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a cotton-wool plug in the neck of an ampoule before it issealed. Such a plug, however, can itself be a source ofdanger; for it is likely to contain fine particles of the driedmaterial, and when it is grasped these particles may bediffused on to the skin or into the air. It is essential,therefore, that the plug should not be touched by thehand and that on withdrawal it should immediately bediscarded into a container that can be sterilised.Living vaccines are used widely in veterinary practice

and occasionally in human medicine. The organismsare non-pathogenic variants, which are presumablyharmless ; but there are technical problems in manu-facture. During vacuum-drying, material may escapefrom the ampoules and reach the interior of the vacuumsystem ; gales of 800 miles per hour occur in an efficientmachine,3 and cross-infection of ampoules is possiblewhen two or more cultures are dried at the same time.Drying plants cannot be satisfactorily sterilised, andtherefore the same machine cannot safely be used to drytwo types of organism, even at different times.

3. Greaves, R. I. N. Ibid, p. 159.4. Duran-Reynals, F. C.R. Soc. Biol. Paris, 1928, 99, 6.5. Meyer, K., Dubos, R., Smyth, E. M. Proc. Soc. exp. Biol., N.Y.

1936, 34, 816.6. Chain, E., Duthie, E. S. Nature, Lond. 1939, 133, 977.7. Hechter, O. J. exp. Med. 1947, 85, 77.8. Day, T. D. J. Path. Bact. 1947, 59, 567 ; Lancet, 1947, ii, 945;

J. Physiol. 1949, 109, 380.9. Flemming, W. Arch. mikr. Anat. 1876, 12, 391.

STRUCTURE OF GROUND SUBSTANCE

To the naked eye interstitial connective tissue has amembranous appearance, but under the microscope thisis replaced by a picture of a network of fibres, withoccasional cells. In the last twenty years the nature ofthe apparently structureless mesenchymal ground sub-stance lying between these collagen fibrils has beenelucidated by numerous studies centring around theadmirable work of Duran-Reynals4 Meyer et al, 5 and Chainand Duthie 6 on spreading factors and mesodermal

polysaccharides. The work of Hechter has underlinedthe importance of the mechanical factors of pressure(e.g., oedema) and volume in determining hyaluronidasespreading action, but little attention has been paid tothe structural aspects of the interfibrillary substancewhich may influence these factors. During the last fiveyears Day 8 has presented a convincing structural

conception of the ground substance, illustrated by simpleand compelling experiments, which does much to explainboth the membranous quality and the especial perme-ability of connective tissue.In 1876 Flemming 9 described cementing substance in

and around the fibre-bundles of connective tissue, andnoted that weak acid caused coagulation and contractionof this substance, whereas the collagen fibres swelled.Day has re-stated and amplified this observation. Hefound that at about pH 4 lamellæ of connective tissuefrom rat fascia became opaque and shrunken, whileincreasing alkalinity caused increasing swelling ; the

collagen fibres themselves showed no microscopical changeuntil the pH exceeded the range 4-11. The concentrationof neutral salts causing swelling became proportionatelyless as the hydrogen ion concentration fell. In wet

preparations of connective tissue he noted irreversiblechanges at a slightly more acid pH (3-6) ; the hithertoclear interfibrillary spaces became opaque under dark-ground illumination, owing to the appearance of exceed-ingly fine branching fibrils and refractile granules. 50-60% ethanol induced similar changes, and Day foundthe resulting microscopic appearance of a fine networklying in the same optical plane very strikingly similarto the membranous naked-eye appearance of connectivetissue. The collagen and elastic fibres were embeddedin the opaque membrane " like twigs in a frozen pond."Trypsin treatment disintegrated this membrane, buthyaluronidase left it structurally intact. Day concludedfrom this, and other work on the hydration of connective

tissue, that a main constituent of the interfibrillary sub-stance was of p protein nature, precipitable at its iso-electric point, organised in structure, and not leached outby water.Contemporary workers have been much preoccupied

with the mucopolysaccharides in ground substance ;and, while opinions have differed as to whether they arefree or bound to the protein element, no clear picturehas hitherto emerged of how the interfibrillary substanceis organised within the meshes (often 50 µ or more

across) of the fibril network. In electron micrographs,although the collagen structure is revealed with greatclarity the ground substance remains amorphous.10More recently Day 11 has described experiments in whichhe measured the rate of flow of saline across a mouse-connective-tissue membrane occluding the end of avertical tube immersed in saline. Hyaluronidase addedto the perfusing fluid increased the rate of flow 10-20times. Subsequent perfusion of starch solution reversedthis effect, while the effect of ptyalin on the starch-perfused membrane mimicked that of hyaluronidase onuntreated membrane. Histologically, iodine treatmentof the starch-perfused membrane showed homogeneousblue staining extending across the interfibrillary spaces.The starch was not removed by prolonged subsequentre-perfusion with saline. Day established that these

findings were not due to a mere viscosity effect of macro-molecular substances ; and he attributes them to asieve-like action of the permanent protein trellis of

ground substance which he previously described. Heconcludes that the structure of the interfibrillary sub-stance is that of an organised protein network, whosemeshes are " water-proofed " by molecules of poly-saccharides susceptible to the action of hyaluronidase.

