1911 Encyclopædia Britannica/Parasitic Diseases - Wikisource, the free online library (2024)

​PARASITIC DISEASES. It has long been recognized that various specific pathological conditions are due to the presence and action of parasites (see Parasitism) in the human body, but in recent years the part played in the causation of the so-called infective diseases by various members of the Schizomycetes—fission fungi—and by Protozoan and other animalparasites has been more widely and more thoroughly investigated(see Bacteriology). The knowledge gained has not onlymodified our conception of the pathology of these diseases, buthas had a most important influence upon our methods of treatmentof sufferers, both as individuals and as members of communities.For clinical and other details of the diseases mentionedin the following classification, see the separate articles on them;the present article is concerned mainly with important moderndiscoveries as regards aetiology and pathology. In certaincases indeed the aetiology is still obscure. Thus, according toGuarnieri, and Councilman & Calkins, there is associated withvaccinia and with small-pox a Protozoan parasite, Cytoryctesvariolae. Guar. This parasite is described as present in thecytoplasm of the stratified epithelium of the skin and mucousmembranes in cases of vaccinia, but in the nuclei of the samecells in cases of variola or small-pox, whilst it is suggested thatthere may be a third phase of existence, not yet demonstrated,in which it occurs as minute spores or germs which are veryreadily carried in dust and by air currents from point to point.In certain other conditions, such as mumps, dengue, epidemicdropsy, oriental sore—with which the Leishman-Donovanbodies (Helcosoma tropicum, Wright) are supposed to be closelyassociated (see also Kála-ázar below)—verruga, framboesiaor yaws—with which is commonly associated a spirochaete(CasteUani) and a special micrococcus (Pierez, Nicholls)—andberi-beri, the disease may be the result of the action of specificmicro-organisms, though as yet it has not been possible todemonstrate any aetiologica relationship between any microorganismsfound and the special disease. Such diseases ashaemoglobinuric fever or black-water fever, which are alsopresumably parasitic diseases, are probably associated directlywith malaria; this supposition is the more probable in that bothof these are recognized as occurring specially in those patientswho have been weakened by malaria.

The following classification is based partly upon the biologicalrelations of the parasites and partly on the pathological phenomenaof individual diseases:—

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Suppuration and Septicaemia.—It is now recognized thatalthough nitrate of silver, turpentine, castor oil, perchlorideof mercury and certain other chemical substances are capableof producing suppuration, the most common causes of thiscondition are undoubtedly the so-called pus-producing bacteria.Of these perhaps the most important are the staphylococci(cocci arranged like bunches of grapes), streptococci (cocciarranged in chains), and pneumococci, though certain otherorganisms not usually associated with pus-formation areundoubtedly capable of setting up this condition, e.g. Bacilluspyocyaneus, Bacillus coli communis, and the typhoid bacillus.These organisms (the products of which, by chemical irritation,stimulate the leucocytes to emigration) bring about the deathand digestion of the tissues and fluids (which no longer “clot”)with which they come in contact, pus (matter) being thusformed: this accumulates in the tissues, in the serous cavities,or even on mucous surfaces; septicaemia or blood-poisoning,secondary infection of tissues and organs at a distance fromthe original site of infection, or pyaemia, with the formation ofsecondary abscesses, may thus be set up.

In septicaemia the pus-forming organisms grow at the seatof introduction, and produce special poisons or toxins,which, absorbed into the blood, give rise to symptoms of fever.From the point of introduction, however, the organisms maybe swept away either by the lymph or by the blood, and carriedto positions in which they set up further inflammatory orsuppurative changes. In the streptococcal inflammationsspreading by the lymph channels appears to be specially prevalent.In the blood the organisms, if in small numbers,are usually destroyed by the plasma, which has a powerfulbactericidal action; should they escape, however, they arecarried without multiplication into the capillaries of the generalcirculation, of the lung, or of the liver, where, being stopped,they may give rise to a second focus of infection, especially ifat the point of impaction the vitality of the tissues is in any waylowered. Unless the blood is very much impoverished, itsbactericidal action is usually sufficiently powerful to bring aboutthe destruction of anything but comparatively large massesof pyogenetic organisms. This bactericidal power, however,may be lost; in such case the pus-forming organisms may actuallymultiply, a general haemic infection resulting. Should microorganismsbe conveyed by the veins to the heart, and there bedeposited on an injured valve, an infective endocarditis is theresult; from such a deposit numerous organisms may becontinuously poured into the circulation. Simple thrombi orclots may also become infected with micro-organisms. Fragmentsof these, washed away, may form septic plugs in thevessels and give rise to abscesses at the points where they becomeimpacted. A distinction must be drawn between sapraemia andsepticaemia. In sapraemia the toxic products of saprophyticorganisms are absorbed from a gangrenous or necrotic mass,from an ulcerating surface, or from a large surface on whichsaprophytic organisms are living and feeding on dead tissues:for example, we may have such a condition in the clots thatsometimes remain after childbirth on the inner surface of thewall of the womb. So long as no micro-organisms follow thetoxins, the condition is purely sapraemic, but should anyorganisms make their way into and multiply in the blood, thecondition becomes one of septicaemia. The term pyaemia isusually associated with the formation of fresh secondary fociof suppuration in distant parts of the body. If the primaryabscess occurs in the lungs, the secondary or metastaticabscesses usually occur in the vessels of the general or systemiccirculation, and less frequently in other vessels of the lung. Whenthe primary abscess occurs in the systemic area, the secondaryabscess occurs first in the lung, and less frequently in thesystemic vessels; whilst if the primary abscess be in the portalarea (the veins of the digestive tract), the secondary abscessesare usually distributed over the same area, the lungs and systemicvessels being more rarely affected.

Infective Endocarditis.—Acute malignant or ulcerative endocarditisoccurs in certain forms of septicaemia or of pyaemia.It is brought about by the Streptococcus pyogenes (see PlateII.fig.2), the pneumococcus, or the Staphylococcus pyogenesaureus (see PlateI. fig.4), or, more rarely, by the gonococcus,the typhoid bacillus or the tubercle bacillus, as they gain accessto acute or chronic valvular lesions of the heart. The aorticand mitral valves are usually affected, the pulmonary andtricuspid valves much more rarely, though Washbourn statesthat the infective form occurs on the right side more frequentlythan does simple endocarditis. A rapid necrosis of the surfaceof the valve is early followed by a deposition of fibrin and leucocyteson the necrosed tissue; the bacteria, though not presentin the circulating blood during life, are found in these vegetationswhich break down very rapidly; ulcerative lesions are thusformed, and fragments of the septic clot (i.e. the fibrinousvegetations with their enclosed bacteria) are carried in thecirculating blood to different parts of the body, and, becomingimpacted in the smaller vessels, give rise to septic infarctsand abscesses. The ulceration of the valves, or in the firstpart of the aorta, may be so extensive that aneurysm, or evenperforation, may ensue.

In certain cases of streptococcic endocarditis the use of antistreptococcicserum appears to have been attended with goodresults. Sir A. Wright found that the introduction of vaccinesprepared from the pus-producing organisms after first loweringthe opsonic index almost invariably, after a very short interval,causes it to rise. He found, too, that the vaccine is speciallyefficacious when it is prepared from the organisms associatedwith the special form of suppuration to be treated. Wheneverthe opsonic index becomes higher under this treatment thesuppurative process gradually subsides: boils, acne, pustules,carbuncles all giving way to the vaccine treatment. Theimmunity so obtained is attributed to the increased activityof the serum as the result of the presence of an increased amountof opsonins. Further, Bier maintains that a passive congestionand oedema induced by constriction of a part by means ofa ligature or by a modification of the old method of cuppingwithout breaking the skin appears to have a similar effect inmodifying localized suppurative processes, that is processesset up by pus-producing bacteria. Wright holds that thistreatment is always more effective when the opsonic index ishigh and that the mere accumulation of oedematous fluid inthe part is sufficient to raise the opsonic index of that fluidand therefore to bring about a greater phagocytic activity ofthe leucocytes that are found in such enormous numbersin the neighbourhood of suppurative organisms and theirproducts.

Erysipelas.—In 1883 Fehleisen demonstrated that in all casesof active erysipelatous inflammation a streptococcus or chainof micrococci (similar to those met with in certain forms ofsuppuration) may be found in the lymph spaces in the skin.The multiplying streptococci found in the lymph spaces forman active poison, which, acting on the blood-vessels, causes themto dilate; it also “attracts” leucocytes, and usually inducesproliferation of the endothelial cells lining the lymphatics.These cells—perhaps by using up all available oxygen—interferewith the growth of the streptococcus and act as phagocytes,taking up or devouring the dead or weakened micro-organisms.Both mild and severe phlegmonous cases of erysipelas arethe result of the action of this special coccus, alone, or in ​combination with other organisms. It has been observed thatcancerous and other malignant tumours appear to recede underan attack of erysipelas, and certain cases have been recordedby both Fehleisen and Coley in which complete cessation ofgrowth and degeneration of the tumour have followed such anattack. As the streptococcus of erysipelas can be isolated andgrown in pure culture in broth, it was thought by these observersthat a subcutaneous injection of such a cultivation might be ofvalue in the treatment of cancerous tumours. No difficulty wasexperienced in setting up erysipelas by inoculation, but in somecases the process was so acute that the remedy was more fatalthan the disease. The virulence of the streptococcus of erysipelas,as pointed out by Fehleisen and Coley, is greatly exalted whenthe coccus is grown alongside the Bacillus prodigiosus andcertain other saprophytic organisms which flourish at the body-temperature.It is an easier matter to control the action of anon-multiplying poison, even though exceedingly active, thanof one capable, under favourable conditions, of producing anindefinite amount of even a weaker poison. The erysipelatousvirus having been raised to as high a degree of activity as possibleby cultivating it along with the Bacillus prodigiosus—thebacillus of “bleeding” bread—in broth, is killed by heat, and theresulting fluid, which contains a quantity of the toxic substancesthat set up the characteristic erysipelatous changes, is utilizedfor the production of an inflammatory process—which can nowbe accurately controlled, and which is said to be very beneficialin the treatment of certain malignant tumours. The accuratedetermination of the aetiology of erysipelas has led to theadoption of a scientific method of treatment of the disease.The Streptococcus erysipelatis is found, not specially in the zonein which inflammation has become evident, but in the tissuesoutside this zone: in fact, the streptococci appear to be mostnumerous in the lymphatics of the tissues in which there is littlechange. Before the appearance of any redness there is a dilatationof the lymph spaces with fluid, and the tissues becomeslightly oedematous. As soon, however, as the distension ofvessels and the emigration of leucocytes, with the accompanyingswelling and redness, become marked, the streptococci disappearor are imperfectly stained—they are undergoing degenerativechanges—the inflammatory “reaction” apparently being sufficientto bring about this result.

If it were possible to set up the same reaction outside theadvancing streptococci might not a barrier be raised against theiradvance? This theory was tested on animals, and it was foundthat the application of iodine, oil of mustard, cantharides and similarrubefacients would prevent the advance of certain micro-organisms.This treatment was applied to erysipelatous patients with the mostsatisfactory result, the spread of the disease being prevented wheneverthe zone of inflammation was extended over a sufficiently widearea. The mere “ringing” of the red patch by nitrate of silveror some other similar irritant, as at one time recommended, is notsufficient: it is necessary that the reaction should extend for somelittle distance beyond the zone to which the streptococci have alreadyadvanced.

Gonorrhoea.—A micro-organism, the gonococcus, is thecause of gonorrhoea. It is found in the pus of the urethraand in the conjunctiva lying between the epithelial cells, whereit sets up considerable irritation and exudation; it occurs in thefluid of joints of patients affected with gonorrhoeal arthritis;also in the pleuritic effusion and in the vegetations of gonorrhoealendocarditis. It is a small diplococcus, the elements of whichare flattened or slightly concave disks apposed to one another;these, dividing transversely, sometimes form tetrads. They arefound in large numbers, usually in the leucocytes, adherent tothe epithelial cells or lying free. They stain readily with thebasic aniline dyes, but lose this stain when treated by Gram’smethod. The gonococcus is best grown on human blood-serummixed with agar (Wertheim), though it grows on ordinarysolidified blood-serum or on blood-agar. Like the pneumococcus,it soon dies out, usually before the eighth or ninth day,unless reinoculations are made. It forms a semi-transparentdisk-like growth, with somewhat irregular margins, or withsmall processes running out beyond the main colony. It actsby means of toxins, which have been found to set up irritativechanges when injected, without the gonococci, into the anteriorchamber of the eye of the rabbit.

2. Caused by Specific Bacilli.
(a) Acute Infective Fevers.

Cholera.—In 1884 Koch, in the report of the German CholeraCommission in Egypt and India, brought forward overwhelmingevidence in proof of his contention that a special bacterium isthe causal agent of cholera; subsequent observers in all countriesin which cholera has been met with have confirmed Koch’sobservation. The organism described is the “comma” bacillusor vibrio, one of the spirilla, which usually occurs as a slightlycurved rod 1 to 2μ in length and 0·5 to 0·6μ in thickness. Thesecomma-shaped rods occur singly or in pairs; they may be joinedtogether to form circles, half-circles, or “S”-shaped curves (seePlateII. fig.3).

In cultivations in specially prepared media they may be sogrouped as to form long wavy or spiral threads, each of which maybe made up of ten, twenty, or even thirty, of the short curved vibrios;in the stools of cholera patients, especially during the earlier stagesof the disease, they are found in considerable numbers; they may alsobe found in the contents of the lower bowel and in the substanceof the mucous membrane of the lower part of the small intestine,especially in the crypts and in and around the epithelium liningthe follicles. It is sometimes difficult, in the later stages of thedisease, to obtain these organisms in sufficiently large numbers to beable to distinguish them by direct microscopic examination, but byusing the Dunbar-Schottelius method they can be detected evenwhen present in small numbers. A quantity of faintly alkalinemeat broth, with 2% of peptone and 1% common salt, is inoculatedwith some of the contents of the intestine, and is placed in anincubator at a temperature of 35°C. for about twelve hours, when,if any cholera bacilli are present, a delicate pellicle, consistingalmost entirely of short “comma” bacilli, appears on the surface.If the growth be allowed to continue, the bacilli increase in length,but after a time the pellicle is gradually lost, the cholera organismsbeing overgrown, as it were, by the other organisms. In order toobtain a pure culture of the cholera bacillus, remove a small fragmentof the young film, shake it up thoroughly in a little broth, andthen make gelatine-plate cultivations, when most characteristiccolonies appear as small greyish or white points. Each of these,when examined under a low-power lens, has a yellow tinge; themargins are wavy or crenated; the surface is granular and has apeculiar ground-glass appearance; around the growing colonyliquefaction takes place, and the colony gradually sinks to thebottom of the liquefying area, which now appears as a clear ring.The organism grows very luxuriantly in milk, in which, however,it gives rise to no very noticeable alteration; its presence can onlybe recognized by a faint aromatic and sweetish smell, which canscarcely be distinguished from the aromatic smell of the milk itself,except by the most practised nose.

