1069

8. Carter, C. O., Hamerton, J. L., Polani, P. E., Gunalp, A., Weller,S. D. V. ibid. Sept. 24, 1960, p. 678.

9. Fraccaro, M., Kaijser, K., Lindstern, J. ibid. 1960, i, 724.10. Edwards, J. H., Harnden, D. G., Cameron, A. H., Crosse, V. M.,

Wolff, O. H. ibid. p. 787.11. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., Wagner, H. P.

ibid. p. 790.12. Hayward, M. D., Bower, B. D. ibid. Oct. 15, 1960, p. 844.13. De Carli, L., Nuzzo, F., Chiarelli, B., Poll, E. ibid. July 16, 1960, p. 130.14. Sandberg, A. A., Crosswhite, L. H., Gordy, E. J. Amer. med. Ass.

1960, 174, 221.15. Jacobs, P. A., Harnden, D. G., Court-Brown, W. M., Goldstein, J.,

Close, H. G., MacGregor, T. N., Maclean, N., Strong, J. A. Lancet,1960, 1213.

16. Stewart, J. S. S., Sanderson, A. ibid. July 2, 1960, p. 21.17. Fraser, J., Campbell, J., MacGillivray, R. C., Boyd, E., Lennox, B.

ibid. Sept. 17, 1960, p. 626.18. Jacobs, P. A., Harnden, D. G., Court-Brown, W. M., Baikie, A. G.

ibid. Aug. 13, 1960, p. 368.

most remarkable family. Two mongol sibs each had46 chromosomes, with the same 21/15 translocation-fusion to account for it. In addition, three normalfemale relatives were found to have 45 chromosomes

only. In them an essentially normal chromosome com-plement had apparently been affected by the

" fusion "of one chromosome each from the pairs 15 and 21. In

this family the translocation had obviously occurred atleast in the great-grandparents. The mere joiningtogether of two chromosomes had no recognisableeffect, but the tendency to imbalance during gameteformation inseparable from this fusion gave rise to someoffspring with too much chromosomal material, whowere the mongols. The importance of this form oftransmission has been established by the descriptionof a very similar but even larger family group by CARTERet al.8 The mechanism is fairly easy to follow from thediagram (fig. 4) Of POLANI et al .6 sAnother remarkable family was reported by FRACCARO

et al.9 Here the mongol patient had 46 chromosomes,and an abnormality of the smaller chromosomes whichwas thought at first to represent the ordinary mongoltrisomy of no. 21, with translocatory pseudo-fusion oftwo of the three to produce an abnormal single largerchromosome. His father, who appeared perfectlynormal and is a minister of religion (and who may thusbe the first exception to the rule that chromosomalanomalies and university degrees are incompatible) wasfound to have 47 chromosomes and to be trisomic forno. 19. The findings in this family admit of no simpleexplanation with our present knowledge, unless indeed(as seems unlikely) the diagnosis of the child as a mongolis at fault. But clearly we must expect some strangefindings from the systematic examination of familialmongols. There are rumours of yet other variants onthe way.Anomalies of other chromosomes form a much more

confusing picture. Trisomies of no. 17 10 and of one ofthe 13-15 group

11 seem well established. Trisomy ofno. 22 is also not unlikely,l2 though identification of thechromosome present is not very certain (might it evenhave been an extra Y ?) and its relation to the Sturge-Weber syndrome present cannot yet be acceptedconfidently. Trisomy of no. 11 13 and of no. 6 14 haveboth been claimed, but both cases had the double sexchromatin characteristic of the XXX syndrome,15—17and, as we 1 and others 18 have already suggested for thefirst of these, these may well both be examples of theXXX syndrome with perhaps minor irregularities ofone of the X chromosomes concerned. Multiple tri-

19. Ford, C. E., Jones, K. W., Miller, O. J., Mittwoch, U., Penrose, L. S.,Ridler, M., Shapiro, A. ibid. 1959, i, 709.

20. Scandinavian cases cited by Fraccaro et al. (footnote 21).21. Fraccaro, M., Kaijser, K., Lindsten, J. Lancet, Oct. 22, 1960, p. 899.22. Book, J. A., Santesson, B. ibid. 1960, i, 858.23. Swanson, C. P. Cytology and Cytogenetics; p. 188. London, 1958.

somies have also been reported,19 20 the most strikingbeing FRACCARO et al.’s case 21 with 49 chromosomes

altogether (nos. 8 and 11 trisomic, plus XXY); andindeed, except for the viability of the patients, there isnothing incredible about this, for the conditions whichcause non-disjunction of one chromosome pair couldquite reasonably be supposed equally to affect others.Perhaps the most nearly incredible of all the findings isthe demonstration by BOOK and SANTESSON 22 of trisomyof every chromosome pair, giving a triploid individualwith 69 chromosomes.

