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in the opposite direction ; and until more evidence isavailable it does not seem necessary to urge compulsoryE.E.G. examination of all professional boxers in thiscountry.

1. Goltz, R. W. Medicine, Baltimore, 1952, 31, 381.2. Wells, G. C. Brit. J. Derm. 1952, 64, 169.3. Baker, G. P., de Navasquez, S., Maclean, K. S. Guy’s Hosp. Rep.

1949, 98, 95.4. Lindsay, S. Amer. Heart J. 1946, 32, 419.

AMYLOIDOSIS

IN classical amyloidosis of parenchymatous organs,amyloid is deposited in the skin to a degree which is

rarely more than microscopical. In the form known as

atypical or primary systematised amyloidosis, however,there is striking clinical involvement of the skin or

mucous membranes in about half the cases. Naturallythese patients are seen by dermatologists and attractattention in dermatological circles ; but the importanceof the syndrome to general physicians has been latelyshown by Goltz.1Primary systematised amyloidosis differs from classical

lardaceous " disease in several respects. It is notusually associated with chronic suppurative disease. Theamyloid deposits are mainly in and around blood-vesselsin connective tissue and muscle, sparing the parenchymaof liver, spleen, and kidneys. Microscopically the amyloidtakes up the usual stains, such as methyl violet or congored, only with difficulty, and special techniques may berequired to demonstrate it. The skin of the face, neck,axillse, hands, and perineum shows a variety of changes.It may be studded with papules, which are so discreteand translucent that they resemble blisters. The infiltra-tion may be diffuse, giving the skin a sclerodermatous ormyxoedematous appearance. The resemblance to hypo-thyroidism may be enhanced by pallor and loss of hair.Haemorrhages occur into papules or into skin which isclinically normal. Macroglossia is often striking and,together with xerostomia resulting from involvement ofthe salivary glands, may seriously interfere with chewingand swallowing. The surface of the tongue may be smoothor crowded with pseudovesicles. Involvement of the

larynx may cause hoarseness.The patient’s initial complaint may be of breathlessness

due to amyloidosis of the heart muscle or valves. Indeed,death in this condition is often the result of cardiacfailure. Voluntary muscle may be infiltrated, causingweakness and severe pain, and where the gut is involvedthere may be constipation, diarrhoea, or even fatal

haemorrhage. Some cases show Bence-Jones proteinuriaand non-invasive plasmocytosis of the bone-marrow. Thisfinding is of particular interest, for true multiple myelo-matosis may be associated with amyloidosis which mayassume the " primary " type of distribution. Wells 2

described a case of primary systematised amyloidosisshowing benign plasmocytosis of the marrow. Therewas no Bence-Jones protein in the urine, but an abnormalbeta globulin was detected in the serum. He regarded themarrow changes as reactive-i.e., the result of the disease-producing mechanism-rather than causative. Never-theless, he treated his patient with urethane, but withoutbenefit.Some people regard amyloidosis in general as a disease

of disordered immunity. Classical amyloid disease

develops in association with chronic infection, such astuberculosis or syphilis ; and it also occurs in animals usedfor the production of antisera. The young doctor whodied of primary systematised amyloidosis 3 was sure thathe was hypersensitive to milk, and he said he was betterwhen he stopped taking milk and milk products. Anotherpatient was strongly sensitive to egg.4 Some peoplebelieve that the plasma cell is the site of antibodyproduction, and plasmocytosis of the marrow has been.shown to coincide with maximum antibody productionin hyperimmunised rabbits. This plasmocytosis associ-ated with the appearance of abnormal serum globulins

was reported in two cases of sulphonamide sensitivity. SThe subject is further complicated by the occurrence oflocalised forms of amyloidosis-for instance, in the heartor skin. Frendenthal described amyloid in a variety ofdistinctive skin lesions, including epithelioma and nsevi.He also gave the name lichen amyloidosus to a conditionresembling at times lichen planus ; this condition lacksthe distinctive pathological lesions of lichen planus, butheavy amyloid infiltration is one of its features. It

produces intractable irritation, which is not a symptomof primary systematised amyloidosis.

It may be that we are caught in the terminologicaltrap referred to by Trotter in a discussion of skin

myxoedema. The latter term is used in the sense of a

generalised disease--i.e., hypothyroidism-or to mean atissue change detected microscopically. In " amyloid-osis " we are comparing a variety of conditions, somegeneralised and fatal, others purely local, in which theonly common factor is a similar tinctorial quality. Itseems certain that there are several " amyloids," differingin physical state and probably in chemical composition.Further chemical and cytochemical work is required toenable us to identify comparable states of amyloidosis.

5. Robertson, T. Amer. J. Med. 1950, 9, 315.6. Frendenthal, W. Arch. Derm. Syph. Berlin, 1930, 162, 40.7. Trotter, W. R. Proc. R. Soc. Med. 1947, 40, 703.8. Gross. J., Schmitt, F. O. J. exp. Med. 1948, 88, 555.9. Schmitt, F. O., Hall, C. E., Jakus, M. A. J. cell. comp.