The cholera bacillus may remain alive in water for sometime, but it appears to be less resistant than many of the putrefactiveand saprophytic organisms. It grows better in a salinesolution (brackish water) than in perfectly fresh water; itflourishes in serum and other albuminous fluids, especially whenpeptones are present. Its power of forming poisonous substancesappears to vary directly with the amount and nature of thealbumen present in the nutrient medium; and though it growsmost readily in the presence of peptone, it appears to form themost virulent poison when grown in some form or other ofcrude albumen to which there is not too free access of oxygen.From the experiments carried out by Koch, Nicati and Rietsch,and Macleod, there appears to be no doubt that the healthystomach and intestine are not favourable breeding-grounds forthe cholera bacillus. In the first place, it requires an alkalinemedium for its full and active development, and the acid foundin a healthy stomach seems to exert an exceedingly deleteriousinfluence upon it. Secondly, it appears to be incapable ofdeveloping except when left at rest, so that the active peristalticmovement of the intestine interferes with its development.Moreover, it forms its poison most easily in the presence of crudealbumen. It is interesting to note what an important bearingthese facts have on the personal and general spread of cholera.Large quantities of the cholera bacillus may be injected into thestomach of a guinea-pig without any intoxicative or othersymptoms of cholera making their appearance. Further,healthy individuals have swallowed, without any ill effect, pills ​containing the dejecta from cholera cases, although cases arerecorded in which “artificial” infection of the human subject hasundoubtedly taken place, whilst, as Metchnikoff demonstrated,very young rabbits, deriving milk from mothers whose mammaryglands have been smeared with a culture of the cholera vibrio,soon succumbed, suffering from the classical symptoms of thisdisease.

If, however, previous to the injection of the cholera bacillusthe acidity of the stomach be neutralized by an alkaline fluid,especially if at the same time the peristaltic action of the intestinebe paralysed by an injection of morphia, a characteristicattack of cholera is developed, the animal is poisoned, andin the large intestine a considerable quantity of fluid faecescontaining numerous cholera bacilli may be found. Thereappear to be slight differences in the cholera organisms foundin connexion with different outbreaks, but the main characteristicsare preserved throughout, and are sufficiently distinctiveto mark out all these organisms as belonging to the cholera group.Amongst the known predisposing causes of cholera are theincautious use of purgative medicines, the use of unripe fruit,insufficient food and intemperance. These may be all lookedupon as playing the part of the alkaline solution in alteringthe composition of the gastric juices, and especially as settingup alkaline fermentation in the stomach and small intestine;beyond this, however, the irritation Set up may bring about anaccumulation of inflammatory serous fluid, from the albumensof which, as we have seen, the cholera organism has the powerof producing very active toxins.

The part played by want of personal cleanliness, overcrowdingand unfavourable hygienic conditions may be readily understoodif it be remembered that the cholera bacillus may growoutside the body. The number of cases in which epidemics ofcholera have been traced to the use of drinking-water contaminatedwith the discharges from cholera patients is now considerable.The more organic matter present the greater is thevirulence of water so contaminated; and the addition of suchwater to milk has, in one instance at least, led to an outbreak.If cholera dejecta be sprinkled on moist soil or damp linen, andkept at blood-heat, the bacillus multiplies at an enormous ratein the first twenty-four or thirty-six hours; but, as seen in theDunbar-Schottelius method, at the end of three or four daysit is gradually overcome by the other bacteria present, which,growing strongly and asserting themselves, cause it to die out.The importance of this saprophytic growth in the propagationof the disease can scarcely be over-estimated. Water which containsan ordinary amount of organic and inorganic matter in solutiondoes not allow of the multiplication of this organism, whichmay soon die out; but when organic matter is present in excess,as at the margin of stagnant pools and tanks, developmentOccurs, especially on the floating solid particles. This bacillusgrows at a temperature of 30°C. on meat, eggs, vegetables andmoistened bread; also on cheese, coffee, chocolate and dilutesugar solutions. In some experiments carried out by CartwrightWood and the writer in connexion with the passage of thecholera organism through filters it remained alive in the charcoalfiltering medium for a period of at least forty-two days, andprobably for a couple of months. It must be rememberedthat cholera bacilli are gradually overcome or overgrown byother organisms, as only on this supposition can the immunityenjoyed by certain regions, even after the water and soil havebeen contaminated, provided that no fresh supply is brought in“to relight the torch,” be explained. In most of the regionsin which cholera remains endemic the wells are merely dug-outpits beneath the slightly raised houses, and are open for thereception of sewage and excreta at all times. These dejectacontain organic material which serves as a nutriment on whichinfective organisms, derived from the soil and ground-water,may flourish. Not only dejecta, but also the rinsings from soiledlinen and utensils used by cholera patients should be removedas soon as possible, “without allowing them to come into contactwith the surface of the soil, with wells,” or with vegetablesand the like. The discovery of Koch's comma bacillus has soaltered our conceptions of the aetiology of this disease that wenow study the conditions under which the bacillus can multiplyand be disseminated, instead of concerning ourselves with thecholera itself as some definite entity. Telluric agencies becomemerely secondary factors, the dissemination of the disease bywinds from country to country is no longer regarded as beingpossible, whilst the spread of cholera epidemics along the linesof human intercourse and travel is now recognized. Thevirulent bacillus requires the human organism to carry it fromthose localities in which it is endemic to those in which epidemicsoccur. The epidemiologist has come to look upon the studyof the cholera organism and the conditions under which itexists as of more importance than mere local conditions, whichare only important in so far as they contribute to the propagationand distribution of the cholera bacillus, and he knows thatthe only means of preventing its spread is the careful inspectionof everything coming from cholera-stricken regions. He alsorecognizes that the herding together of people of depressedvitality, under unhygienic and often filthy conditions, in quarantinestations or ships, is one of the surest means of promotingan epidemic of the disease; that attention should be confinedto the careful isolation of all patients, and to the disinfectionof articles of clothing, feeding utensils, and the like; that thecomma bacillus can only be driven out of rooms by means oflight and fresh air; that thorough personal, culinary and householdcleanliness is necessary; that all water except that knownto be pure should be carefully boiled; and that all excess, bothin eating and drinking, should be avoided. The object of thephysician in such cases must be first to isolate as completelyas possible all his cholera patients, and then to get rid of allpredisposing causes in the patients themselves, causes whichhave already been indicated in connexion with the aetiologyof the disease.

Attention has frequently been drawn to the fact that patientswho have lived for some time in a cholera region, or who havealready suffered from an attack of cholera, appear to enjoy apartial immunity against the disease. Haffkine, working onthe assumption that the symptoms of cholera are produced by atoxin formed by the cholera organism, came to the conclusionthat, by introducing first a modified and then a more virulentpoison directly into the tissues under the skin, and not into thealimentary canal, it would be possible to obtain a certain insusceptibilityto the action of this poison. He found that for thispurpose the cholera bacillus, as ordinarily obtained in pureculture from the intestinal canal, is too potent for the preliminaryinoculation, but is not sufficiently active for the second, if anymarked protection is to be obtained. By allowing the organismto grow in a well-aerated culture the virulence is graduallydiminished, and this virulence, once abolished, does not returneven when numerous successive cultures are made on agar orother nutrient media. On the other hand, by passing thecholera bacillus successively through the peritoneal cavities ofa series of about thirty guinea-pigs, he obtains a virus of greatactivity; this activity is soon lost on agar cultivations, and it isnecessary, from time to time, again to pass the bacillus throughguinea-pigs, three or four passages now being sufficient toreinforce the activity.

Evidence has been collected that spirilla, almost identical inappearance with the cholera bacillus, may be present in waterand in healthy stools, and that it is in many cases almost impossibleto diagnose between these and the cholera bacillus; butalthough these spirilla may interfere with the diagnosis, they donot invalidate Koch’s main contention, that a special form ofthe comma bacillus, which gives a complete group of reactions,is the cause of this disease, especially when these reactionsare met with in an organism that comes from the human intestine.

Typhoid Fever.—Our information concerning the aetiologyof typhoid fever was largely increased during the last twentyyears of the 19th century. In 1880 Eberth and Klebs independently,and in 1882 Coats, described a bacillus which has sincebeen found to be intimately associated with typhoid fever.This organism (PlateII. fig.4) usually appears in the form ofa short bacillus from 2 to 3μ in length and 0·3 to 0·5μ in breadth;it has slightly rounded ends and is stained at the poles; it mayalso occur as a somewhat longer rod more equally stained throughout.Surrounding the young organism are numerous long andwell-formed flagella, which give it a very characteristic appearanceunder the microscope. At present there is no evidence thatthe typhoid bacillus forms spores. These bacilli are found in theadenoid follicles or lymphatic tissues of the intestine, in themesenteric glands, in the spleen, liver and kidneys, and may alsobe detected even in the small lymphoid masses in the lung andin the post-typhoid abscesses formed in the bones, kidneys, orother parts of the body; indeed, it is probable that they werefirst seen by von Recklinghausen in 1871 in such abscesses.They undoubtedly occur in the dejecta of patients sufferingfrom typhoid fever, whilst in recent years it has been demonstratedthat they may also be found in the urine. It is evident,therefore, that the urine, as well as the faeces, may be the vehicleby means of which the disease has been unwittingly spread incertain otherwise inexplicable outbreaks of typhoid fever,especially as the bacillus may be present in the urine when theacute stage of the disease has gone by, and when it has beenassumed that, as the patient is convalescent, he is no longer afocus from which the infection may be spread. Easton andKnox found typhoid bacilli in the urine of 21% of a series oftheir typhoid patients.

In 1906 Kayser demonstrated what had previously been suspected,that the typhoid bacilli may persist for considerable periods inthe bile duct and gall bladder, whence they pass into the intestinaltract and are discharged with the evacuations. Patients in whomthis occurs are spoken of as “typhoid carriers.” They becomeconvalescent and except that now and again they suffer from slightattacks of diarrhoea they appear to be perfectly healthy. It hasbeen observed, however, especially during these attacks of diarrhoea,that typhoid bacilli may be found in the faeces. Curiously enoughthe bacilli are as virulent as are those isolated when the disease isat its height. Hence these typhoid carriers are exceedingly dangerouscentres of infection, and as women act as “carriers” much morefrequently than do men, although, as is well known, typhoid feverattacks men much more frequently than women, the facilitiesfor the distribution of the disease are great, as women so frequentlyact as laundresses, cooks, housemaids, nurses and the like. Froschstates that out of 6708 typhoid patients 310 excreted bacilli for morethan 10weeks after convalescence; 144 of these were no longerinfective at the end of three months; 64 had ceased to be infectiveat the end of a year, and 102 at the end of three and a-half years;further back than this no authentic records could be obtained, butfrom a critical examination of the histories of 25 such carrier caseshe was convinced that 14 had been continuously infective for fromfour to nine years. DrDonald Greig, in 1908, reported a case inwhich the patient appears to have been a typhoid carrier for fifty-twoyears from the time of convalescence. Frosch pointed out,what has now been fully confirmed, that the bacilli in these casesthough often present in the faeces in enormous numbers may disappearand again reappear from time to time, and that a continuousseries of examinations is necessary before a convalescent patientcan be acquitted of being a “typhoid carrier.” In this connexionit is interesting to note that Blumenthal and Kayser have discoveredtyphoid bacilli in the interior of gall-stones. DrsAlexander andJ.C.G. Ledingham, examining the 90 female patients and attendantsin a Scottish asylum in which, during some four or five years, 31cases of typhoid had occurred in small groups in which the source ofinfection could not be traced to any recognized channel, foundamongst them three “typhoid carriers.” The importance of such adiscovery amongst asylum patients may be readily understood whenthe careless and uncleanly habits of insane patients are borne inmind. As it has been demonstrated that the typhoid bacillus isfound, not merely in the lymphatic tissue but, in 75% of the cases,actually circulating in the blood, the appearance of the bacillus inthe secretions and excretions may be readily understood.

There can be little doubt that typhoid bacilli are not, as isvery frequently assumed, present merely in the lymphaticglands and in the spleen (see PlateII. fig.5): they may be foundin almost any part of the lymphatic system, in lymph spaces,in the connective tissues, where they appear to give rise tomarked proliferation of the endothelial cells, and especially inthe various secreting organs. It is probable that the proliferationoften noticed in the minute portal spaces in the liver, incases of typhoid fever, is simply a type of a similar proliferationgoing on in other parts and tissues of the body. It was for longassumed that the typhoid bacillus could multiply freely in water,but recent experiments appear to indicate that this is not the case,unless a much larger quantity of soluble organic matter is presentthan is usually met with in water. The fact, however, that theorganism may remain alive in water is of great importance; and,as in the case of cholera, it must be recognized that certain ofthe great epidemics of typhoid or enteric fever have been theresult of “water-borne infection.” The bacillus, a facultativeparasite, grows outside the body, with somewhat characteristicappearances and reactions: it flourishes specially well on aslightly acid medium; in the presence of putrefactive organismswhich develop strongly alkaline products it may gradually dieout, but it appears to retain its vitality longer in the presenceof acid-forming organisms. It may, however, be stated generallythat after a time the typhoid bacillus becomes weakened, andmay even die out, in the presence of rapidly growing putrefactiveorganisms. In distilled water it may remain alive for a considerableperiod—five or six weeks, or even longer. It growson all the ordinary nutrient media. It does not coagulatemilk; hence it may grow luxuriantly in that medium withoutgiving rise to any alteration in its physical characters; contaminatedmilk, therefore, is specially dangerous affording as itdoes an excellent vehicle for the dissemination of the typhoidbacillus which may also be conveyed by food and even bywater. To food the bacillus is readily conveyed by flies, ontheir limbs or by the proboscis, which become infected by theexcrement on which they crawl and feed. The observations ofphysicians working amongst the British troops in South Africaafford abundant evidence that the typhoid bacillus may alsobe carried along with dust from excreta to fresh patients, foralthough these bacilli die very rapidly when they are desiccated,they remain alive sufficiently long to enable them to multiplyand flourish when again brought into contact with moist food,milk, &c.

When inoculated on potato, careful examination will revealthe fact that certain almost invisible moist patches are present;these are made up of rapidly multiplying typhoid bacilli. The

typhoid bacillus grows in gelatin, especially on the surface. ​

Fig. 5.

Fig. 10.

Fig. 3.

Fig. 7.

Fig. II.

Fig. 4.

Fig. 15. Fig. 16. Fig. 19.