-

It is too early to hope to decipher the pattern whichmust lie behind the varied clinical manifestations ofthese anomalies. The sex-chromosome disorders presentat least some trace of logic; and mongolism, though wehave no glimmer of hint as to the mechanism by whichthe chromosome defect produces its highly specificeffects, presents at least a consistent pattern. Of theothers hardly any two cases are sufficiently alike forconclusions to be possible. It seems not unlikely thatthere will be found to be some non-specific tendencyto congenital anomalies related more to the amountthan to the nature of the chromosomal anomaly (mentaldefect being the most constant element), and a firsttask will be the identification, behind this screen, ofmore specific patterns related to disorders of individualchromosomes.The demonstration in viable children of triploidy 22

or trisomy of three large chromosomes 21 at one end ofthe scale, and in normal individuals of trisomy 9 ortranslocations 78 at the other, shows that the humanorganism is not as sensitive to such changes as was oncesupposed. Every one of the twelve chromosome pairsof that old friend of the materia medica, Datura

stramonium,23 can exist in a trisomic form, and everyone has its characteristic phenotype, or, as one calls it inmedicine, its characteristic clinical syndrome. Perhapswe will soon recognise equally characteristic syndromesfor each of our own twenty-two autosome pairs.

Tumours of the BladderIN the past decade the causes, treatment, and pre-

vention of bladder tumours have aroused much interest.

Fascinating questions surround the incidence of thisdisease. Why is it increasing in younger males ? Whyis it apparently commoner in towns than in the country ?Why is it rare in Japan and India ? Now that -naph-thylamine is no longer employed in the dye, chemical,or rubber industry, which industries still use carcinogenssuch as benzidine ?A possible cause of bladder tumours is the excretion

in the urine of an abnormal metabolite of tryptophane.Some biochemists believe that this metabolite is

hydroxykynurenin, others that it is hydroxyanthranilicacid or an allied compound. These chemicals can be

suppressed in at least three ways: by administering

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1. Report from the Institute of Urology and Southern Metropolitan CancerRegistry.

pyridoxine, which alters tryptophane metabolism; or byadministering saccharolactone, which inhibits enzymeactivity in the urine; or by altering the urinary pH.Whether it will be possible by chemical means to

prevent so-called " recurring " tumours, which may,in fact, be new tumours due to the persistence of acarcinogenic stimulus, depends on whether the mucosalchanges are reversible or whether, once the mucosa hasbeen stimulated by a chemical carcinogen, neoplasia isinevitable even if the stimulus is removed. Double-blind trials now in hand may provide the answer.

In the treatment of the established case one adversefactor that can be attacked is delay. Patients often

recognise hxmaturia as a symptom of possibly gravesignificance. But this view is not always shared by thepatient’s doctor, who may treat painless haematuria,without associated frequency or pain, as a case of

cystitis; and when the bleeding stops the patient andhis relatives are lulled into a false sense of security. In

hospital, too, the possible gravity of the cause ofhsematuria is often not appreciated: recently a patientwith this symptom was given an appointment to beseen in the outpatient department three months later.We accept pain in the right iliac fossa as a matter ofurgency. Why cannot hasmaturia be given similar

priority ? In cases of carcinoma of the bladder, whenthe delay between the onset of hxmaturia and treatmentis less than a month the 3-year-survival rate is 705%;but when the delay is 6 months the 3-year-survival ratedrops to 36’8%.1 Quick and accurate diagnosis is pos-sible, and this is likelier to improve the results than anychanges in the techniques of radical surgery or

radiotherapy.In the past ten years surgery and radiotherapy have

each held sway in turn. Nowadays the limitations ofsurgery and the dangers of excessive radiotherapy areappreciated; the surgeon and radiotherapist work as ateam, seeing, treating, and following up each case

together. This makes for better results-for example,in cases treated surgically in which metastases developand require irradiation, and in cases treated by radio-therapy in which surgery is needed for resultant

complications.Many factors, including the age and general condition

of the patient, must be taken into account in treatingbladder tumours. When the disease is localised andconfined to the mucosa the choice lies between intensive

diathermy (either cystoscopic or open) or some formof radiation. The complications of intracavitary radia-tion-contracted bladder, mucosal atrophy, and hoemor-rhage-have led to its abandonment in such cases untilbetter techniques can be evolved. Diathermy-eitherelectrocoagulation or electroresectioh-is therefore themethod of choice. The skilled surgeon can deal witheven large tumours by this method; but this techniquecannot be safely left to a junior. For limited tumours

infiltrating no farther than the muscle coat interstitialirradiation mav be applied. Formerlv such tumours 2. Bloom, H. J. G. Brit. J. Radiol. 1960, 33, 471.