Physiol. 1942, 20, 11.10. See Lancet, 1952, ii, 774.11. Tunbridge, R. E., Tattersall, R. N., Hall, D. A., Astbury, W. T.,

Reed, R. Clin. Sci. 1952, 11, 315.

AGE AND SKIN STRUCTURE

THE skin of elderly people is characteristically wrinkledand thin, especially in exposed sites, and shows an obviousloss of elasticity. Histological stains nevertheless revealan apparent increase in the elastic-staining tissue fromthese sites, although both conventional histology andelectron microscopy 8 9 agree that the chief componentof normal human dermis is collagen. Much work withthe electron microscope has centred on connective tissue,with the structure and genesis of collagen as its focus.10Tunbridge and his colleagues,"- at Leeds, have now usedelectron microscopy to investigate the more generalfibrous structure of normal human skin, and particularlythe changes in elasticity accompanying ageing and certaininherited skin abnormalities. They found only smallnumbers of elastic fibres in normal skin, and they attributeits " elasticity " to the flexibility of the network structureof the collagen fibres. As others have reported, thesefibres are long, banded, straight or smoothly curvedfibrils of uniform width, and they are associated with asmall amount of fluffy amorphous material which can beremoved by trypsin treatment. This is probably theinterfibrillar cementing material or ground substance.

Senile skin from exposed sites gives a different picture.There is a considerable increase in amorphous materialbut not in elastic fibres. The collagen fibres them-selves are often short, kinked, and frayed. Treatment withtrypsin removes not only the amorphous material, butalso the misshapen collagen fibrils and the materialresponsible for the increased elastic staining, so that

only normal collagen fibrils remain. It was also foundthat normal skin takes up more elastic stain after treat-ment with pepsin, which attacks collagen. From theseresults, it is reasonably concluded that in senile skinthere is no increase in elastic tissue, but rather a,

degeneration of some of the collagen, fibrils, wherebythey acquire a capacity for taking up elastic stain anda susceptibility to the action of trypsin. The puzzlingfeature is that these changes seem to develop only inskin taken from -exposed areas of the body. A similarchange was found in pseudoxanthoma elasticum-arare disease whose manifestations include a generallooseness of the skin, a tendency for stride to form, and

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a characteristic histological picture of swollen elastictissue. Electron microscopy showed that in fact therewas no increase in elastic fibres in this condition, but thatthe collagen fibres were abnormally short : it is these

collagen fibres that take up the elastic stain. On theother hand, not all abnormal collagen stains like elasticfibres. In Werner’s syndrome, where the electronmicroscopes shows grossly degraded collagen in the skin,histologically the elastic staining is normal.The discrepancy between the results of histological

staining and electron microscopy, and its convincingexplanation bv the Leeds workers, throws some lighton the nature of the morphological changes in the skinwith age. It also underlines the inadequacy of stainingtechniques alone as a means of interpreting the morpho-logy of connective-tissue lesions in general. It is reason-able to hope that the simple technique of enzymaticdigestion, used in conjunction with quantitative bio-chemical analysis and, where feasible, with electron

microscopy, may give much help in the elucidation ofconnective-tissue disease.

1. Alam, M., Smirk, F. H. J. Physiol. 1937, 89, 372 ; Ibid, 1938,92, 167.

2. Thompson, M. B., Gellhorn, E. Proc. Soc. exp. Biol., N.Y. 1945,58, 146.

3. Wolff, H. G., Hardy, J. D., Goodell, H. J. Pharmacol. 1942,75, 38.

4. Hewer, A. J. H., Keele, C. A., Keele, K. D., Nathan, P. W.Lancet, 1948, i, 431. Keats, A. S., Beecher, H. K., Mosteller,F. J. appl. Physiol. 1950, 1, 35. Beecher, H. K. Anesthesiology,1951, 12, 633. Nathan, P. W. Brit. med. J. 1952, ii, 903.

5. Croft, P. J. ment. Sci. 1952, 98, 1, 7.

SIGNS OF PAIN

PAIN, being essentially subjective, is not easilyassessed. It has objective counterparts, such as wincing,reflex withdrawals, vocal expressions, sweating, and

changes in respiration, heart-rate, and blood-pressure;for example, in association with ischaemic muscular painAlam and Smirk 1 recorded increases in blood-pressureand heart-rate, and Thompson and Gellhorn 2 reductionin electrical skin resistance. But such changes varygreatly from one person to another, and are slight orabsent with mild or moderate pain ; and in gauging theaction of an analgesic drug it is important to rememberthat this drug may influence the accompaniments of painby mechanisms unrelated to those which underlie its relief.Wolf et al.3 have distinguished between pain percep-

tion and the reaction pattern to pain. The reactionpattern involves withdrawal, fear, flight, or anxiety andis associated with visceral reactions such as those alreadymentioned. Its association with pain is extremelyvariable ; indeed the reaction pattern may be inducedby mere apprehension of pain, as when sitting in adentist’s chair. The most important way in whichmorphine relieves pain is by preventing the usual reactionpattern, even though pain is still perceived and recognisedas such. Thus analgesic drugs are best judged byrecording the patient’s own words ; and the reliabilityof this evidence can be tested by careful control of thenature and doses of the drugs given.4 4