Fig. 2.— -Streptococcus pyogenes, red blood corpuscles and pus cells in the pus from a case of empyaema. (X 1000 diams.) Fig. 3. — Choleraspirillum, from eight days' agar culture, showing many involution forms. Flagella well stained. (X 1000.) Fig. 4. — Bacillus tvphiabdominal is (typhoid bacillus), with well-stained flagella. Young agar cultivation. (X 1000.) Fig. 5. — Group of typhoid bacilli, in asection of spleen. (X 1000.) Fig. 7. — Preparation from young cultivation of Bacillus pestis (plague bacillus). Flagella well stained(X 1000.) Fig. 9. — Bacillus diphtheria, from twenty-four hours' culture. (X 1000.) Fig. 10. — Free edge of false membrane from caseof diphtheria containing numerous diphtheria bacilli. (X looo.) Fig. ii. — Bacillus tetani, with well-stained flagella. Twenty-fourhours' culture. (X 1000.) Fig. 12. — Scraping from a wound in a case of tetanus, showing several spore-bearing and a few nonspore-bearingtetanus bacilli. (X 1000.) Fig. 15. — Bacillus tuberculosis. Bacilli in a giant-cell in the human liver in a case of acutetuberculosis. (X 1000.) Fig. 16. — Bacillus leprae. Bacilli in endothelial cells of splenic tissue. (X 1000.) Fig. 19. — Amoebaein wall of dysenteric abscess of liver, from specimen kindly lent by Professor Greenfield. (X 1000.)

XX. 774. ​somewhat like the bacillus coli communis, but with a lessluxuriant growth. This organism, when taken from youngbroth cultures twelve to twenty-four hours old—during theperiod at which flagella are best seen—and examined microscopically,exhibits very lively movements. When, as pointedout by Gruber and Durham, blood-serum, in certain dilutions,from a case of typhoid fever is added to such a culture, the broth,at first turbid, owing to the suspended and moving microorganisms,gradually becomes clear, and a deposit is formedwhich is found to be made up of masses or clumps of typhoidbacilli which have lost their motility. This reaction is socharacteristic and definite, that when the mixture is kept underexamination under the microscope, it is quite possible to followthe slowing-down movement and massing together of theorganisms. It is found, moreover, that normal diluted blood-serumhas no such effect on the bacilli. This property of theblood-serum is acquired at such an early date of the disease—sometimeseven at the end of the first week—and occurs with suchregularity, that typhoid fever may now actually be diagnosedby the presence or absence of this “agglutinating” propertyin the blood. If serum taken from a patient supposed to besuffering from typhoid fever, and diluted with saline solutionto 1 in 10, to 1 in 50, or in still greater dilution, causes the bacillito lose their motility and to become aggregated into clumpswithin an hour, it may be concluded that the patient is sufferingfrom typhoid fever; if this agglutination be not obtained witha dilution of 1 in 10, in from 15 to 30 minutes, experience hasshown that the patient is not suffering from this disease.Certain other diseases, such as cholera, give a similar specificserum reaction with their specific organisms. These sera have,in addition, a slight common action—a general agglutinatingpower—which, however, is not manifested except in concentratedsolutions, the higher dilutions failing to give any clumpingaction at all, except with the specific bacillus associated withthe disease from which the patient, from whom the serum istaken, is suffering.

Wright and Semple, working on Haffkine’s lines, introduced amethod of vaccination against typhoid, corresponding somewhatto that devised by Haffkine to protect against cholera. They firstobtained a typhoid bacillus of fairly constant virulence and of suchstrength and power of multiplication that an agar culture of 24hours’ growth when divided into four, and injected hypodermically,will kill four fairly large guinea-pigs, each weighing 350 to 400grammes. A similar culture emulsified in bouillon or saline solutionand killed by heating for five minutes at 60°C. is a vaccine sufficientfor from four to twenty doses. In place of the agar culture a bouillonculture heated for the same period may be used as the vaccine. Ineither case the vaccine is injected under the skin of the loin wellabove the crest of the ileum. This injection is usually followedby local tenderness and swelling within three or four hours, andswelling and tenderness in the position of the nearest lymphaticglands, marked malaise, headache, a general feeling of restlessnessand discomfort and a rise of temperature. The blood of a patientso treated early causes agglutination of typhoid bacilli and acts onthese bacilli much as does cholera serum in Pfeiffer’s reaction. Atthe end of ten days a second and stronger dose is given. After eachinjection there is, according to Wright, a “negative phase” duringwhich the patient is somewhat more susceptible to the attacks ofthe typhoid bacillus. This negative phase soon passes off and adistinct positive or protected phase appears. The practical outcomeof this is that wherever possible a patient who is going into a typhoidinfected area should be vaccinated some little time before he sets out.There seems to be no doubt that if this be done a very marked,though not complete, protection is conferred. For a time the agglutinativeand lytic powers of the serum continue to rise and the patientso vaccinated is far less susceptible to the action of the typhoidbacillus. It is recorded in favour of this method of treatment thatof 4502 soldiers of the Indian army inoculated 0·98% contractedtyphoid, while of 25,851 soldiers of the same army who were notinoculated over 212% (2·54) contracted typhoid. Similarly, atLadysmith, of the whole of the besieged soldiers only 1705 had beeninoculated, but of these only 2% contracted typhoid, whilst of 10,529uninoculated men 14% were attacked. Wright, who has beenindefatigable in carrying out and watching this method of treatment,has been able to accumulate statistics dealing with 49,600 individuals—ofthese 8600 were inoculated, and 214% contracted typhoid, 12%of these succumbing to the disease. Of the 41,000 uninoculatedmen 534% contracted the disease, 21% of those attacked succumbing.

Mediterranean or Malta Fever.—Until comparatively recently,Mediterranean fever was looked upon as a form of typhoidfever, which in certain respects it resembles; the temperaturecurve, however, has a more undulatory character, except inthe malignant type, where the temperature remains highthroughout the course of the attack. According to Hughes,this disease is widely distributed in the countries borderingupon the Mediterranean south of latitude 46°N., and along theRed Sea littoral. Analogous forms of fever giving a “specific”serum reaction with the micrococcus of this disease are also metwith in parts of India, China, Africa and America.

The Micrococcus melitensis vel Brucei (1887), which is found mostabundantly in the enlarged spleen of the patient suffering fromMalta fever, is a very minute organism (0·33μ in diameter), ovoidor nearly round, arranged in pairs or in very short chains. If adrop of the blood taken directly from the spleen be smeared overthe surface of agar nutrient medium, minute transparent colourlesscolonies appear; in thirty-six hours these have a slight amber tinge,and in four or five days from their first appearance they becomeopaque. These colonies, which flourish at the temperature of thehuman blood, cease to grow at the room-temperature except insummer, and if kept moist, soon die at anything below 60°F., thoughwhen dried they retain their vitality for some time. As the organismgrows and multiplies in broth there is opacity of the medium at theend of five or six days, this being followed by precipitation, so thata comparatively clear supernatant fluid remains. It grows beston media slightly less alkaline than human blood; it is very vigorousand may resist desiccation for several weeks.

This organism is distinctly pathogenetic to monkeys, and itsvirulence may be so increased that other animals may be affectedby it. Though unable to live in clean or virgin soil, it may leada saprophytic existence in soil polluted with faecal matter.Hughes maintains that the “virus” leaves the body of goats andof man along with the faeces and urine. The importance ofthis in ambulatory cases is very evident, especially when it isremembered that goats feeding on grass, &c. which has comein contact with such urine are readily infected. It seldomappears to be carried for any considerable distance. Infectionis not conveyed by the sputum, sweat, breath or scraping ofthe skin of patients, and infected dust does not seem to play avery important part in producing the disease. Hughes dividesthe fever into three types. In the malignant form the onset issudden, there are headache, racking pain over the whole body,nausea and sometimes vomiting; the tongue is foul, coated andswollen, and the breath very offensive; the temperature maycontinue for some time at 103° to 105° F. The stools in thediarrhoea which is sometimes present may be most offensive.At the end of a few days the lungs become congested and pneumonic,the pulse weak, hyperpyrexia appears, and death ensues.A second type, by far the most common, is the “undulatory”type, in which there is remittent pyrexia, separated by periodsin which the patient appears to be improving. These pyrexialcurves, from one to seven in number, average about ten dayseach, the first being the longest,—eighteen to twenty-three days.In an intermittent type, in which the temperature-curve closelyresembles the hectic pyrexial curve of phthisis or suppuration,the “undulatory” character is also marked. A considerablenumber of toxic symptoms make their appearance—localizedneuritis, synovitis, anaemia, emaciation, bronchial catarrh, weaknessof the heart, neuralgia, profuse night-sweats and similarconditions. Patients otherwise healthy usually recover, evenafter prolonged attacks of the disease, but the mortality amongstpatients suffering from organic mischief of any kind may becomparatively high. The diagnosis from malaria, phthisis,rheumatic affections and pneumonia may, in most cases, be madefairly easily, but the serum agglutinating reaction (first demonstratedby Wright in 1897) with cultures of the Micrococcusmelitensis, corresponding to the typhoid reaction with thetyphoid bacillus, is sometimes the only trustworthy featureby which a diagnosis may be made between this fever and theabove-mentioned diseases. About 50% of the goats in Maltagive a positive agglutinative reaction and about 10% excretemilk which contains the micrococcus.

Sir David Bruce, in his investigations on the tsetse fly disease,pointed out that certain wild animals although apparentlyin good health might serve as reservoirs for, or storehouses of,the N’gana parasite. He was therefore quite prepared to find ​that the Micrococcus melitensis might similarly be “stored”in an animal which might show but slight, if any, manifestationsof Malta fever. Indications as to the direction in which tolook were given in the following fashion. There was a strikeamongst the dairymen supplying the barracks in Malta and itbecame necessary to replace the goat’s milk in the dietary ofthe troops by condensed milk. What followed? In the firsthalf of the year 1906 there had been 144 cases (in 1905 there hadbeen 750 cases), in the second half after the alteration of themilk supply, only 32 cases were recorded and in 1907, 7casesduring the whole year. In the navy during the same periodthere were, in 1905, 498 cases, in 1906, 248 cases and, fromJanuary to September 1907, not a single case.

Relapsing Fever.—The specific cause of relapsing fever (faminefever) appears to be the Spirillum Obermeieri, an organismwhich occurs in the blood (during the febrile stages) of patientssuffering from this disease. Between the febrile stages areperiods of intermission, during which the spirillum disappearsfrom the blood and, apparently, retires to the spleen. Thisdisease, in epidemic form, follows in the footsteps of famineand destitution, specially affecting young people between theages of fifteen and twenty; it seldom attacks children underfive years of age, but when it attacks patients over thirty itassumes a very virulent form. In monkeys inoculated with bloodcontaining the Spirillum Obermeieri the first symptoms appearbetween the second and sixth days. In the human subjectthis incubation period may last as long as three weeks; thencomes an attack of fever, which continues for about a week,and is followed by a similar period of apparent convalescence,on which ensues a pyrexial relapse, continuing about half as longas the first. The spirilla, the cause of this disease, are finespirals with pointed ends, three or four times as long as thediameter of a red blood corpuscle. Although it has as yet beenfound impossible to cultivate these spirilla outside the body,human beings, and monkeys injected with blood containingthem, contract the disease; and in monkeys it has been foundthat during the period before the relapse the spirilla have madetheir way into the cells of the spleen. As yet little is knownas to the mode of development of these organisms, and of themethod of their transmission from one patient to another, butit is thought that, as in the case of malaria and the tsetse-flydisease, they may be carried by bloodsucking insects. Relapsingfever is distinguished from typhoid fever by its sudden onset,and by the distinct intermissions; and from influenza by theenlargement of the spleen and liver. The most satisfactorymethod of diagnosis is the examination of the blood for thepresence of the spirillum during the febrile stage. The post-mortem appearances are those of a toxic (bacterial) poisoning. Curious infarction-like masses, in which are numerous spirilla, are found in the spleen; in the liver there is evidence of acute interstitial hepatitis, with cloudy swelling of the liver cells; and similar changes occur in the kidney. Fatty degenerationof the heart and voluntary muscles may also be met with.

Plague.—During recent years opportunities for the studyof plague have unfortunately been only too numerous. In patients suffering from this disease, a micro-organism, capable of leading either a saprophytic life or a parasitic existence in the human body, and in some of the lower animals, was described independently by Kitasato and Lowson and by Yersin, 1894, in Hong-Kong. It is a short moderately thick oval bacillus, with rounded ends, which stain deeply, leaving a clear band in the centre (see PlateII., fig.7). It thus resembles the short diphtheria bacillus and the influenza bacillus. Certain other forms are met with—long rods and “large oval bacilli, pear-shaped or round, imperfectly stained pale involution forms”—but the above is the most characteristic. It grows readily on most media at the temperature of the body, but, like the glanders bacillus, soon loses its virulence in cultivations. It may be obtained in pure cultures from the lymph glands, and from the abscesses that are formed in the groin or other positions in which the glands become enlarged and softened. It may also be found in the spleen and in the blood, and, in the case of patients suffering from the pneumonic form of the disease, even in the lungs and in the sputum. It has also been found in the faeces and urine. (It is very important that these excretions from plague patients should always be most carefully disinfected.) This organism, when obtained in pure culture and inoculated into rats, mice, guinea-pigs or rabbits, produces exactly the same symptoms as does material taken fresh from the softened glands. The symptoms are local swelling, enlargement and softening of the lymphatic glands, and high fever.

The difficulty of explaining the spread of plague, at one timeapparently almost insuperable, has at last been overcome, asit has been found that although the acute pneumonic plagueis undoubtedly highly contagious, the spread of the bubonicand septicaemic forms could not be explained on the samehypothesis. As the pneumonic form is met with in only about2·5% of the whole of the cases, transmission by direct contagionseems to be an utterly inadequate explanation. In the autumnof 1896, when the plague broke out in India, and those dealing ​with the outbreak came to the conclusion that certain houseswere centres of infection, it was noticed that these houses weremost infective at night, and that they might actually be centresof infection although uninhabited; indeed the infection seemedto spread to houses between which and the infected house thereappeared to be no intercommunication of any kind. Thisseemed to be inexplicable except on the assumption that theinfective agent, the Bacillus pestis, was, in some way or other,carried by animals. It had already been noted that ratsdisappeared from plague-stricken houses, many dying before theappearance of the plague in the human population. Simond,noting these conditions, suggested that the plague bacillus mightbe transmitted by the flea from rat to rat and from rat to man.Although he was not able to demonstrate this connexion heindicated a line of research to other observers, who, as knowledgeaccumulated, were able to complete each Unk in the chainof infection. The plague bacillus having been found in the rat,the next step was to demonstrate its presence in the flea, andliving plague germs were found in the stomachs of fleas inhabitingplague-infected houses. Several species seem to be able totransmit this germ, but in none of them does the plague bacillusappear to undergo any special development—alternation ofgenerations or the like—as in the case of the protozoon of malariain its passage from and to the mosquito and the human subject—itsimply passes unchanged through the alimentary canalof the flea, is excreted in the faeces, and is carried into the woundmade by the epipharynx-mandibles of the flea.

