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promanide had no effect on the subsequent scarring ithad some effect on the healing-time, and provides aconvenient (if not strictly accurate) control in assessingthe value of S.P.A.S. Fig. 2 and the accompanying tableshow the comparison, cumulatively, of the healing-times,the figures representing percentages.
SUMMARY
Paramisan sodium seems to reduce considerably thearea and depth of residual scarring in suppurativetuberculous cervical adenitis.More than half the treated cases resolved leaving little
or no evidence of the original lesion in the skin.The healing-time was substantially reduced.The results, in general, bear favourable comparison
with those achieved by more active measures (curettage),and the patient need not be admitted to hospital.The results seem to support the claim that the effect
of s.P.A.s. therapy depends on the concentration of thedrug at the site of the lesion.We wish to thank Dr. D. McAnally, medical consultant,
Herts Pharmaceuticals Ltd., for his help during this investiga-tion ; Dr. T. Francis Jarman for the group of cases treated bycurettage ; Dr. R. Milne, of the Central Tuberculosis Labora-tory, Cardiff, for the bacteriological work ; and Mr. MostynDavies, F.s.s., for his help and advice on the statistical data.
ADDENDUM
Since this article was written, of the 51 cases withcomplete resolution 1 has shown a mild relapse. Asmall pustule developed in the scar twelve months afterconclusion of the initial therapy. This completelyresolved in two weeks with treatment by calciferol cream ;and there has been no further evidence of relapse.
BIBLIOGRAPHYBernheim, F. (1940) Science, 92, 204.
— (1941) J. Bact. 41, 387.Davis, H. (1948) Mon. Bull. Min. Hlth, 7, 109.Feldman, W. H., Karlson, A. G., Hinshaw, H. C. (1947) Proc.
Mayo Clin. 22, 473.Karlson, A. G., Pfuetze, K. H., Carr, D. T., Feldman, W. H.,
Hinshaw, H. C. (1949) Ibid, 24, 85.Lehman, J. (1946) Lancet, i, 15.Nagley, M. M. (1949) Practitioner, 163, 459.
TOXOPLASMOSIS IN HARES IN DENMARKSEROLOGICAL IDENTITY OF HUMAN AND HARE
STRAINS OF TOXOPLASMA
M. CHRISTIANSENDIRECTOR
STATE VETERINARY
SERUM LABORATORY
J. CHR. SIIMM.D.
STATEMS SERUMINSTITUT,COPENHAGEN
Since congenital toxoplasmosis was described by Wolfet al. (1939), who first demonstrated the pathogenicityof toxoplasma of human origin for animals, the syndromecharacteristic of toxoplasmosis in children has beenreported by several other workers. But the source ofinfection and the mode of transmission are still obscure.The discovery by Sabin and Feldman (1948) of a
quantitative dye test for toxoplasmic neutralising (cyto-plasm-modifying) antibody and the reports on preparationof a complement-fixing antigen (Warren and Russ 1948,Sabin 1949) have provided new and efficient tools for thestudy of the epidemiology of toxoplasmosis.We report here the occurrence of toxoplasmosis in wild
hares (Lepus europceus Pall.) and the results of serologicalinvestigations with human and hare strains of toxoplasma.Since 1935 diseases in wild animals have been systema-
tically investigated in Denmark. This has made itpossible for us to examine many wild hares found deadin the open field or shot in a sick condition. Some ofthese hares presented a typical clinicopathological entity,which was later shown to be toxoplasmosis.
OBSERVATIONS AND INVESTIGATIONS
The necropsy findings are very characteristic, withlesions distributed throughout the body. These findingsalone often reveal the diagnosis.