Dr. Phyllis Croft 5 has reported on the reflex tachy-cardia from painful stimuli in rabbits and in man. She

suggests that the " cardiac pain reflex is a reliable andconvenient method of assessing pain perception...particularly useful in conditions of curarization." Herethe " cardiac pain reflex " does not mean, as one mightsuppose, that pain arises in the heart, but that the heart-rate responds by an increase when a nocuous stimulusis applied to the skin. Furthermore, the word " percep-tion " should mean awareness of something and has nomeaning when a’person is unconscious. In the second

stage of anaesthesia the patient is unconscious andunaware of pain, yet his heart-rate and blood-pressure maybe increased by nocuous stimuli. Dr. Croft has sought tocorrelate in rabbits and in ’man the electrical changes inthe brain with pain perception. Much might be learnt

from such observations, but only by making them in man.Conditions in which animals feel pain cannot be deter-mined except by extrapolation from human experience.Sherrington,6 discussing reactions to harmful stimuli inanimals, said : "In all this experimental work on

animals the observer has to work through signs of

subjective states incomparably inferior in most instancesto the verbal communication establishable with an

intelligent human being " ; and Lewis observed that" We have no knowledge of pain beyond that derivedfrom human experience." This of course means, not thatanimals do not suffer when they show the behaviourcharacteristic of human beings in pain, but that in thisfield man is the measure of all things.

6. Sherrington, C. S. Cutaneous sensations. In E. A. Schäfer’sTextbook of Physiology. Edinburgh, 1900; vol. 2, p. 979.

7. Lewis, T. Pain. New York, 1942; p. v.8. Lewis, F. J., Taufic, M. Surgery, 1953, 33, 52.9. Bigelow, W. G., Callaghan, J. C., Hopps, J. A. Ann. Surg. 1950,

132, 531.10. Bigelow, W. G., Lindsay, W. K., Greenwood, W. F. Ibid, p. 849.11. Delorme, E. J. Lancet, 1952, ii, 914.

COLD CARDIAC SURGERYALTHOUGH many uses have been suggested for general

or regional refrigeration in clinical medicine, the resultshave been disappointing.8

"

Hypothermia," however,has recently aroused the interest and ingenuity of theexperimental surgeon. Bigelow and his colleagues,9 10for example, have demonstrated experimentally the

way in which cooling of the patient’s body may helpthe cardiac surgeon. When the body-temperature of

dogs was reduced to 20°C (68°F), the cardiac inflowcould be interrupted for long enough to permit theheart to be opened and its interior examined. Delorme 11described how cooling of the blood-stream seemed to be apracticable method of lowering the respiratory activityof the cell without endangering life. He found thatdogs whose body-temperature had been reduced to 25°C

(77°F) were able to survive long-continued reductionsin blood volume, as well as suspension of blood-flow.Lewis and Taufic have now reported that they couldmake, and subsequently close, atrial septal defects underdirect vision in hypothermic dogs : 27 out of 29 dogssurvived the operation for production of the lesion,and these defects were successfully closed later in 17out of 26 of these animals. These experimental findingshave been excitingly translated into clinical reality ;using the same technique as in dogs Lewis and Taufichave successfully operated on a five-year-old girl with anatrial septal defect. She was anaesthetised and wrappedin refrigerated blankets until, after two hours and tenminutes, her rectal temperature had fallen to 28°C

(82-4°F). The blankets were then removed and the

operation began. The cardiac inflow was occluded for51/2 minutes, and a 2 cm. septal defect was closed underdirect vision. The operation lasted ’58 minutes and thepatient’s rectal temperature after this time was 26°C(78-8°F). She was restored by immersion in hot waterat 45°C (113°F), and after 35 minutes her rectal tempera-ture had risen to 36°C (96-8°F), when she was removedfrom the bath. She did well after the operation, andleft hospital 11 days later. The cardiac murmur had gone.

This technique has all the makings of a major advancein cardiac surgery. But Lewis and Taufic observedventricular fibrillation in some of their dogs after opera-tion, and this possibility, and doubtless others, willneed careful consideration.

THE executive board of W.H.O. met in Geneva onJan. 27 to nominate a successor to Dr. Brock Chisholm,director-general of the organisation, whose term of officeexpires on July 21. They chose Dr. MARCOLINO GrOMEZCANDAU, of Brazil, who is at present assistant directorof the Pan-American Sanitary Bureau in Washington.The nomination will be put before the sixth WorldHealth Assembly which opens in Geneva on May 5.