At least three species of animals, two rats and the humansubject, and three species of fleas are involved in this chain. Therat fleas are Pulex cheopis found in India, and Ceratophyllusfasciatus, the rat flea of northern Europe, and Pulex irritans,the common flea, all of which have the power of transmittingthe disease. In India of course the Pulex cheopis, usuallysolely associated with rats, seems to play the most prominentpart. The two rats involved are the Mus decumanus, or brownrat, which is found in the sewers and develops the plague first,and the Mus rattus, the common black house-rat. From thesewer-rat the house-rat is infected, and from the house-rat man.Under ordinary conditions rat fleas do not attack the humansubject, but, as the rats are attacked by plague and die, theinfected fleas, starve out as it were, leave them and transfertheir attentions to other animals and the human subject,infecting many of those they bite. Colonel Bannerman maintainsthat this infection takes place in the majority of cases, bythis chain of transmission, and that there is no evidence thatthe excreta of these rats infect food or contaminate the soil.Colonel Lamb, summarizing the experimental evidence on thisquestion, writes:—

“1. Close contact of plague-infected animals with healthyanimals, if fleas are excluded, does not give rise to an epizooticamong the latter. As the godowns (experimental huts) were nevercleaned out, close contact includes contact with faeces and urine ofinfected animals, and contact with and eating of food contaminatedwith faeces and urine of infected animals as well as with pus fromopen plague ulcers; (2)close contact of young, even when suckledby plague-infected mothers, did not give the disease to the former;(3)if fleas are present, then the epizootic, once started, spreads fromanimal to animal, the rate of progress being in direct proportion tothe number of fleas present; (4)an epizootic of plague may startwithout direct contact of healthy animal and infected animal;(5)the rat flea can convey plague from rat to rat; (6)infection cantake place without any contact with contaminated soil; (7)aerialinfection is excluded.”

The experiments lead to the conclusion that fleas and fleasalone, are the transmitting agents of infection. Bannermangives in concise form similar evidence in relation to naturallyinfected native houses. Infection is carried from place to placeby fleas, usually on the body or in the clothing of the humanbeing. Such fleas, fed on infected blood, may remain alivefor three weeks, and of this period, we are told, may remaininfective for fifteen days. At the first opportunity these fleasforsake the human host and return to their natural host therat. In most of the epidemics there is a definite sequence ofevents. First the brown rats are attacked, then the black rats,then the human subject, and Colonel Lamb suggests that afterthe rat disappears the flea starves for about three days and thenattacks the human subject. Then comes the incubation periodof plague, three days. Following this is the period of averageduration of the disease, five or six days. This time-table, hesays, corresponds to the period—when the epidemics are attheir height—that intervenes between the maximum death-ratein rats and the maximum death-rate in man, about ten tofourteen days. This history of the connexion between the flea,the rat, and the human subject reads almost like a fairy tale,but it is now one of the well-authenticated and sober facts ofmodern medicine.

In India, where the notions of cleanliness are somewhatdifferent from those recognized in Great Britain, most of theconditions favourable to the spread of the plague bacillus areof the most perfect character. This organism may pass intothe soil with faeces; it may there remain for some time, and thenbe taken into the body of one of the lower animals, or of man,and give rise to a fresh outbreak. Kitasato and Yersin wereboth able to prove that soil and dust from infected houses containthe bacillus, that such bacillus is capable of inducing an attackof plague in the lower animals, and that flies fed on the dejectaor other bacillus-containing material, die, and in turn containbacilli which are capable of setting up infection. Hankin claimsthat ants may carry the plague to and from rats, and so to thehuman being. It has already been mentioned that the organismrapidly loses its virulence when cultivated outside the body;on the other hand, on being passed through a series of animalsits virulence gradually increases. Thus may be explained thefact that in most outbreaks of plague there is an early periodduring which the death-rate is very low; after a time the percentagemortality is enormously increased, the virulence of thedisease being very great and its course rapid. There seem tobe notable differences in the degree of susceptibility of differentraces and different individuals, and those who have passed safelythrough an attack appear to have acquired a marked degree ofimmunity.

Pneumonia.—The case in favour of acute lobar pneumoniabeing an infective disease was a very strong one, even beforeit was possible to show that a special organism bore any etiologicalrelation to it. In 1880, Friedlander claimed that hehad isolated such an organism, but the pneumo-bacillus thendescribed appears to be inactive as compared with the pneumococcusisolated by Fraenkel and Talamon. This latter organismwhich is usually found in the sputum, is an en capsuled diplococcus.Grown on serum or agar over which sterile bloodhas been smeared, it occurs as minute, ghstening, rather prominentpoints, almost like a fine spray of water or dew. Whenthe organism is cultivated in broth the capsule disappears, andchains of diplococci are seen. It resembles the influenza bacillusin a most remarkable manner. It may be found, in almostevery case of pneumonia, in the “rusty” or “prune-juice”sputum. Injected into rabbits, it produces death with verygreat certainty; and by passing the organism through theseanimals its virulence may be markedly increased. Like theinfluenza bacillus and even the diphtheria bacillus, this organismmay be present in the mouth and lungs of perfectly healthyindividuals, and it is only when the vitality of the system islowered by cold or other depressing influences that pneumoniais induced; two factors, the presence of the bacillus and thelowered vitality, being both necessary for the production of thisdisease in the human subject. It is quite possible, however,that, as in the case of cholera, a slight inflammatory exudationmay supply a nutrient medium in which the bacillus rapidlyacquires greatly increased virulence, and so becomes a muchmore active agent of infection.

It is claimed by the brothers Klemperer, by Washbourn and byothers, that they have been able to produce an anti-pneumococcicserum, by means of which they are able to treat successfully severecases of pneumonia. The catarrhal pneumonia so frequently metwith during the course of whooping-cough, measles and otherspecific infective fevers, is also in all probability due to the action ofsome organism of which the influenza bacillus and the Diplococcuspneumoniae are types.

Infective meningitis is, in most of the recent works on medicine,divided into four forms: (1)the acute epidemic cerebro-spinalform; (2)a posterior basic form, which, however, is closelyallied to the first; (3)suppurative meningitis, usually associatedwith pneumonia, erysipelas, and pyaemia; and (4)tubercularmeningitis, due to the specific tubercle bacillus.

1. The first form, acute infective or epidemic cerebro-spinalmeningitis, is usually associated with Weichselbaum's Diplococcusintracellularis meningitidis (two closely apposed disks),which is found in the exudate, especially in the leukocytes, ofthe meninges of the brain and cord. It grows, as transparentcolonies, on blood-agar at the temperature of the body, butdies out very rapidly unless reinoculated, and has little pathogeneticeffect on any of the lower animals, though under certainconditions it has been found to produce meningitis when injectedunder the dura mater.

More or less successful attempts have been made to treat acuteepidemic cerebro-spinal meningitis by means of antisera obtainedfrom different sources. Flexner uses the serum of horses that havebeen highly immunized against numerous strains of the meningococcus,the process of immunization extending over four or fivemonths. Meister, Lucius and Briining supply Ruppel’s antibacterialserum derived from animals immunized against severalstrains of meningococcus of high pathogenic activity. Both thesesera may be looked upon as polyvalent sera. Ivy Mackenzie andMartin, pointing out that the cerebro-spinal fluid, even of patientswho have recovered from this form of meningitis, contains no antibodies,tried and recommended injections of the patient’s own bloodserum into the spinal canal. In all cases the action seems to be muchthe same. These sera contain immune body and complement, andare distinctly bactericidal, acting on the meningococcus and renderingit much more easily taken up and digested by the white bloodcorpuscles. It is possible that these sera may also exert some slightanti toxic action. The serum is injected directly into the spinalcanal, a corresponding quantity of the cerebro-spinal fluid havingfirst been withdrawn by lumbar puncture. The treatment thusresembles the treatment of lockjaw, where the anti tetanus serumis brought as directly as possible into contact with the nerve centres.The dose of these sera ranges from 15 to 40cc. according to theseverity of the disease. Although the general mortality of the diseaseis from 50 to 80%, it is stated that where Flexner’s serum is usedthe mortality falls to 33%. The result corresponds somewhatclosely to those obtained with anti diphtheria serum in diphtheria.In patients injected on the first day of the disease the mortality wasonly about 15%. on and from the fourth to the seventh day 22%,but after the seventh day 36%. From this it is evident that althoughthe serum has a distinct effect in bringing about the phagocytosisof the meningococcus and the neutralization of the to.xins produced,it cannot make good any damage already done to the tissues.Mackenzie and Martin treated 20 cases with the blood taken frompatients suffering, or convalescent, from meningitis. Of 16 acutecases treated 14 received serum from patients who had alreadyrecovered from the disease, 8 of the patients recovered, 6 died, and2cases which received their own serum both recovered. In thepresence of these anti-cerebro-spinal-fever sera the meningeal coccibecome diminished in number and do not stain so readily, whilst,simultaneously, the polymorpho-nuclear leukocytes seem to be diminishedin number. The serum should be given until the temperaturebecomes normal. Mackenzie and Martin' assert that even normalhuman blood contains substances which are bactericidal to themeningeal coccus, but that these substances increase “in amountand activity in the blood serum of patients suffering from an acuteor chronic meningococcic infection, and the serum of a patientrecently recovered from an infection shows the evidence of thepresence of these substances in a still greater degree.” They wereable to demonstrate, moreover, that the destructive action on thecocci depends on an immune body which requires the presence of acomplement to complete the process. The cerebro-spinal fluid differsfrom the serum in that it does not contain substances which killthis meningeal coccus in vitro, nor are the immune body and complementpresent in the blood, found in this cerebro-spinal fluid. Hencethe efficacy of the blood when it is called upon to replace the fluidin the cerebro-spinal canal.

2. Posterior basic meningitis, according to Dr Still, “isfrequently seen during the first six months of life, a period atwhich tuberculous and epidemic cerebro-spinal meningitis arequite uncommon.” The organism found in this disease resemblesthe diplococcus intracellularis meningitidis very closely, butdiffers from it in that it remains alive without recultivation fora considerably longer period. It is less pathogenetic than thatorganism, of which possibly it is simply a more highly saprophyticform. This is a somewhat important point, as it wouldaccount for the great resemblance that exists between thesporadic and the epidemic forms of meningitis.

3. In suppurative meningitis these two organisms may stillbe found in a certain proportion of the cases, but their placemay be taken by the pneumococcus or Diplococcus pneumoniaeor Fraenkel’s pneumococcus—Diplococcus lanceolatus—whichappears to grow in two forms. In the first it is an encapsulatedorganism, consisting of small oval cocci arranged inpairs or in short chains; the capsule is unstained. When thepneumococcus grows in chains—the second form—as whencultivated outside the body, on blood-serum or on agar overthe surface of which a small quantity of sterile blood has beensmeared, it produces very minute translucent colonies. LikeWeichselbaum’s bacillus, it must be re cultivated every three orfour days, otherwise it soon dies out. Unlike the other formspreviously described, it may, when passed through animals,become extremely virulent, very small quantities being sufficientto kill a rabbit. Although the pneumococcus is found in themajority of these cases, especially in children, suppurative ​meningitis may also accompany or follow the various diseasesthat are set up by the Streptococcus pyogenes and Streptococcuserysipclatis; whilst along with it staphylococci and the Bacilluscoli communis have sometimes been found. In other cases,again, there is a mixed infection of the pneumococcus and theStreptococcus pyogenes, especially in cases of disease of themiddle ear. As might be expected in meningitis occurring inconnexion with the specific infective diseases, e.g. influenza andtyphoid fever, the presence of the specific baciUi of these diseasesmay usually be demonstrated in the meningeal pus or fluid.

4. The fourth form, tubercular meningitis (acute hydrocephalus),is met with most frequently in young children. It is nowgenerally accepted that this condition is the result of the introductionof the tubercle bacillus into the blood-vessels and lymphspaces of the meninges at the base of the brain, and along thefissures of Sylvius.

Influenza. — From 1889 up to the present time, influenza hasevery year with unfaiUng regularity broken out in epidemicform in some part of the United Kingdom, and often has sweptover the whole country. The fact that the period of incubationis short, and that the infective agent is extremely active at avery early stage of the disease, renders it one of the most rapidly spreadingmaladies with which we have to deal. The infectiveagent, first observed by Pfeiffer and Canon, is a minute bacillusor diplococcus less that i/i in length and o-5;u in thickness; it isfound in little groups or in pairs. Each diplococcus is stainedat the poles, a clear band remaining in the middle; in this respectit resembles the plague bacillus. It is found in the blood thoughhere it seems to be comparatively inactive — and inenormous numbers in the bronchial mucus. It is not easilystained in a solution of carbol-fuchsin, but in some cases suchnumbers are present that a cover-glass preparation may showpractically no other organisms. Agar, smeared with blood,and inoculated, gives an almost pure cultivation of very minutetransparent colonies, similar to those of the Diplococcus pneumonia,but as a rule somewhat smaller. This organism, foundonly in cases of influenza, appears to have the power of formingtoxins which continue to act for some time after recovery seems tohave taken place; it appears to exert such a general devitalizingeffect on the tissues that micro-organisms which ordinarilyare held in check are allowed to run riot, with the result thatcatarrh, pneumonia and similar conditions are developed,especially when cold and other lowering conditions co-operatewith the poison. This toxin produces special results in thoseorgans which, through over-use, impaired nutrition or disease,are already only just able to carry on their work. Hence incases of influenza the cause of death is usually associated withthe failure of some organ that had already been working up toits full capacity, and in which the margin of reserve power hadbeen reduced to a minimum. It is for this reason that rest,nutrition, warmth and tonics are such important and successfulfactors in the treatment of this condition.