The spleen is much enlarged and hypersemic. Theliver is enlarged, light-coloured, and degenerate, withscattered submiliary necrotic red-yellow foci, sometimessurrounded by a narrow hsemorrhagic zone; andscattered haemorrhages are often seen in the liver. Themesenteric lymph-nodes are swollen, hard, and injected,with small or large necrotic foci, sometimes haemorrhagic.The lungs are distended, cedematous, and hypersNnic,and there is much reddish serous fluid in the chest.(Hares infected with toxoplasma are sometimes noticedto be very short of breath, and when they are examinedshortly afterdeath a red-dish foam isfound in theirnostrils.)Occasionally,jaundice maybe observed.Evidently thedisease runs
an acutecourse, for thenutritionalstate is s
usually good.B acterio-
logical exami-nation gaveno clue to the
aetiology, andattempts totransmit thedisease eto otheranimals,includinghares, gavenegative re-
Seasonal incidence of toxoplasmosis in hares inDenmark.
sults. But
recently histological examination showed toxoplasma, inconsiderable numbers, in the organs with pathologicalchanges (especially the spleen) and also in the brain.IncidenceFrom January, 1935, to August, 1950, 264 (9.4%)
of 2812 hares examined showed signs of toxoplasmosis.In Denmark the peak of incidence (see figure) is in the coldseason (January-March), but some cases are also seenin spring and autumn :
_month No. of No. with.tMt hares examined toxoplasmosisJanuary.. 249 42 (16-9%)February 381 60 (15’7%)March 354 46 (13-0%)April ...... 288 31 (10-8%)May 224 5 (2-2%)June 133
. 2 (1-5%)
July 106 1 6-9%)August 107 6 (5-6%)September ’ 209 16 7-?’%)October 297 17 -7%)November 248 16 (6-5%)December 216 22 (102%)
Total 2812 264 (9-4%)
The seasonal incidence is similar in Sweden, where
toxoplasma was first found in sick hares by directexamination (Hulphers et al. 1947).The incidence of toxoplasmosis in all parts of Denmark
is about the same, except that on the island of Bornholm23 of 82 hares examined (28%) were infected.
It must be emphasised that in any hare populationtoxoplasmosis only occurs in isolated cases. Occasionallya few infected hares may be encountered in the sameherd. Enzootic infections in any area with a large harepopulation were not found.isolation of Toxoplasma by gnimal InoculationIt was first possible to isolate toxoplasma strainswhen 1 ml. of a 10% suspension of spleen from recently
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TABLE I-NEUTRALISING ANTIBODY IN 24 HARES WITH TOXO-PLASMOSIS AND IN 44 CONTROL HARES
dead animals-i.e., within twenty-four hours after death-was inoculated intraperitoneally into mice. In this
way four strains were isolated. To exclude the possibilityof spontaneous infection, uninoculated mice of the samestock were checked by passaging their spleen and brain :these experiments were all negative.
Pathogenicity of Toxoplasma from HaresMice injected intraperitoneally with 0,5 ml., or intra-
cerebrally with 0’03 ml., of peritoneal exudate (1 : 10) froman infected mouse died in 4-6 days.
Intracutaneous injections of 0-2 ml. of a suspension ofinfected mouse brain (1 : 10) into rabbits gave rise to a
characteristic papule with central haemorrhagic necrosis, therabbits dying in 8-10 days.Hares infected subcutaneously, intra-abdominally, or orally,
died in 7-9 days with lesions pathologically indistinguishableboth from those induced by the human strain RH and fromthose observed in spontaneous toxoplasmosis.When embryonated hens’ eggs, aged 9 or 10 days, were
inoculated with peritoneal exudate 0-1 ml. on the chorio-allantoic membrane they died after incubation periods of5 or 6 days, the membrane showing the characteristic necroticfoci.
These results correspond closely to those observedafter inoculation with human strains.
TABLE II-COMPLEMENT-FIXING ANTIBODY IN 21 HARES WITHTOXOPLASMOSIS AND IN 32 CONTROL HARES
Serological InvestigationsSerum or the serous fluid in the chest was tested for
toxoplasmic antibodies after inactivation by heat forhalf an hour at 56°C.
For the complement-fixation test the antigen was preparedfrom toxoplasma-infected chorio-allantoic membranes (Sabin1949). The titres recorded represent the dilutions of thesera-in the mixture of serum, complement, and antigenbefore addition of the sensitised red cells-which gave 50%haemolysis with the toxoplasmic antigen and no reaction withthe control antigen prepared from uninoculated chorio-allantoic membranes.For the cross-complement-fixation test the human strain
RH originally isolated by Sabin and a hare strain were usedto prepare antigens as described above.