10. Gross, J. Ann. N.Y. Acad. Sci. 1950, 52, 964.11. Day, T. D. Nature, Lond. 1950, 166, 785; J. Physiol. 1952, 117, 1.12. Loeffler, W. Beitr. Klin. Tuberk. 1932, 79, 368.13. Reeder, W. H., Goodrich, B. E. Ann. intern. Med. 1952, 36, 1217.14. Ruzic, J. P., Dorsey, J. H., Huber, H. L., Armstrong, S. H.

J. Amer. med. Ass. 1952, 149, 534.15. Maier, C. Helv. med. Acta, 1943, 10, 95.16. Harkavy, J. J. Allergy, 1943, 14, 507.17. Lyon, E., Kleinhaus, E. M. Acta med. orient. 1945, 4, 144.

P.I.E. OR P.U.O. ?

TWENTY years have passed since Loeffler 12 firstdescribed a symptom-complex comprising- transientpulmonary infiltrations and eosinophil leucocytosis inthe blood. His cases ran a brief and benign course, andin a high proportion there was a history of diseases ofallergy. Since then many similar cases have been;described, but in some the patients have been ill longerand more seriously. Reeder and Goodrich 13 suggest thatthe classical syndrome represents the benign end of arange of disorders extending by degrees to severe andirreversible disease, as in periarteritis nodosa. Theypropose the introduction of a new term-" P.I.E. syn-drome " to denote pulmonary infiltration with eosino-philia.

Ruzic et al.14 feel that Loeffler’s syndrome should beunderstood to include transient infiltrations in otherorgans. They report a case with asthmatic symptoms,vomiting, and abdominal pain in which transient pul-monary shadows and blood and marrow eosinophiliawere found. The abdominal symptoms led to suspicionof gastric carcinoma, but gastrotomy showed a purelysubmucosal mass lying along the lesser curve. Biopsyshowed an inflammatory infiltrate containing a fairlylarge number of eosinophils. The mass resolved spon-taneously within two months. Loeffier’s syndrome hasalso been described in conjunction with eosinophilicinfiltrations of lymph-glands, muscle, and epididymis,15and inflammation of serous membranes.16 s Lyon andKleinhaus 17 reported this syndrome associated with skineruptions resembling erythema multiforme, but unfor-tunately no biopsies were done. More recently, Argen-

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tinian workers 18 have described an erysipeloid-like skinlesion with blood eosinophilia and fleeting infiltrationsof the lungs in a case of lymphoid leukaemia after treat-ment with urethane. Skin biopsy showed an infiltratewhich, in the subcutaneous layers and the fat, containednumerous eosinophils.

"

Eosinophilic granuloma of theskin " is not an entity, but at least some of the lesionsdescribed under that name are probably allergic in origin.Lewis and Cormia 19 reported a case associated with tineapedis : the lesions were aggravated by injection of tri-chophytin, and similar patches appeared where the

injections were made. This resembles the experience ofDostrowsky and Sagher,20 who described positive reac-tions to the antigen of Dirofilaria immitis in cases of" eosinophilic erythrœdema " of the skin, with in threeinstances recrudescence of the skin lesions. It would be

interesting if Leoffier’s syndrome could be shown tobe present in endocarditis parietalis fibroplastica, whereeosinophilia and residence in the tropics raises the sus-picion of allergy to parasites-e.g., loa loa.21-

-

How pertinent is the eosinophilia in these cases ?Over-emphasis on its importance has led to groupingof quite dissimilar lesions-e.g., the eosinophilic granu-

. lomas of the skin. We do not know the function of theeosinophil leucocyte ; but clearly an allergic reaction is

only one of many processes that can evoke eosinophilia,just as allergy is only one cause of fibrinoid degeneration.Perhaps we are dazzled by these mysterious beauties,whose presence may be more ornamental than significant.Several notable histopathologists are colour-blind.

18. Cordiviola, L. A., Sanchez Caballero, H. J., Bosq, P. Rev. argent.Dermatosif. 1950, 34, 106.

19. Lewis, G. M., Cormia, F. E. Arch. Derm. Syph. 1947, 55, 176.20. Dostrowsky, A., Sagher, F. J. Palestine Jewish Ass. 1946, 30, 33.21. Gray, I. R. Brit. Heart J. 1951, 13, 387.22. Lancet, July 5, 1952, p. 19.