Yellow Fever, endemic in the West Indies and the north-easterncoast of South America, may become epidemic whereverthe temperature and humidity are high, especially along theseashore in the tropical Atlantic coast of North America. Itappears to be one of the specific infective fevers in which theliver, kidney, and gastro-intestinal systems, and especiallytheir blood-vessels, are affected. In 1897 Sanarelli reported,in the Annales de I'lnstitut Pasteur, that he had found a bacillusin the blood-vessels of the liver and kidneys, and in the ■'cells ofthe peritoneal fluid, but never in the alimentary tract, of yellowfever patients. These, he maintained, were perfectly distinctfrom the putrefactive microbes occurring in the tissues in thelater stages, their colonies not growing like those of the bacilluscoli communis. They grow readily on all the ordinary artificialnutrient media, as short rods with rounded ends, usually abtttit2 to 4fi in length and about half as broad as they kre loh'^. ' Theyare stained by Gram's method and readily by mos't of the anilinedyes, are cihated, and do not liquefy gelatine. They flourishspecially well alongside moulds, in the dark, in badly-ventilated,warm, moist places, and remain alive for some time in sea-water:

these facts, as Sanarelli points out, may afford an explanationof the special persistence of yellow fever in old, badly-ventilatedships, and in dark, dirty and insanitary sea-coast towns. Oncethe organism, whatever it may be, finds its way into the system,it soon makes its presence felt, and toxic symptoms are developed.The temperature rises; the pulse, at first rapid, gradually slowsdown; and after some time persistent vomiting of bile comeson. At the end of three or four days the temperature and pulsefall, and there is a period during which the patient appearscomparatively well; this is followed in a few hours by icterusand scanty secretion of urine. There may be actual anuria,or the small quantity of urine passed may be loaded with castsand albumen; delirium, convulsions and hemorrhage's fromall the mucous surfaces may now occur, or secondary infectionsof various kinds, boils, abscesses, suppuration's and septicaemia,may result. These often prove fatal when the patient appearsto be almost convalescent from the original disease. As regardsprognosis, it has been found that the " lower the initial temperaturethe milder will the case be " (Macpherson). An initialtemperature of 106° F. is an exceedingly unfavourable sign.Patients addicted to the use of alcohol are, as a rule, much moreseverely affected than are others. Treatment is principallydirected towards prevention and towards the alleviation ofsymptoms, though SanareUi has hopes that an " anti "-serummay be useful. More recently S. Flexner, working with theAmerican Commission, isolated another organism, which, hemaintains, is the pathogenetic agent in the production of yellowfever; whilst Durham and Myers maintain that a small bacilluspreviously observed by G. M. Sternberg and others is the truecause of this disease.

Professor Boyce, enumerating the hypotheses as to the cause ofyellow fever, points out that as in the case of malaria, suspicionturned to " that form of Miasm which was supposed to arisefrom the mixture, in a marsh or on a mud flat, of salt with freshwater." It was early recognized that yellow fever was notcarried directly from person to person, but little of definitecharacter was known as to the poison and the method of itsdissemination, and Fergusson states that " it is a terrestrialpoison which high atmospheric heat generates amongst thenewly arrived, and without that heat it cannot exist." Thefollowing passage from Beauperthuy (see his collected paperspublished in 1891) is quoted by Boyce: " But rubbish! thesmall amount of sulphuretted hydrogen or marsh gas whichmight arise from a marsh could not possibly hurt a fly, muchless a man. It is not that, it is a mosquito called in Cumanathe ' Zancudo bobo, ' the striped or domestic mosquito."Beauperthuy, recently as he wrote, then stood almost alonein this opinion. Now we know that yellow fever, in commonwith other specific diseases, is caused by the action of an organizedvirus. The search for a vegetable parasite, bacillus or micro coccus,as above indicated, has been very close and strenuous,but it may now be held that up to the present no bacillus ormicro coccus, well authenticated as capable of causing yellowfever, has been discovered. Latterly a search has been made forprotozoa organisms, organisms similar to those present in theblood of malarious patients and like conditions, or for spirochaetessimilar to those associated with relapsing fever, andBoyce draws attention to the fact that a spirochaete has recentlybeen identified in the tissues taken from cases of yellow fever.It has however been demonstrated that the virus, whatever itmay be, is carried by a species of mosquito; this seems to favourthe protozoan hypothesis, especially as it is found that theStegomyia fasciata, Fab. (or 5. calopus, Meig.), after taking theblood from an infected patient is not infective immediatelybut only becomes capable of infecting by its bite at the endof twelve days. It would appear therefore that residencein this mosquito is necessary for the material to becomefully infective. During this period some special metamorphosismay occur, and metamorphosis essential to thedevelopment of the parasite, or, on the other hand, the timemay be required for it to make its way to some position fromwhich it may emerge from the mosquito when that insect ​“strikes.” In the interval between the bite of an infectedStegomyia and the appearance of the disease (5 or 6 days) theblood of the patient contains a virus which, when taken into themosquito, may develop into the infective material; moreover,this virus persists alive and active for three days after thedisease is fully developed, but at the end of this time it disappears,so far, at any rate, as its infective power is concerned,from the blood, secretions and tissues of the patient. Further,there is no evidence that the infective virus is ever transmitteddirectly from the patient in secretions or in fact in anythingbut blood or blood-serum. The infective material, then, is presentin the human subject for about eight days, during which theblood and even the blood-serum may serve as a vehicle forthe infective agent. If during this period the patient is bittenby the Stegomyia the mosquito cannot distribute the infection fortwelve days, but after this the power of transmitting reinfectionpersists for weeks and even months during cold weather whenthe insect is torpid. As soon, however, as the warm weathercomes round and the mosquito becomes active and again beginsto bite there is evidence that it still maintains its power oftransmitting infection; indeed Boyce states that mosquitosinfected in one year are capable of transmitting infection andstarting a fresh epidemic in the following warm season. Whenit is remembered that a mosquito by a single bite is capable ofsetting up an attack of the disease, we see how important isthis question.

The Stegomyia, known as the domestic or house mosquito,is spoken of as the “Tiger” mosquito, “Scots’ Grey,” or “Blackand White Mosquito,” from the fact that there is “a lyre shapedpattern in white on the back of the thorax, transversewhite bands on the abdomen, and white spots on the sides ofthe thorax; while the legs have white bands with the last hindtarsal joint also white” (Boyce). It is also spoken of as the“cistern mosquito,” as it breeds in the cisterns, barrels, waterbutts, &c., containing the only water-supply of many houses.It may pass through its various stages of development in anysmall vessels, but the larvae are not usually found in naturalcollections of water, such as gutters, pools or wells, ifthe ovipositing insect can gain access to cleaner and purerwater.

The egg of the Stegomyia deposited on the water develops infrom 10 to 20 hours into the larval form, the so-called “wiggle waggle.”It remains in this stage for from i to 8 days, thenbecomes a pupa, and within 48 hours becomes a fully developedmosquito. The larvae can only develop if they are left inwater, though a very small amount of water will serve to keepthem alive. The eggs on the other hand are very resistant,and even when removed from water may continue viable foras long a period as three months. The Stegomyia affects cleanwater-butts and cisterns by preference. Consequently itspresence is not confined to unhygienic districts; they may,however, “seek refuge for breeding purposes in the shallowstreet drains and wells in the town.” The Stegomyia does notannounce its advent and attack by a “ping” such as that madeby the Anopheles, it works perfectly noiselessly and almostceaselessly (from 3 p.m. to early morning) so that any humanbeings in its neighbourhood are not safe from its attacks eitherafternoon or night.

The most important prophylactic measures against the Stegomyiaare ample mosquito nets “with a gauge of eighteenmeshes to the inch” (Boyce), so arranged that the person sleepingmay not come near the net; these nets should be used not onlyat night but at the afternoon siesta. Then the living roomshould be screened against the entrance of these pests, thoroughventilation should be secured; and all pools and stagnant waters,especially in the neighbourhood of houses, should be drained,water-butts and cisterns should be screened and all stagnantwaters oiled with kerosene or petroleum, where drainage isimpossible. What has been done through the carrying outof these and similar measures may be gathered from the recordof the Panama Canal. In 1884 the French Panama CanalCompany, employing from 15,000 to 18,000 men, lost by death60 per 1000 annually (in 1885 over 70 per 1000). In iqo4,when the Americans had taken over the work of construction.Col. W. C. Gorgas undertook to clear the country of the Stegomyia,and within two or three years yellow fever had been eradicated.The death-rate from malaria was also greatly diminished, andby the end of 1907 the death-rate per annum amongst 45,000workers was only 18 per 1000, a lower death-rate than is met within many large English towns. Similar examples might be citedfrom other places, but the above is sufficiently striking to carryconviction that the methods employed in carrying on thewarfare against tropical diseases have been attended withunexampled success. These diseases, at one time so greatlyfeared, are now so much under control that some one has said“ere long we shall be sending our patients to the tropics in searchof a health resort.”

Weil’s disease, a disease which may be considered along withacute yellow atrophy and yellow fever, is one in which there is anacute febrile condition, associated with jaundice, inflammation ofthe kidney and enlargement of the spleen. It appears to be a toxiccondition of a less acute character, however, than the other two,in which the functions and structure of the liver and kidney arespecially interfered with. There is a marked affection of the gastrointestinalsystem, and the nervous system is also in some casesprofoundly involved. Hæmorrhage into the mucous and serousmembranes is a marked feature. The liver cells and kidney epitheliumundergo fatty changes, though in the earlier stages there is acloudy swelling, probably also toxic in origin. Organisms of theProteus group, which appear to have the power, in certain circ*mstances,of forming toxic substances in larger quantities than can bereadily destroyed by the liver, and which then make their appearancein the kidney and spleen, are supposed to be the cause of thiscondition.

Diphtheria.—In regard to no disease has medical opinion undergonegreater modification than it has in respect of diphtheria.Accurately applied, bacteriology has here gained one of itsgreatest triumphs. Not only have the aetiology and diagnosisof this disease been made clear, but knowledge acquired inconnexion with the production of the disease has been apphedto a most successful method of treatment. In 1875 Klebsdescribed a small bacillus with rounded ends, and with, hereand there, small clear unstained spaces in its substance. He,however, also described streptococci as present in certain casesof diphtheria, and concluded that there must be two kinds ofdiphtheria, one associated with each of these organisms. In1883 he again took up the question; and in the following yearLoeffler gave a systematic description of what is now knownas the Klebs-Loeffler bacillus, which was afterwards proved byRoux and Yersin and many other observers to be the causacausans of diphtheria. This bacillus is a slightly-curved rodwith rounded, pointed, or club-shaped end or ends (see PlateII.fig9). It is usually from 1·2 to 5μ or more in length andfrom 0·3 to 0·5μ in breadth; rarely it may be considerablylarger in both dimensions. It is non-motile, and may exhibitgreat variety of form, according to the age of the culture and thenature of the medium upon which it is growing. It is stainedby Gram’s method if the decolorizing process be not too prolonged,and also by Loeffler’s methylene-blue method. Exceptin the very young forms, it is readily recognizable by a seriesof transverse alternate stained and unstained bands. Thebacillus may be wedge-shaped, spindle-shaped, comma-shapedor ovoid. In the shorter forms the polar staining is usually wellmarked; in the longer bacilli, the transverse striation. Verycharacteristic club-shaped forms or branching filaments are metwith in old cultures, or where there is a superabundance of nutritivematerial. In what may be called the handle of the clubthe banded appearance is specially well marked. These specificbacilli are found in large numbers on the surface of the diphtheriticmembrane (PlateII. fig.10), and may easily be detachedfor bacteriological examination. In certain cases they may befound by direct microscopic examination, especially when theyare stained by Gram’s method, but it is far more easy to demonstratetheir presence by the culture method. On Loeffler’sspecial rpedium the bacilli flourish so well at body-temperature—about37°C.—that, like the cholera bacillus, they outgrow theother organisms present, and may be obtained in comparatively ​pure culture. Distinct colonies may often be found as earlyas the eighth or twelfth hour of incubation; in from eighteen toLvventy-four hours they appear as rounded, elevated, moderatelytranslucent, greyish white colonies, with a yellow tinge, thesurface moist and the margins slightly irregular or scalloped.They are thicker and somewhat more opaque in the centre.When the colonies are few and widely separated, each may growto a considerable size, 4 to 5 mm.; but when more numerous andcloser together, they remain small and almost invariably discrete,with distinct intervals between them. In older growths thecentral opacity becomes more marked and the c renal ion moredistinct, the moist, shiny appearance being lost. When thesurface of the serum is dry, the growth, as a rule, does not attainany very large size.

These " pure " colonies, when sown in slightly alkaline broth,grow with great vigour; and if a small amount of such a 48hours' culture be injected under the skin of a guinea-pig, theanimal succumbs, with a marked local reaction and distinct symptomsof to.xic poisoning very similar to those met with in cases ofdiphtheria of thehumansubject. Roux and Yersin demonstratedthat the poison was not contained in the bodies of the bacilli,but that it was formed and thrown out by them from and intothe nutrient medium. Moreover, they could produce all the toxicsymptoms, the local reactions, and even the paralysis whichoften follows the disease in the human subject, by injecting theculture from which they had previously removed the whole ofthe diphtheria bacilli by filtration. This cultivation, then,contains a poisonous material, which, incapable of multiplyingin the tissues, may be given in carefully graduated doses. If,therefore, there is anything in the theory that tissues may begradually "acclimatized" to the poisons of these toxic substances,they saw that it should be possible to prove it in connexionwith this disease. Behring, going still further, found that thetissues so acclimatized have the power of producing a substancecapable of neutralizing the toxin, a substance which, at firstconfined to the cells, when formed in large quantities overflowsinto the fluids of the blood, with which it is distributed throughoutthe body. The bulk of this toxin-neutralizing substanceremains in the blood-serum after separation of the clot. Inproof of this he showed that (1) if this serum be injected intoan animal before it is inoculated with even more than a lethaldose of the diphtheria bacillus or its products, the animalremams perfectly well; (2) a certain quantity of this serum,mixed with diphtheria toxin and injected into a guinea-pig, givesrise to no ill effects; and (3) that even when injected somehours after the bacillus or its toxins, the serum is still capableof neutralizing the action of these substances. In these experimentswe have the germ of the present anti toxic treatmentwhich has so materially diminished the percentage mortalityin diphtheria. This serum may also be used as a prophylacticagent.

The anti toxic serum as now used is prepared by injecting intothe subcutaneous tissues of a horse the products of the diphtheriabacillus. The bacillus, grown in broth containing peptone andblood-serum or blood-plasma, is filtered and heated to a temperatureof 68° or 70° C. for one hour. It then contains only a small amountof active toxin, but injected into the horse it renders that animalhighly insusceptible to the action of strong diphtheria toxins, andeven induces the production of a considerable amount of antitoxin.This production of antito.xin, however, may be accelerated by subsequentrepeated injections, with increasing doses of strongdiphtheria toxin, which may be so powerful that | to J of a drop, oreven less, is a fatal dose for a medium-sized guinea-pig. The anti toxicserum so prepared may contain 200, 400, 600 or even more" units " of antitoxin per c.c. — the unit being that quantity ofantitoxin that will so far neutralize 100 lethal doses (a lethal dose isthe smallest quantity that will kill a 250-gramme guinea-pig on thefifth day) of toxin for a 250-gramme gumea-pig, that the animalcontinues alive on the fifth day from the injection. This, however,is a purely arbitrary standard of neutralizing power, as it is foundthat, owing to the complicated structure of the toxin, the neutralizingand the lethal powers do not always go hand in hand; but as thetoxin used in testing the antitoxin is always compared with theoriginal standard, accurate results are easily obtained.