In the dye test the titrations were made according to thetechnique originally described by Sabin and Feldman (1948)and modified by S. Gard (personal communication).In cross-neutralisation, as antigen in the dye test two
strains of toxoplasma were used, a human (RH) and a strainof hare origin, the latter after having been adapted to themouse peritoneal cavity by several passages.
24 hares, all of which showed the typical pathologicallesions of toxoplasmosis and in which toxoplasmas werefound in smears from the spleen, gave strongly positive
dye tests with titres from 250 to 6250 (table i), andpositive complement-fixation tests with titres from 32to 1024 (table u).As controls, 46 hares were examined which presented
characteristic evidence of other diseases-e.g., pseudo-tuberculosis, staphylomycosis, pasteurellosis, listeriosis,coccidiosis, amyloidosis, leuksemia, alveolitis, or Bact.coli infections. 40 gave negative dye tests (titre _<_1 : 10) and only 4 weak positive reactions (1 : 50). Only1 of 32 hares examined showed a positive .complement-fixation test (1 : 8), the rest being negative.The examination of toxoplasmic hares and of control
hares showed complete correlation between the resultsof the dye test and the complement-fixation test.From the cross-neutralisation reaction (table in), the
cross-complement-fixation test (table iv), and a pre-
TABLE III-RESULTS OF CROSS -NEUTRALISATION TESTS USING
AS ANTIGEN IN DYE TEST HUMAN AND HARE STRAINS OF
TOXOPLASMA
liminary cross-absorption experiment the human strainand the hare strain appeared serologically identical.
DISCUSSION
Toxoplasmosis occurs in hares as an acute fatal systemicdisease. Slight or subclinical cases are seldom seen;only a few weak positive serological reactions have sofar been found in control hares. Investigations are inprogress to determine the frequency of toxoplasmosisin a living hare population, both in the manifest and sub-clinical forms, and to attempt to clarify the mode oftransmission of the infection to hares.
Until now, it has not been possible to explain thecharacteristic seasonal incidence. Even more pro.nounced is the high incidence of pseudotuberculosis ofhares in the winter months.How the infection is transmitted to man is still
unknown. The possibility of direct transmission by con-taminated material should be considered, and the
possibility that the disease may be conveyed by ticks orby mosquitoes cannot be excluded.From an epidemiological point of view it is of interest
that the pathogenicity of the hare strain evidentlycorresponds to that of the human strain RH, and thatthe two strains appear to be serologically identical.Consequently, in handling recently dead toxoplasmicTABLE IV-RESULTS OF CROSS-COMPLEMENT-FIXATION TESTS
USING AS ANTIGEN HUMAN AND HARE STRAINS OF TOXOPLASMA
hares people may risk infection. Experience in theisolation experiments show that toxoplasma survivesfor only a short time in the infected tissues. However,it is considered that pregnant women should not beengaged in cleaning freshly shot hares, but only thosewhich have hung for several days; animals frozen at- 30°C and later thawed do not seem to be infective.
Studies by one of us (J. C. S.) on the incidence oftoxoplasmosis in domestic animals (dog, cat, cow, and
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pig) have shown that the dog, and possibly the cat,may play a not inconsiderable part in transmitting theinfection to man, especially in view of the usually closecontact between dog and man. In Copenhagen, verymany house-dogs gave significant positive serologicalreactions for toxoplasmosis (Siim 1950). As in adult
man, the infection in the older dogs may run a verymild course or may not even be apparent, and thesecases may be of particular importance in spreadingtoxoplasmosis.
SUMMARY
Toxoplasmosis in hares is a well-established clinico-
pathological entity, whose characteristic seasonal inci-dence in Denmark has its maximum in January-Marchand minimum in June-July.The toxoplasma of hares appears to be serologically
identical with the human strain RH, and is equallypathogenic.The epidemiological significance of these findings is
discussed.We wish to thank Miss E. Schwartz-Moller and Miss E.
Lauritzen for their valuable and untiring assistance.
REFERENCES
Hülphers, G., Lilleengen, K., Rubarth, S. (1947) Svensk Veterinär-tidskr. 52, 295.
Sabin, A. B. (1949) Pediatrics, 4, 443.— Feldman, H. A. (1948) Science, 108, 660.
Siim, J. C. (1950) Trans. sixth International Congress for Pediatrics ;p. 365.