3. Morrison, R. Clin. Radiol. 1960, 11, 125.4. Magri, J. Personal communication.5. Wallace, D. M. Brit. J. Radiol. 1960, 33, 487.

would have been treated by radon seeds, but nowadaysartificially produced radioactive isotopes (gold or tanta-lum) are used. This represents a technical improvement;for radioactive gold grains are smaller, safer, moreaccurately implanted, and obtainable in various strengths;while tantalum is relatively cheap, has a much longerhalf-life than gold, and can be kept at hand so that aftercystoscopy the bladder can be opened, the tumour

excised, and wire implanted at a single operation.2The supervoltage radiotherapy beam, directed either

from generators, such as a linear accelerator or a

Van de Graaf machine, or from artificially producedisotope bombs (telecobalt or telecassium units), alsohas a place in treatment. This therapy can render abladder tumour-free, but sometimes it completely failsto affect the tumour. Furthermore external radio-

therapy in high dosage can produce radiation damage tothe pelvic contents, including loops of small intestine.These risks, though small, must be weighed againstthe possibility of cure and the chance of conserving anormally functioning bladder. Using a linear acceleratorat 8 MeV MORRISON 3 found that with a tumour dose

totalling 4500-5500 rads in 4 weeks, 31% of patientshad no tumour visible on follow-up cystoscopy. Therewas a better response with the earlier tumours (mucosaltumours disappeared completely in 43%, and a further19% became appreciably smaller) but the more advancedtumours also regressed in many cases. These resultsshow that supervoltage therapy is an extremely potentweapon and should be considered before recourse toradical surgery.

Partial cystectomy has tended to fall into disrepute,largely because it has been employed in the wrong typeof case. MAGRI has found that with single lesions,irrespective of the histological type (80% were solidanaplastic and infiltrating), where a clear margin of atleast an inch was obtained there was a 71% 5-year-survival rate. Where, however, the line of excision cutthrough the tumour or its submucous extensions therewere no survivors after 5 years. Partial cystectomy,though fairly easy, should be undertaken only aftercareful thought.

Radical surgery following radiotherapy is not difficultprovided that irradiation has not been applied over tooshort a time to too large a volume of tissue or inexcessive dosage. Radical cystectomy involves theremoval of all the pelvic contents except the rectum,and also the lymph-nodes along the iliac vessels.WALLACE 5 has found that this operation, undertakenafter radiotherapy, as the last weapon in the thera-

peutic armoury, carries a mortality of 21%; but thatit can prolong life by 3 or more years in half the cases ofmucosal tumours, a third of the cases in which muscleis infiltrated, and a quarter of the cases in which theperivesical fat has been invaded.The treatment of bladder cancer is still far from

satisfactory, but much can be done with our present

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6. See Lancet, 1959, ii, 958.7. Oxf. med. Sch. Gaz. 1960, 12, 41.

resources to check the disease. It is heartening to knowthat a subcommittee of the International Union againstCancer has agreed on a provisional method of classifyingand reporting cases, similar to that adopted for cancerof the breast. 6 If this recommendation is accepted theanalysis of results should be greatly simplified.

Annotations

POMP AND CIRCUMSTANCE

THE ceremonial ward round has long been a familiarfeature of our teaching hospitals. The Chief, surroundedby acolytes and- disciples, proceeds in pomp from bed tobed, pausing now and then to correct a point of history,to confirm or deny the physical findings, to discuss thedifferential diagnosis, or to pontificate on methods oftreatment. Ward-clerks and dressers stand around,shifting from foot to aching foot; bored registrars con-verse in whispers; nurses tiptoe past with bedpans;patients lie glum and silent while the Round drones on.

Is this the best way of teaching " bedside " medicineand surgery ? The Oxford Medical School Gazette thinksnot. In a pungent editorial, entitled " Is Your W.R.