Diphtheria, though still prevalent in cities, has now lost manyof its terrors. In the large hospitals under the Metropolitan

Asylums Board the death-rate fell from nearly 40% in 1889to under 10% in 1003; and if antitoxin be given as soon as thedisease manifests itself, the mortality is brought down to a veryinsignificant figure. It has been maintained that as soon asantitoxin came into use the number of cases of paralysis increasedrather than diminished. This may be readily understood whenit is borne in mind that many patients recover under the useof antitoxin who would undoubtedly have succumbed in thepre-antitoxin days; and it cannot be too strongly insisted thatalthough the antitoxin introduced neutralizes the free toxinand prevents its further action on the tissues, it cannot entirelyneutralize that which is already acting on the cells, nor can itmake good damage already done before it is injected. Evenallowing that antitoxin is not accountable for the whole of theimprovement in the percentage mortality statistics since 1896, ithas undoubtedly accounted for a very large proportion ofrecoveries. Antitoxin often cuts short functional albuminuria,but it cannot repair damage already done to the renal epitheliumbefore the antitoxin was given. The clinical evidence of thevalue of antitoxin in the relief that it affords to the patientis even more important than that derived from the considerationof statistics.

The diphtheria bacillus or its poison acts locally as a caustic andirritant, and generally or constitutionally as a protoplasmic poison,the most evident lesions produced by it being degeneration of nervesand muscles, and, in acute cases, changes in the walls of the blood vessels.Other organisms, streptococci or staphylococci, whenpresent, may undoubtedly increase the mortality by producingsecondary complications, which end in suppuration. Diphtheriabacilli may also be found in pus, as in the discharges from cases ofotorrhoea.

Tetanus {Lockjaw). — Although tetanus was one of the laterdiseases to which a definite micro-organismal origin could beassigned, it has long been looked upon as a disease typical ofthe "septic" group. In 1885 Nicolaier described an organismmultiplying outside the body and capable of setting up tetanus,but this was only obtained in pure culture by Kitasato, aJapanese, and by the Italians in 1889. It has a very characteristicseries of appearances at different stages of its development.First it grows as long, very slender threads, which rapidly breakup into shorter sections from 4 tos^u in length (see Plate II. fig.11). In these shorter rods spores may appear on the second or upto the seventh day, according to the temperature at which thegrowth occurs. The rods then assume a very characteristic pin ordrumstick form; they are non-motile, are somewhat rounded atthe ends, and at one end the spore, which is of greater diameterthan the rod, causes a very considerable expansion. Beforesporulation the organisms are distinctly motile, occurring in rodsof different lengths, in most cases surrounded by bundles of beautifulflagella, which at a later stage are thrown off, the presenceof flagella corresponding very closely with the " motile " period.The bacillus grows best at the temperature' of the body; itbecomes inactive at 14° C. at the one extreme, and at from 42°to 43° C. at the other; in the latter case involution forms, clubsand branching and degenerated forms, often make their appearance.It is killed by exposure for an hour to a temperature offrom 60° to 65° C; the spores however are very resistant to theaction of heat, as they withstand the temperature of boilingwater for several minutes. The organism has been found ingarden earth, in the excrement of animals — horses — and indust taken from the streets or from living-rooms, especiallywhen it has been allowed to remain at rest for a considerableperiod. It has also been demonstrated in, and separated fromthe pus of wounds (see Plate II. fig. 12) in patients sufferingfrom lockjaw, though it is then invariably found associatedwith the micro-organisms that give rise to suppuration.

It is important to remember that this bacillus is a strict anaerobe,and can only grow when free oxygen has been removed from thecultivation medium. It may be cultivated in gelatine to which hasbeen added from 2 to 3% of grape-sugar, when, along the line of thestab culture, it forms a delicate growth, almost like a fir-tree, thetip of which never comes quite to the surface of the gelatine. Themost luxuriant growth — evidenced by the longest branches — occursin the depth of the gelatine away from free oxygen. After a time the ​gelatine becomes sticky, and then undergoes slow liquefaction, thegrowth sinking and leaving the upper layers comparatively clear.This organism is not an obligate parasite, but a facultative; it maygrow outside the body and remain alive for long periods.

Lockjaw is most common amongst agricultural labourers,gardeners, soldiers on campaign, in those who go about withbare feet, or who, like young children, are liable to get theirknees or hands accidentally wounded by rough contact withthe ground. Anything which devitaUzes the tissues — such ascold, bruising, malnutrition, the action of other organisms andtheir products — may all be predisposing factors, in so far asthey place the tissue at a disadvantage and allow of the multiplicationand development of the specific bacillus of tetanus. Inorder to produce the disease, it is not sufficient merely to inoculatetetanus bacQli, especially where resistant animals areconcerned: they must be injected along with some of theirtoxins or with other organisms, the presence of which seems toincrease the power of, or assist, the tetanus organism, by divertingthe activity of the cells and so allowing the bacUlus todevelop. The poison formed by this organism resembles theenzymes and diphtheria poison, in that it is destroyed at atemperature of 65° C. in about five minutes, and even at thetemperature of the body soon loses its strength, although, whenkept on ice and protected from the action of light, it retains itsspecific properties for months. Though slowly formed, it istremendously potent, jsuJfisu part of a drop (the five-millionthpart of a c.c.) of the broth in which an active culture has beenallowed to grow for three weeks or a month being sufficient tokill a mouse in twenty-four hours, ^h of a drop killing a rabbit,T>'.T a dog, or -^ of a drop a fowl or a pigeon; it is from 100 to 400times as active as strychnine, and 400 times as poisonous asatropine. It has been observed that, quite apart from size,animals exhibit different degrees of susceptibility. Frogs keptat their ordinary temperature are exceedingly insusceptible,but when they are kept warm it is possible to tetanize them,though only after a somewhat prolonged incubation period, suchas is met with in very chronic cases of tetanus in the humansubject. In experimentally-produced tetanus the spasmsusually commence and are most pronounced in the muscles nearthe site of inoculation. It was at one time supposed that thiswas because the poison acted directly upon the nerve terminations,or possibly upon the muscles; but as it is now known thatit acts directly on the cells of the central nervous system, itmay, as in the case of rabies, find its way along the lymphaticchannels of the nerves to those points of the central nervoussystem with which these nerves are directly connected, spasmsoccurring in the course of the muscular distribution of the nervesthat receive their impulses from the cells of that area. As theamount of toxin introduced may be contained in a very smallquantity of fluid and still be very dilute, the local reaction of theconnective-tissue cells may be exceedingly slight; consequentlya very small wound may allow of the introduction of a strongpoisonous dose. Many of the cases of so-called idiopathictetanus are only idiopathic because the wound is trifling incharacter, and, unless suppuration has taken place, has healedrapidly after the poison has been introduced. In tetanus, asin diphtheria, the organisms producing the poison, Lf found inthe body at all, are developed only at the seat of inoculation;they do not make their way into the surrounding tissues. Inthis we have an explanation of the fact that all the earlierexperiments with the blood from tetanus patients gave absolutelynegative results. It is sometimes stated that the productionof tetanus toxin in a wound soon ceases, owing to the arrest ofthe development of the bacillus, even in cases that ultimatelysuccumb to the disease. Roux and Vaillard, however, maintainthat no case of tetanus can be treated with any prospect of successunless the focus into which the bacilli have been introduced isfreely removed. The anti tetanus serum was the first anti toxicserum produced. It is found, however, that though the antitetanicserum is capable of acting as a prophylactic, and ofpreventing the appearance of tetanic symptoms in animals thatare afterwards, or simultaneously, injected with tetanus toxin,

it does not give very satisfactory results when it is injected aftertetanic symptoms have made their appearance. It wouldappear that in such cases the tetanus poison has become toofirmly bound up with the protoplasm of the nerve cells, and hasalready done a considerable amount of damage.

(b) More Chronic Infective Diseases {Tissue Parasites).

Tuberculosis. — In no quarter of the field of preventive medicinehave more important results accrued from the discovery of a.specific infective organism than in the case of Koch's demonstrationand separation in pure culture of the tubercle bacillusand the association of this bacillus with the transmission oftuberculosis. In connexion with diagnosis — both directly fromobservation of the organism in the sputum and urine of tuberculouspatients, and indirectly through the tuberculin test,especially on animals — this discovery has been of very greatimportance; and through a study of the life-history of the bacillusand its relation to animal tissues much has been learned as tothe prevention of tuberculosis, and something even as tomethods of treatment. One of the great difficulties met within the earlier periods of the study of this organism was its slow,though persistent, growth. At first cultivations in fluid mediawere not kept sufficiently long under observation to allow of itsgrowth; it was exceedingly difficult to obtain pure cultures, andthen to keep them, and in impure cultures the tubercle bacilliwere rapidly overgrown. Taken directly from the body, theydo not grow on most of the ordinary media, and it was onlywhen Koch used solidified blood-serum that he succeeded inobtaining pure cultures. Though they may now be demonstratedby what appear to be very simple methods, before these methodswere devised it was practically impossible to obtain any satisfactoryresults.

The principle involved in the staining of the tubercle bacillusis that when once it has taken up fuchsin, or gentian violet, itretains the stain much more firmly than do most organisms andtissues, so that if a specimen be thoroughly stained with fuchsinand then decolonized by a mineral acid — 25% of sulphuric acid,say — although the colour is washed out of the tissues and mostother organisms, the tubercle bacilli retain it; and even afterthe section has been stained with methylene-blue, to bring theother tissues and organisms into view, these baciUi still remainbright red, and stand out prominently on a blue background.If a small fragment of tuberculous tissue be pounded in a sterilemortar and smeared over the surface of inspissated blood-serumsolidified at a comparatively low temperature, and if evaporationbe prevented, dry scaly growths make their appearance at theend of some fourteen days. If these be reinoculated throughseveral generations, they ultimately assume a more saprophyticcharacter, and will grow in broth containing 5% of glycerin, oron a peptone beef-agar to which a similar quantity of glycerinhas been added. On these media the tubercle bacillus growsmore luxuriantly, though after a time its virulence appears to bediminished. On blood-serum its virulence is preserved for longperiods if successive cultivations be made. It occurs in thetissues or in cultivations as a dehcate rod or thread 1-5 to 3'5ft inlength and about 0-2 to o-s;u in thickness (see Plate II., fig. 15).It is usually slightly curved, and two rods may be arranged end toend at an open angle. There is some doubt as to whether tuberclebacilli contain spores, but little masses of deeply-stained protoplasmcan be seen, alternating with clear spaces within thesheath; these clear spaces have been held to be spores. Thisorganism is found in the lungs and sputum in various forms ofconsumption; it is met with in tuberculous ulcers of the intestine,in the lymph spaces around the vessels in tuberciflous meningitis,in tuberculous nodules in all parts of the body, and in tuberculousdisease of the skin — lupus. It is found also in the tuberculouslesions of animals; in the throat-glands, tonsils, spleen and bonesof the pig; in the spleen of the horse; and in the lungs and pleuraof the cow. Tuberculosis may be produced artificially by injectingthe tubercle bacillus into animals, some being much moresusceptible than others. Milk drawn from an udder in which thereare breaking-down tuberculous foci, may contain an enormous ​number of active tubercle bacilli; and pigs fed upon thismilk develop a typical tuberculosis, commencing in the glandsof the throat, which can be traced from point to point, with theutmost precision. It must be assumed that what takes placein the pig may also take place in the human subject; and asufficient number of cases are now on record to show that theswallowing of tuberculous material is a cause of tuberculosis,especially amongst children and adolescents. Inhaled tuberclebacilli from the recently-dried sputum of phthisical patients, likemilk derived from tuberculous udders, may set up tuberculosisof the lungs or of the alimentary tract, especially when the epitheliallayer is unhealthy or imperfect. The two main causes ofthe prevalence of tuberculosis in the human subject are: (i)tubercle bacilli may become so modified that they can flourishsaprophytic ally; as yet it has not been possible to trace thee.act conditions under which they live, but we are graduallycoming to recognize that, although when they come from thebody they are almost obligate parasites, they may graduallyacquire saprophytic characters. (2) Many of the domesticanimals are readily infected with tuberculosis, and in turn maybecome additional centres from which infection may radiate.

Koch's tuberculin has been of inestimable value in the earlydiagnosis of tuberculosis, especially in animals.

Tuberculin, from which the tuberculin test derives its name,consists of the products of the tubercle bacillus when grown for amonth or si.x weeks in peptone meat-broth to which a small proportion,say 5 or 6%, of glycerin has been added. The tubercle bacilliare then killed at boiling-temperature, and are partially removed bysedimentation, and completely by filtration through a Berkfcldor Pasteur-Chamberland filter. If a large dose of this filtered fluidbe injected under the skin of a healthy man or brute, it is possibleto produce some local swelling and to induce a rise of temperature;but in a similar patient suffering from tuberculosis a very muchsmaller dose (one which does not affect the healthy individual inthe slightest degree) is sufficient to bring about the characteristicswelling and rise of temperature. To obtain trustworthy resultsthe dosage must always be carefully attended to. The reaction isonly obtained under certain well-defined conditions. Drivenanimals seldom, if ever, react properly. Cattle to be tested shouldbe allowed to remain at rest for some time; they should be wellfed, and be carefully protected from cold or draughts. After aninjection of tuberculin into the subcutaneous tissues (usually infront of the shoulder or on the chest-wall) they should be kept underthe same conditions and should be watched very carefully; the temperatureshould be taken at the sixth hour, and every three hoursafterwards up to the twenty-first or even twenty-fourth hour. Ifduring this time the temperature rises to 104° F., there can be littledoubt that the animal is tuberculous; but if it remains under 103°,the animal must be considered free from disease: if the temperatureremains between these points the case is a doubtful one, and, accordingto Sir John M'Fadyean, should be retested at the end of a month.It is interesting to note that the test is not trustworthy in the caseof animals in which tuberculosis is far advanced, especially when thetemperature is already high — 103° F. In such cases, however, itis an easy matter to diagnose the disease by the ordinary clinicalmethods. At first objections were raised to this test on two grounds:(l) that mistakes in diagnosis are sometimes made; (2) that tubercuUnmay affect the milk of healthy animals into which it is injected.As the methods of using the tuberculin have been perfected, and asthe conditions under which the reaction is obtained have becomebetter known, mistakes have rapidly become fewer; whilst it hasbeen amply proved that tuberculin has not the slightest deterioratingeffect on the quality of the milk.