Warren, J., Russ. S. B. (1948) Proc. Soc. exp. Biol., N.Y. 67, 85.Wolf, A., Cowen, D., Paige, B. H. (1939) Amer. J. Path. 15, 657.
BOWEL RHYTHM IN THE HEALTHY
INFANT
ITS SUGGESTED RELATIONSHIP WITH CHRONICCONSTIPATION
ISRAEL GORDONM.D. Edin., M.R.C.P., D.P.H.
MEDICAL OFFICER OF HEALTH, ILFORD
THERE appears to be no sort of scientific agreementas to the frequency of defaecation among healthy infants.Yet the matter is important ; for if an infant variesfrom some generally accepted mean,- efforts are almostsure to be made to put things right, and the resultsmay have a lasting effect on the child-and the manwhom (tradition states) he fathers.There are two schools of thought, but it seems that
neither has made a comprehensive or detailed studyof the subject. Both have relied on impressions andmade ex-cathedra statements derived’ therefrom.Hurst (1919) for the traditional school says that
" up to the age of 4 months the bowels are opened from2-4 times a day, during the remainder of the first yearthey are generally opened twice, but in some infantsonly once, a day." Hutchison (1933), and more recentlyGesell and Ilg (1943) make similar statements ; so doBrennemann (1948), and-even more surprisingly-Sunderman and Boerner (1949) in Normal Values inClinical Medicine, probably the most’formidable collectionof information about the normal yet published ; andmany others could be quoted.Those of the modern school such as Plaunder and
Schlossman (1935), Williamson (1947), Ellis (1947),Watkins (1948), and Spock (1947) have discovered thatit is not necessary for a healthy breast-fed infant tohave bowel movements every day but none of themhas produced evidence that a number of normal infantshave been studied or that the scatter with respect toage, and type of feeding, has been investigated. Largesections of the medical public, together with grand-mothers and nurses, are still unaware, to the detrimentof the child, of the normal bowel rhythm of infants.In fact, because of the popularity of Spock. (1947) manymodern mothers are better informed on the matter
than their medical advisers. Fukushima (1930) andTakai (1935), both in Japan, produced small series, butdecided that those with infrequency were abnormal.Takai in fact suggested that they had beriberi, andmade the surprising statement that in breast-fed infantsdefaecation is more frequent than in bottle-fed. AbdelKhalik et al. (1932) investigated 242 breast-fed babiesand decided that only 13 were constipated, althoughtheir criterion of constipation was less than 2 stoolsin 24 hours. It is apparent that infants in Egypt andJapan must behave very differently from British andAmerican children.
THE PRESENT INVESTIGATION
The data here presented refer to 1499 infants whomI saw personally in the infant-welfare centres in Ilfordover a period of about four years. Of these, 799 werebreast-fed and 700 bottle-fed. Numbers in the firstmonths are much greater than those in the later months,and, figures of the third and fourth trimesters had to becombined to get sufficient data. This is because moreinfants attend in the early months than in the later.A child was considered to have been breast-fed if it hadbeen entirely breast-fed up to the age of four and a halfmonths, when additional factors are added to the diet.No infants fed, at the time of the inquiry, partly onthe breast and partly on the bottle are included in thesurvey. If a child under four and a half months hadbeen bottle-fed for a week or more it was included asbottle-fed. The predominance of breast-fed infants isdue to the fact that so many children were only one ortwo months old, before many of the mothers had goneover to the bottle. Mothers were advised not to giveany form of purgative, but no doubt many did, andaccordingly even in this series the record of bowel move-ments shows a greater frequency than Nature intended.Each infant was recorded only once. The figures forthe first month do not include the first two weeks oflife, for infants do not attend the welfare centres in thatperiod.From the accompanying tables and chart, certain
observations stand out clearly. The great frequency ofbowel movements in breast-fed babies in the early weeksis apparent, many having a motion with each feed.Nevertheless the tendency to miss a day is alreadyevident. In the third, fourth, and fifth months thisbecomes so pronounced that 41% may be expected tomiss a day regularly ; for those under six months the
figures is 28%. Mixed feeding is begun at four and ahalf months. In the sixth month bowel actions are
TABLE I-FREQUENCY OF MOTIONS IN 799 BREAST-FED INFANTS