TUBERCULOSIS IN THE COMMONWEALTHTHE third Commonwealth Health and Tuberculosis

Conference of the National Association for the Preventionof Tuberculosis (N.A.P.T.), held in-London this month,has brought visitors and views- from many parts of theworld. Representatives from Mauritius, Singapore, BritishGuiana, and the Colonial African Territories reportedgreat advances in the use of tuberculin-testing andX-ray surveys to measure infectivity and find new cases.Africans, it seems, cannot stomach bed rest or isolationin hospital ; but chemotherapy has given us the meansto combat their diseases in spite of these prejudices,and fortunately results are as good with them as withwhite men. Moreover the old notion that Africans andAsians cannot withstand tuberculosis appears to beill founded ; or perhaps their resistance is improving.At all events speakers from many tropical regions agreed

that, provided the environment was satisfactory, theirpatients resisted well enough. B.C.G. vaccination is now

widely used, and plans are on foot in Jamaica andTrinidad to immunise all susceptible children within thenext two years. An annual X-rav examination is proposed

. for the 300,000 African miners of the Witwatersrandgold mines, among whom an incidence of 4 active casesof tuberculosis per 1000 radiographed has already beenfound. India has already made history with a recordof 8 million people tuberculin-tested and 21/2 millionvaccinated with B.c.G.-yet this is a mere beginning inthat vast population of 356 million. Pakistan, estimatedto have 2 million cases, is mainly agricultural, and hasmeagre resources to deal with its problem. Progress isslow and at present depends largely on the help of theWorld Health Organisation. This may be contrastedwith the enviable position of Canada, where there are18,000 sanatorium beds-a ratio of 5 beds to 1 annualdeath from tuberculosis. There Koch’s bacillus is

pursued in mobile mass X-ray units of the bus type,augmented by equipment carried in railway coaches.News of isoniazid was much the same as we have had

already from the British Tuberculosis Association,22 but

Prof. Ralph Tomsett, from the Cornell Medical centre,warned his hearers against the possibility of florid fatalrelapses in patients who have developed resistant mutants.At a joint meeting of the N.A.P.T. with the B.T.A.,

to discuss childbearing and tuberculosis, Dr. C. - J.Stewart surprised some of his hearers by concludingthat whether the disease is minimal, moderately advanced,far advanced, or quiescent, its progress is uninfluencedby pregnancy, parturition, or the puerperium. He basedthis opinion on the five years’ after-history of a largeseries of lung cases, comparing it with a control groupwho were not pregnant. He averred, too, that thereare no medical indica,tions for terminating pregnancy onaccount of tuberculosis. Nevertheless he counselledagainst a woman with active or unstable disease havinga baby within two years of quiescence, and held of coursethat a mother with active disease should not breast-feedher baby (who, incidentally, should be vaccinated withB.C:G.). Dr. Raymond C. Cohen confirmed these mainconclusions from a study of 400 mothers in his ownmaternity unit at-Black Notley Sanatorium, and empha-sised the need to avoid haemorrhages and fatigue duringlabour in the more anaemic tuberculous women. He

suspends pneumoperitoneum refills for two months beforethe confinement, and counsels against resuming themtoo soon afterwards. In all acute cases, he thinks,

-lactation should be suppressed by the use of concentratedoestrogens. Dr. Geoffrey Beven, however, reportedenlargement of cavities in 17 out of 41 puerperal cases,and moreover, in a group of 150 women sputum-negativebefore pregnancy, he had seen 10 become sputum-positive after delivery. Mr. Camac Wilkinson drewattention to the spontaneous improvement often seen,

during pregnancy, in patches of cutaneous lupus, withrelapse after childbirth. This, he suggested, might bedue to the temporary increase in plasma sterols duringpregnancy. A useful suggestion for case-finding wasmade by Dr. Cohen : if all pregnant women were givena routine X-ray examination of the chest, he said, wemight expect to find 4 or 5 cases of pulmonary tubercu-

losis in every 1000, and hence some 3000 new cases inEngland and Wales each year.The social aspects of the disease are changing with

the change in methods of treatment. The Australian

government have introduced a scheme by which theunfit tuberculous worker, if a married man, can be paidjE8 5s. a week, and may also retain £4 a week additionalincome from other sources. Our own scales, of course,fall short of this. Our tuberculous patients are nothoused as well as they should be. Dr. W. Hartstonmentioned that while only 3% of all London’s families,and 5% of its tuberculous adults, are believed to liveunder conditions of overcrowding, as defined in the

Housing Act of 1936, yet barely half of the 30,000tuberculous adults in the metropolis have a bedroom tothemselves. Priority is given to tuberculous Londonfamilies for rehousing outside the county ; but this hascaused some misgivings because the proportion oftuberculous in the rehoused communities may sometimesbe as much as 3 or 4 times the proportion in London asa whole. Dr. Hartston, however, has found an incidenceof new cases, in these rehoused communities, of only about,a third of what might reasonably have been expectedfrom the numerical prevalence. This applies not onlyto the tuberculous families but also to their neighbours.Nor has he been able to find evidence of an increasedincidence among the-often rural-populations of thedistricts where the new estates are established.

ON July 14 Lord Tedder opened the InternationalCongress of Physical Medicine which is being held inLondon this week under the presidency of Lord Horder.Mr. lain Macleod, the Minister of Health, welcomed thedelegates, who have come from 23 countries.

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