIN-SECRETING PITUITARYTUMOURS

SEVERAL mice subjected in 1951 to whole-body ionisingradiation in an atomic explosion were found in old age tohave pituitary tumours.l 2 Furth and his colleagues 3examined 9 of these tumours by grafting them into

young hosts of the same strain, and 3 gave evidenceof adrenotrophic secretion, 1 was predominantly somato-trophic, and 5 stimulated the mammary glands of theirhosts. Mammary stimulation was reflected in duct orJobular growth, or both combined, and by milk-likesecretion. Some grafts were dependent on oestrogen,but others were autonomous. There was no sign in thehosts of increased production of oestrogen. Furth et al.conclude that these tumours were secreting a mamma-trophic hormone (formerly better known as prolactin), thatthey were of the same nature as rat pituitary tumoursinduced with oestrogen, and that they had similar

properties.4 4 Furth et al. believe that the ultimate mecha-nism of induction is the same : oestrogen is either adminis-tered or is produced in excess by ionising radiation, firstby atrophy, then by granulosa-celled oestrogen-secretingtumours which arise in the ovary.These mammatrophin-secreting tumours provide an

opportunity for comparing the action of this hormone assecreted from grafts (or obtained by extraction) with thatderived from cattle and sheep pituitaries. It is knownthat extracted prolactin does not influence the mammaryrudiments of male mice in the absence of added cestrogen,though in the rat it does. The mammary glands of malemice with mammatrophin tumours consisted of collapsedrudimentary ducts only ; but the mammary glands ofcastrated males bearing ovarian grafts in addition weresimilar to those of intact females. A graft of a pituitarytumour induced in a rat with stilbcestrol caused both

proliferation and secretory changes in the mammarygland, even in gonadectomised animals. As with prolactinthere is here a species difference in response. The validityof the conclusion that the grafts were secreting mamma-trophin would have been enhanced had they been grownin hypophysectomised animals, for in some mouse strainsovarion hormones stimulate the male rudiment toextensive proliferation, and even milk-like secretion,provided that a mere fragment of hypophysis is present :otherwise there is no response. Therefore, to prove thepresence in the grafts of mammatrophin the hosts ownhypophysis must be completely removed. Furth et al.state that in unpublished experiments in rats the mamma-tropic-tumour grafts replaced natural hypophysealprolactin in this respect. No reference is made to com-parison by the pigeon-crop test, but just as prolactininjections into pigeons caused enlargement of abdominalorgans, so there was a great increase in the size andweight of livers and kidneys in mice and rats bearingthese tumour grafts. It may be argued that extractedprolactin contains traces of somatotrophin, and on Furthet al.’s admission some and possibly all of the pituitarytumours were of mixed cells containing somatotropesas well. It has been reported, however, that highlypurified mammatrophic hormone from the tumourshas induced somatotrophin-like action on the tibial

plate.Pituitary cells which secrete mammatrophin are

called mammatropes, to conform with thyrotropes,