Really Necessary ? ", the Gazette reminds us that suchmethods are frequently discourteous and may sometimesharm patients. There the patient lies, sometimes half-naked, a forgotten object while the discussion rages overhis bed. He is listening, moreover, with apprehension tothe list of alarming investigations proposed for him, totalk of frightful-sounding diseases that he might have,sometimes to obvious differences of opinion about treat-ment. The more intelligent and educated he is, the worsehis ordeal, for the more likely is he to glean from un-guarded remarks some of the grimmer truths about hisillness and to penetrate the thin veil of medical euphem-isms. It is easy to forget that nowadays, thanks to tele-vision and other media of mass information, many patientshave a smattering of medical terminology and jargon. Andeven if the Round removes itself a few beds away to discuss

prognosis, other patients have ears, and ward gossipspreads. The physical suffering imposed on ward-clerksby the peripatetic ward round is a less serious matter; butthey might listen better and learn more if allowed to sitdown comfortably.The Oxford Medical School Gazette suggests that all

" bedside " teaching should take place in a room adjacentto the ward, with chairs, blackboard, and X-ray screen,into which patients can be brought when needed, or fromwhich the Round can emerge for a brief visit to the bed-side. This sensible idea has already been adopted by someteaching hospitals. We commend it to all. Such an

arrangement has the additional advantage of ensuring thatthe formal " round " is recognised as purely for teachingpurposes, as it should be, and is not mixed up with theday-to-day management of patients. It is impossible toteach properly on more than a few cases at a time. Prac-tical therapy should be dealt with by the Chief later, whenhe goes round his beds privately with his junior staff. Thetraditional royal progress from bed to bed, with a graciousgreeting and a few pearls of wisdom dropped at each one,may awe the impressionable but is not the best way eitherto teach clinical medicine or to cure patients.

NEONATAL RESPIRATORY DISTRESS

1. Cook, C. D., Barrie, H., Avery, M. E. Advanc. Pediat. 1960, 11, 11.2. See Lancet, Nov. 5, 1960, p. 1014.3. James, L. S. Pediatrics, 1959, 24, 1069.4. Usher, R. ibid. p. 562.5. See Lancet, 1960, i, 583.6. Reardon, H. S., Baumann, M. L., Haddad, E. J. J. Pediat. 1960, 57, 151

RESPIRATORY distress in the premature infant is a

common cause of neonatal death. Most of the affectedinfants have no evidence of congenital malformation orbirth injury; hence they should survive if the distresscould be prevented, and their recovery should be completeif it were more amenable to treatment. The challenge toobstetricians (for prevention of prematurity is the bestmeans of preventing these deaths) and to pxdiatriciansis being met, and there is some encouraging progress toreport.

In the past, research into respiratory distress has beenlargely concerned with the pulmonary and circulatoryaspects.l This has proved less enlightening than washoped ; for the xtiology of pulmonary hyaline membraneremains obscure,2 and the reported disturbances in themechanics of breathing do not add greatly to our under-standing, nor do they suggest any sound alternatives topresent methods of treatment based on the administrationof oxygen and nursing the infant in a humid atmosphere.

Interest has turned towards the biochemical changesassociated with respiratory distress, and this may wellprove a more productive approach. The present positionhas been well summarised by James. Infants with birth

asphyxia or respiratory distress become severely acidoticwith hyperkalasmia, hypoglycsemia, and possibly hypo-calcxmia. These changes are the expected consequence ofanoxia and retention of carbon dioxide. They may well beresponsible for death; and treatment with glucose,bicarbonate, and insulin holds out some promise ofsuccess.4

The maintenance of a stable blood hydrogen-ionconcentration (pH) depends on the lungs and on thekidneys; and the newborn baby is unique in both pul-monary and renal function.5 Some of the peculiaritiesof this period are now being elucidated. Helen Reardonand her colleagues 6 have reported the results of a

technically brilliant investigation into the chemical aspectsof the control of respiration in the early newborn period.They sampled blood not only from the umbilical vesselsat birth but also from the temporal artery at various

periods afterwards. They analysed the blood samples forplasma pH, C02 content, protein, O2 content and capacity,and hxmatocrit. From these measurements the pCO2,buffer base, and oxygen saturation were calculated. Theresults showed that the normal full-term infant is bornwith mild acidosis which is of both metabolic and

respiratory origin. This is presumably due to an excessof fixed acids or deficiency of base which is uncompensatedby hyperventilation. The rise in pCO2 (respiratoryacidosis) suggests that the birth process not only preventscompensation of the metabolic acidosis but leads to

impaired CO elimination. Within an hour of birth the

respiratory component disappears owing to the efficacyof pulmonary ventilation, but the metabolic acidosis

(decrease in bicarbonate or other buffer anions) tends toincrease. There is thus a state of uncompensated meta-bolic acidosis. During the next few hours ventilationbecomes efficient enough to compensate for the metabolicacidosis, and in some infants there is evidence of

respiratory alkalosis. Correction of, rather than com-

pensation for, the metabolic acidosis takes place in breast-,