Tuberculin and similar substances are sometimes used as specificreagents in the diagnosis of tuberculosis in the human subject. Whensmall quantities of old tuberculin are injected subcutaneously into atuberculous patient in whom, however, no tubercle bacilli may bedemonstrable, the temperature begins to rise in six or eight hoursand continues to rise for twelve hours or, in rare cases, for an evenlonger period, a rise of a single degree being considered sufficient toindicate the presence of the disease. Along with this there is usuallysome swelling and tenderness, with perhaps redness at the seat ofinjection, whilst there is also some evidence of a vascular congestionin the neighbourhood of any tuberculous lesion. A second methodof applying tuberculin as a diagnostic reagent is that of Pirquet,who, after diluting old tub'erculin with two parts of normal salinesolution and one part of 5% carbolic glycerin, places a drop of themixture on the skin and scrapes away the epidermis in lines with" a small dental burr." The skin is similarly treated with normalsaline some 2 or 3 in. away from that at which the tuberculin is used.In the tuberculin area a little papule develops; this may becomea vesicle, surrounded by slight redness and swelling (in the " saline "area nothing of the kind appears). The swelling begins about sixhours after the scarification is made and continues to increase for

24 hours. Reactions, however, are obtained by this test in patientswho are not suffering from any active tubercular lesion, whilst on theother hand in certain cases it fails to indicate the presence of tuberclewhen it is undoubtedly there. Calmette's or Wolff-Eisner's ophthalmicreaction test, a third method of using tuberculin, consists indropping a weak solution of tuberculin into the conjunctiva sac ofone eye; this is followed by a mild attack of conjunctivitis orinflammation of the eye in the tuberculous patient, whilst in thenormal patient no such inflammation should appear. Although thistest appears to be of considerable value, it fails to give any informationin cases of advanced tuberculosis, of general miliary tuberculosisand of tuberculous meningitis. It certainly possesses onegreat advantage over the others — it does not give any reaction inthe presence of dormant tubercle in persons clinically sound andhealthy. The inflammation of the eye may, however, be so acute,especially where strong solutions of tuberculin are used, thatconsiderable damage may be done, more especially should there beany dormant disease of the eye. It must be remembered that in allthese tests the exhibition of tuberculin increases for a time the sensitivenessof the patient each time it is administered. It sets up anegative phase, as already described, and renders the patient moresusceptible to the action of a fresh dose. It is evident, therefore,that the carefid worker wishing to oljtain minimal effects will givesmall doses and gradually repeat these as he may find necessary.

In 1890 Koch, whose brilliant researches on tuberculosishad opened up a new field of investigation and had inspired newhope in the breasts of patients and physicians alike, followed uphis method of diagnosis with a method of vaccination with theproducts of the tubercle bacillus separated from glycerinatedbroth culture after the vitality of the bacilli had been destroyed.As is frequently the case with new remedies, this was used soindiscriminately that it soon fell into disrepute. The resultsin certain cases, however, were so successful that careful investigationsinto the character and action of tuberculin and into theconditions under which it may be used with advantage wereundertaken. Tuberculins composed of the triturated bodies oftubercle bacilli, of the external secretions of these bacilli, and oftheir various constituents in different combinations, were experimentedwith, but at the present time Koch's two tuberculinsespeciallyhis new tuberculin — hold the field. The " oldtubercuhn " consists of the glycerin broth culture of the tuberclebacilli mentioned above. The new tuberculin consists of thecentrifugalized deposit from a saline solution of the extract ofthe triturated dead tubercle bacilli; this is stored in small tubes,each containing two milligrammes of solid substance. This isdiluted with distilled water containing 20% of glycerin, greatcare being taken to maintain the sterility of the solution. Thedose is usually from -j^^u to T()W oi a milligramme for anadult, increasing to ^J(j^; according to Sir A. Wright it shouldnot go beyond this.

Perhaps no one has done more to rehabilitate the tuberculintreatment than Sir Almroth Wright, who after a long series ofexperiments devised what he called the tuberculo-opsonic index,about which a few words may be of interest. It is well-knownthat certain cells in the human blood have the power of takingbacteria into their substance and there digesting them. This, theso-called " phagocytic power " of Metchnikoff, was found to varysomewhat under different conditions, and Wright set himself todetermine, if possible, what were the factors that modified thisvariability. He found that the white blood corpuscles, the polymorphonuclearcells, whether from healthy or tuberculous patients,always showed practically the same phagocytic activity whenmixed with a fine emulsion of tubercle bacilli and the serum froma healthy patient. If, however, corpuscles from the same individuals,whether healthy or tuberculous, were allowed to act upon the bacilliin the presence of seruin drawn from a tuberculous patient, one ofthree things might happen: (i) the bacilli might be taken up insmaller numbers than in the above series of experiments; (2) theymight be taken up in larger numbers; or (3) they might be takenup in what might bo called normal numbers. In (i) and (2) Wrightholds there is evidence of a tuberculous condition, in (3) of coursethe evidence is negative. He found, however, that when a doseof tuberculin was injected into a tuberculous patient there wasa distinct fall in the number of tubercle bacilli taken up by theleukocytes treated with the serum of the patient. This conditionWright speaks of as the " negative phase." Increased phagocyticactivity of the cells is associated with what is spoken of as the positivephase. The theory is that the blood serum has the power ofpreparing bacteria to be eaten by the phagocytes in the samesense that boiling, say, prepares food for ready digestion by thehuman subject, and W'right applied the term opsonin to the unknownconstituent or complex of constituents of the serum that ​exerts this action upon the bacteria. The opsonic index is obtainedby comparing the average number of bacilli taken up by, say,100 leukocytes, to which the serum from a tuberculous patienthas been added, with the number of bacteria taken up by ajhundredsimilar corpuscles to which normal serum has been added, theratio between the two giving the opsonic index. Wright maintainsthat after the injection of small doses of tuberculin duringa negative phase which first appears, i.e. whilst there is a fall inthe number of bacilli taken up by the leukocytes of the blood, thepatient is more susceptible than before to the attacks of the tuberclebacillus. Following this, however, there is a gradual rise in theopsonic index until it passes the normal and the patient entersa positive phase, during which the susceptibility to the attacksof the tubercle bacillus is considerably diminished. When theeffects of this dose are passing off a fresh injection should be made;this again induces a negative phase, but one that should not be somarked as in the first instance, whilst the positive phase whichsucceeds should be still more marked than that first obtained. Ifthis can be repeated systematically and regularly the patientshould begin, and continue, to improve. The difficulties involvedin the determination of the opsonic index are, however, exceedinglygreat, and the personal factor enters so largely into the questionthat some observers are very doubtful as to the practical utilityof this method. In Wright's hands, however, and in the hands ofthose who work with him, very satisfactory results are obtained.The tuberculin treatment, fortunately, does not stand or fall bythe success of the opsonic index determination, especially as mostvaluable information as to the course of the disease and the effectsof the tuberculin may be obtained by a study of the daily temperaturechart and of the general condition of the patient.

Tuberculin should not be injected more frequently than aboutonce in 10 or 14 days, and it is well not to increase the dose toorapidly. Wherever the temperature continues high, even a degreebeyond normal, and where the pulse is over 100, it is not wise to givetuberculin, nor does it seem to be of any great value where thedisease is making rapid headway or has become generalized,especially where there is meningitis or bleeding from the lungs.

It is interesting to note, in connexion with the diagnosticsignificance of the opsonic index, that in non-tuberculous subjectsthe administration of a small dose of tuberculin is followed by nonegative phase such as is met with in the tuberculous subject.The phagocytic power of the white blood corpuscles is determinedby noting the number of organisms taken up by the leukocytes whenmixed with equal parts of a standard emulsion of tubercle bacilliand blood serum incubated in fine glass tubes for 15 minutes ata temperature of 37° C. If the period of incubation is much shorterthan this the results are irregular, whilst if the period is longer somany organisms are taken up that it becomes impossible to differentiatetwo sets of sera.

As an example we might adduce the following. Taking a tuberculouspatient's serum + leukocytes + tubercle bacilli, let us say wehave an average of i-S bacilli per leukocyte in 50 or 100 leukocytescounted; with normal serum -f- corpuscles -t- tubercle bacilli theaverage number of bacilli per leukocyte in the same number ofcells counted is 3. From these figures the opsonic index obtainedis 1-8 -j- 3 = 0-6 = opsonic index.

Leprosy. — Armauer Hansen in 1871, and Neisser in 1881,described a " leprosy bacillus " corresponding in size and incertain points of staining reaction to the tubercle bacillus, andit is now generally accepted that this bacillus is the direct andspecific causal agent of leprosy. The discovery of this organismpaved the way for the proof that the tubercular and anaestheticforms of leprosy are essentially the same disease, or rather are themanifestations of the action of a common organism attackingdifferent series of tissues.

To demonstrate the presence of the leprosy bacillus, tie anindiarubber ring firmly around the base of one of the leprosytubercles. As soon as the blood is driven out, leaving thenodule pale, make a puncture with the point of a sharp knife.From this puncture a clear fluid exudes; this, dried on a cover glass,stained with carbol-fuchsin, and rapidly decolonized with aweak mineral acid, shows bacilli stained red and very liketubercle bacilli; they differ from that organism, however, inthat they are somewhat shorter, and that if the acid be too strongor be allowed to act on them for too long a time, the colour isdischarged from them much more readily. These organisms,which are from 4 to 6/i in length and o-^n in breadth, are as a rulemore rigid and more pointed than are the tubercle bacilli (seePlate II., fig. 16). It is doubtful whether they form spores.They are found in large numbers lying embedded in a kind ofgelatinous substance in the lymphatics of the skin, in certain cellsof which they appear to be taken up.

It is curious that these bacilli affect specially the skin and

nerves, but rarely the lungs and serous membranes, thus being insharp contrast to the tubercle bacillus, which affects the lattervery frequently and the former more rarely. They are seldomfound in the blood, though they have been described as occuringthere in the later stages of the disease. It is stated that leprosyhas been inoculated directly into the human subject, the patientdying some five or six years after inoculation; but up to the presentno pure culture of the leprosy bacillus has been obtained; ithas therefore been impossible to produce the disease by theinoculation of the bacillus only. What evidence we have at ourdisposal, however, is all in favour of the transmissibility of thedisease from patient to patient and through the agency of theleprosy bacillus. None of the numerous non-bacillary theoriesof leprosy account at all satisfactorily for this transmissibilityof the disease, for its progressive nature, and for the peculiarseries of histological changes that are met with in various partsand organs of the leprous body. Leprosy occurs in all climates.It is found where no fish diet can be obtained, and where pork andrice are never used, though to these substances has been assignedthe power of giving rise to the disease. Locality appears toinfluence it but little, and with improved sanitation and increasedcleanliness it is being graduaUy eradicated. The only factorthat is common in all forms of leprosy, and is met with in everycase, is the specific baciflus; and in spite of the fact that it hasyet been found impossible to trace the method of transmission,we must from what is known of the presence and action of bacilli,in other diseases, especially in tuberculosis, assign to the leprosybacillus the role of leprosy-producer, until much stronger evidencethan has yet been obtained can be brought forward in favour ofany of the numerous other causes that have been assigned. Twocases are recorded in which people have contracted leprosy frompricking their fingers with needles whilst sewing a leper's clothes;and a man who had never been out of Dublin is said to havecontracted the disease by sleeping with his brother, a soldier whohad returned from India suffering from leprosy.

Glanders. — Farcy in the human subject resembles the samedisease experimentally produced in animals with material froma slandered animal, and as there is no pathological distinctionbetween the two, from the etiological standpoint, they may beconsidered together. If the pus from a glanders abscess bemixed with a little sterile saline solution and spread over thecut surface of a boiled potato kept at the body-temperature,bright yellow or honey-coloured, thick, moist-looking coloniesgrow very rapidly and luxuriantly. These colonies graduallybecome darker in colour, until they assume a cafe-au-lait, or evena chocolate, tint. On examining one of them microscopically, itis found to be made up of bacilli 2 to 5/x long and 1 to |- of theirown length broad (see Plate I., fig. 2 and fig. 6). The bacillus isusually straight or slightly curved and rounded at one end; itappears to be non-motile. As first pointed out by Loeffler andSchiitz, when a portion of a culture is inoculated subcutaneously,typical farcy, with the acute septicaemia or blood-poisoning socharacteristic of certain cases of glanders and farcy, is the result.The human subject is usually inoculated through wounds orscratches, or through the application of the nasal discharge of aslandered animal to the mucous membrane of the nose or mouth.Man is not specially susceptible to the glanders virus, but as hefrequently comes into contact with slandered horses a considerablenumber of cases of farcy in man are met with, althoughamongst knackers it is a comparatively rare disease. Cattlenever contract it by the ordinary channels, and even when inoculatedexhibit nothing more than localized ulceration. The goatappears to occupy an intermediate position between cattle andthe horse in this respect; in sheep, which are fairly susceptiblethe disease runs its course slowly, and appears to resemblechronic farcy in man. In rabbits and the dog the disease runsa very slow and modified course. Although field-mice are extraordinarilysusceptible, white mice and house mice, unlesspreviously fed on sugar or with phloridzin, are unaffected byinoculation of the glanders bacillus. The pigeon is the onlybird in which glanders has been produced. Lions and tigers aresaid to contract the disease, and to take it in a very severe and ​rapidly fatal form. The glanders organism soon loses itsvirulence and even its vitality. Dry, it dies in about tendays; placed in distilled water, in about five days; but keptmoist, or on culture media, it retains its vitality for about amonth, although its activity soon becomes considerably lessened.These bacilli are readily killed at a temperature of 55° C; theycan pass through the kidneys, even when there is no lesion to bemade out either with the naked eye or under the microscope(Sherrington and Bonome).

The glanders bacillus grows best in the presence of oxygen,but it may grow anaerobically; it then appears to have the powerof forming toxin, either more in quantity or of greater activitythan when it has access to a free supply of oxygen. This poison(mallein) is used for the purpose of diagnosing the presence ofglanders. A cultivation is made in peptonized bouillon to whicha small portion of glycerin has been added. The bacillus is allowedto grow and multiply at the temperature of the body for a monthor six weeks; the organisms are then killed by heat and 0-5%carbolic acid is added. The cultivation is then filtered through aporcelain filter in order to remove the bodies of the bacilli, andthe resulting fluid, clear and amber-coloured, should have thepower, when injected in quantities of i c.c, of giving the specificreaction in an animal suffering from glanders; in a healthy animal6 c.c. will give no reaction. The suspected animal should bekept at rest and in a warm stable for twenty-four to forty-eighthours before the test is applied. The temperature should benormal, as no proper reaction is obtained in an animal in whichthe temperature is high. This reaction, which is a very definiteone, consists in a rise of temperature of from 2° to 4° F., and theappearance of a swelling of from 3 to 4 iw. in diameter andfrom I to 15 in. in height, before the sixteenth or eighteenthhour; this swelling should continue to increase for some hours.It has been suggested that the injection of -j"^- to ^3- c.c. ofmallein, at 'intervals of two or three days, may be used withadvantage in the treatment of glanders. Glandered horses seemto improve under this treatment, and then certainly do notreact even to much larger doses of mallein. The mallein testhas revealed the fact that glanders is a far more common andmore widespread disease than was at one time supposed.

II. — To Higher Vegetable Parasites

Actinomycosis. — This disease is very prevalent in certainlow-lying districts, especially amongst cattle, giving rise to thecondition known as " sarcoma, " " wooden tongue, " " wens, "" bony growths on the jaw, " &c. It is characterized by thepresence of a fungus, which, at first growing in the form of longslender threads that may be broken up into short rods and cocci,ultimately, as the result of a degenerative process, assumes theform of a " ray-fungus, " in which a series of club-like rays arearranged around a common centre (see Plate I., fig. 8). It isprobably a stTeptothrix—Streptotlirix Forsteri. Numerouscases have been observed in the human subject. Suppurationand the formation of fistulous openings, surrounded by exuberantgranulation's, " proud flesh, " usually supervene where it isgrowing and multiplying in the tissues of the human body, andin the pus discharged are yellowish green or reddish brown points,each made up of a central irregular mycelium composed of shortrods and spores, along with the clubs already mentioned. Themycelial threads may reach a considerable length (20 to loo/i);some of them become thicker, and are thus differentiated fromthe rest; the peripheral club is the result of swelling of the sheath;the filaments nearer the centre of the mycelial mass containspores, which measure from i to 2jx in diameter. This fungusappears to lead a saprophytic existence, but it has the power ofliving in the tissues of the animal body, to which it makes itsway through or around carious or loose teeth, or through abrasionsof the tongue or tonsils. After the above positions, theabdomen, especially near the vermiform appendix, is a specialseat of election, or in some cases the thorax, the lesions beingtraceable downwards from the neck. Any of the abdominalor thoracic organs may thus be affected. The process spreadssomewhat slowly, but once started may extend in any direction,

its track being marked by the formation of a large quantity offibrous tissue, often around a long fistula. In the more recentgrowths, and in solid organs, cavities of some size, containinga soft semi-purulent cheesy-looking material, may be found,this mass in some cases being surrounded by dense fibroustissue. When once a sinus is formed the diagnosis is easy, butbefore this the disease, where tumours of considerable size arerapidly formed, may readily be mistaken for sarcoma, or whenthe lungs are affected, for tuberculosis, especially as bronchitisand pleuritic effusion are frequently associated with bothactinomycosis and tuberculosis.

Mycetoma, the Madura foot of India, is a disease very similarto actinomycosis, and, like that disease, is produced by a somewhatcharacteristic streptolhrix. It usually attacks the feet andlegs, however, and appears to be the result of infection throughinjured tissues. Under certain conditions and in long-standingcases the fungus appears to become pigmented (black) anddegenerated.

Other forms of fungus disease or Mycoses are described. Aspergillosis,or pigeon-breeders' disease, is the result of infection withthe Aspergillus fumigalus. Certain tumours appear to be the resultof the action of a yeast, Blastomycosis or Saccharomycosis. Thespores of the Pcncillium glauciim, and of some of the Mucors, arealso said to have the power of setting up irritation, which mayend in the formation of a so-called granuloma or granulation tissuetumour. These, however, are comparatively rare.

B. — Diseases due to Animal Parasites.

I.— To Protozoa

Malaria. — Following Laveran's discovery, in 1880, of aparasite in the blood of patients suffering from malaria, ourknowledge of this and similar diseases has increased by leapsand bounds, and most important questions concerning tropicaldiseases have now been cleared up. Numerous observationshave been carried out with the object of determining the parasiticforms found in different forms of malaria — the tertian, quartan,and aestivo-autumnal fever — in each of which, in the red bloodcorpuscles, a series of developmental stages of the parasite froma small pale translucent amoebiform body may be followed.This small body first becomes lobulated, nucleated and pigmented;it then, after assuming a more or less marked rosette shapewith a deeply pigmented centre, breaks up into a seriesof small, rounded, hyaline masses of protoplasm, each of whichhas a central bright point. The number of these, contained in akind of capsule, varies from 8 to 10 in the quartan, and from 1 2 to20 in the tertian and aestivo-autumnal forms. There are certaindifferences in the arrangement of the pigment, which is presentin larger quantities and distributed over a wider area in thesomewhat larger parasites that are found in the tertian andquartan fevers. In the parasite of the aestivo-autumnal feverthe pigment is usually found in minute dots, dividing near thepole at the point of division of the organism, along with it in theearlier stages (see Plate I., fig. 5). Here, too, the rosette formis not so distinct as in the parasite of tertian fever, and in thelatter is not so distinct as in the quartan parasites. Thesedividing forms make their appearance immediately before theonset of a malarial paroxysm, and their presence is diagnostic.The process of division goes on especially in the blood-formingorgans, and is therefore met with more frequently in the spleenand in bone-marrow than in any other situation. The parasites,at certain stages of their development, may escape from the redblood corpuscles, in which case (especially when exposed tothe air for a few minutes) they send out long processes of protoplasmand become very active, moving about in the plasma andbetween the corpuscles, sometimes losing their processes, which,however, continue in active movement. In the aestivo-autumnalfever curious crescent-shaped or ovoid bodies were amongstthe first of the parasitic organisms described as occurring in theblood, in the red corpuscles of which they develop. Alansonmaintains that from these arise the flagellate forms, all of which,he thinks, are developed in order that the life of the malarialparasite may be continued outside the human body. It isprobable that most of the pigment found in the organs taken from ​malarial patients is derived from red blood corpuscles brokendown by the malarial parasites; many of these, in turn, aredevoured by leukocytes, which in malarial blood are usuallygreatly increased in number, and frequently contain much pigment,which they have obtained either directly from the fluidplasma or from the pigmented parasitic organism. The workrecently carried out by Bruce on the tsetse-fly parasite, by A. J.Smith on Texas fever, and by W. S. Thayer and Hewitson on theblood parasites of birds, has opened up the way for the furtherstudy of the malarial parasites outside the human body. Therecan be no doubt as to the close relation of the multiplication andsporulation of the malarial parasite with the ague paroxysm:the anaemia results from the breaking down of blood corpuscles.Toxic substances are present in the blood during the settingfree of the spores; of this we have proof in the increased toxicityof the urine during the paroxysmal stages of the disease; moreovernecrotic areas, similar to those found in acute toxic feversproduced by other micro-organisms, are met with. It is well tobear in mind that the accumulation of debris of parasites andcorpuscles in the capillaries may be an additional factor in thisnecrosis, especially when to this is added the impairment ofnutrition necessarily involved by the impoverished condition ofthe malarial blood. It is interesting to note that, although,as pointed out by NuttaU, the Italian and Tirolese peasantryhave long been firmly of the opinion that malaria is transmittedthrough the mosquito, and although the American, Dr JosiahNott, in 1848 referred to malaria as if the mosquito theory hadalready been advanced, httle attention was given to thisquestion by most observers. StiU earlier, Rasori (in 1846) hadstated that " for many years I have held the opinion that intermittentfevers are produced by parasites, which renew theparoxysm by the act of their reproduction, which recurs more orless rapidly according to the variety of the species"; and thisappears to be the first well-authenticated reference to this subject.Nuttall, who gives an excellent summary of the literature on themosquito hypothesis of malaria, assigns to King the honour ofa*gain drawing attention to this question. Laveran in 1891,Koch in 1892, Manson in 1894, Bignami and Mendini in 1896,and Grassi in 1898, all turned their attention to this hypothesis.Manson, basing his hypothesis upon what he had observed asregards the transmission of Filaria by the mosquito, suggested aseries of experiments to Major Ronald Ross. These were carriedout in 1895, when it was found that in mosquitoes that had takenup blood containing amoeboid parasites, crescents, which werefirst described as cells, appeared in the stomach-wall after fouror five days; these contained a number of stationary vacuolesand pigment granules, ten to twenty in number, bunched togetheror distributed in lines. Grassi, Bignami and Bastianelliconfirm and supplement Ross's observations; they find thatAnopheles daviger, taking the blood from a patient sufferingfrom malaria, soon develops haemosporidia in the intestine.These parasites are then found between the muscular fibres ofthe stomach; they increase in size, become pigmented, and moreand more vacuolated, until they project into the body-cavity.On the sixth day these large spheres contain an enormousnumber of minute bodies, refractive droplets like fat, and adiminishing amount of pigment. On the seventh day numerousfilaments, arranged in rows around several foci, are seen. Theyare very delicate, are stained with difficulty, and appear to beperfectly independent of each other, though grouped within acapsule. After the capsule has ruptured, these thread-like" sporozooites, " escaping into the body-cavity, gradually maketheir way to and accumulate in the cells or tubules of the salivaryglands, whence their passage through the proboscis into thehuman blood is easily understood.

Thus two phases or cycles of existence have been demonstrated— one within the human body, the second in the mosquito.Development That within the human body appears to be capableof the of going on almost indefinitely as long as the patient

Malarial lives, but that in the mosquito appears to be anarasite. offshoot or an intermediate stage. The minutespecks of protoplasm, the amoebulae, which have already been

described as occurring in the red blood corpuscles of the higheranimals, increase in size, take up blood pigment, probably fromthe red corpuscles, and then become developed into sporocytesor gametocytes. The sporocyte is the form which, remainingin the body, ultimately breaks up, as already seen, into a seriesof minute spores or amoebulae, which in turn go through the samecycle again, increasing in size and forming spores, and so onindefinitely. Gametocytes (the true sexual form) are in certainspecies, to outward appearance, very similar to the sporocyte,but in others they assume the crescentic shape, and can thus berecognized. The male cell resembles the female cell very closely,except that the protoplasm is hyaline and hom*ogeneous-looking,whilst that of the female cell is granular. It has already beennoted that when the blood is withdrawn from the body certainof the malarial parasites become flagellated. These flageflamay be looked upon as sperm elements, which, forming in themale gametocyte, are extruded from that cell, and, once set free,seek out the granular female gametocytes. A single flagellumbecomes attached to a small projection that appears on the femalecell; it then makes its way into the protoplasm of the femalecell, in which rapid streaming movements are then developed.In certain species the female ceU is somewhat elongated, and maybe peculiarly constricted. It becomes motile, and appears tohave the power of piercing the tissues. In this way the first stagesof development in the mosquito are passed. The gametocytes,taken along with the blood into the stomach of this insect,pass through the various phases above mentioned, thoughthe zygote form of the human malarial parasite has not yet beentraced. In the blood of a patient bitten by an infected mosquitothe ordinary malarial parasite may be demonstrated withoutany difficulty at the end of a week or ten days, and the cyclerecommences.

This theory, now no longer a hypothesis, in which themosquito acts as an intermediary host for one stage of theparasite and transmits the parasite to man, affords an explanationof many apparently anomalous conditions associatedwith the transmission of malaria, whilst it harmonizes withmany facts which, though frequently observed, were verydifficult of explanation. Malaria was supposed to be associatedwith watery exhalations and with the fall of dew, buta wall or a row of trees was seemingly quite sufficient toprevent the passage of infection. It was met with on wetsoils, on broken ground, in marshes, swamps and jungles;on the other hand, it was supposed to be due to the poisonousexhalations from rocks. All this is now explained by the factthat these are the positions in which mosquitoes occur: whereverthere are stagnant pools, even of a temporary nature, mosquitoesmay breed. It has been observed that although themalarial "miasma" never produces any ill effects in patientsliving at more than a few feet from the surface of the ground,malaria may be found at a height of from 7000 to 9000 ft. abovesea -level; and the fact that a belt of trees or a wall will stop thepassage of the poison is readily exphcable on the mosquitotheory. These insects are incapable, owing to their limited powerof flight, of rising more than a few feet from the ground, andcannot make their way through a belt of trees of even moderatethickness. Broken ground, such as is found in connexion withrailway cuttings and canals, may be a focus from which malariamay spread. In such broken ground pools are of commonoccurrence, and afford the conditions for the development of themosquito, and infected tools used in one area may easily conveythe ova to another. AU these facts afford further support ofthis theory. The conditions of climate under which malaria ismost rife are those which are most suitable for the developmentof the mosquito. The protection afforded by fires, the recognizedvalue of mosquito curtains, the simultaneous disappearanceof Anopheles and malaria on the complete draining of a neighbourhood,the coincidence of malaria and mosquitoes, and theprotection afforded by large e.xpanses of water near walls andtrees are also important in this conne.xion.

The mosquitoes specially associated with the transmissionof malaria in the human subject belong apparently to the genus ​Anopheles. Anopheles claviger (maculipennis) and Anopheles

bifurcates both are found in Great Britain; Anopheles pictus is

another species found in Europe, but so far not in

Species of Q^g^^ Britain. A member of the genus Culex, the

Mosquito ^ I f . . 1 . 1

Concerned, grey mosquito or Lulex jahgans, is the mtermcdiatehost of the proteosoma of birds, on which many ofthe intermediate phases of the life-history of these parasiteshave been studied. Ross describes a dappled-wing mosquito asthe one with which he performed his experiments on birds inIndia. Anopheles claviger is interesting in view of the formerprevalence of malaria in Great Britain.

The remedy for malaria appears to be the removal or spoilingof the breeding grounds of the mosquito, thorough drainage ofpools and puddles, or, where this cannot be easily effected, thethrowing of a certain amount " of kerosene on the surface of thesepools" (Nuttall).

Amoebic Dysentery. — In addition to the dysentery set up bybacteria, a form — amoebic dysentery or amoebic enteritis — hasbeen described which is said to be due to an animal parasite, andit has been proposed to separate the various types of dysenteryaccording to their aetiology, in which case the amoebic group isprobably more specific than any other. The amoeba {.Amoebadysenteriae, Entamoeba histolytica, of Schaudinn) supposed togive rise to this condition was first described by Losch in 1875.Since then this amoeba has been described either as a harmlessparasite or as a cause of dysentery in Europe, Africa, the UnitedStates and in Brazil, and more recently in India. This organism,which is usually placed amongst the rhizopods, consistsof a small rounded, ovoid or pear-shaped globule of protoplasm,varying in size frem 6 to 40/x, though, as Lalleurpoints out, these limits are seldom reached, the organism beingusually from one and a half to three times the diameter of aleukocyte — from 12 to 26/i (see Plate II., fig. 19). Its marginsare well defined, and the body appears to consist of a granularinner portion and a hom*ogeneous outer portion, the latter beingsomewhat lighter in colour than the inner; in the resting stagethis division cannot be made out. The organism appears topass through at least two phases, one corresponding to a cystic,the other to an amoeboid, stage. In the latter stage, if the organismbe examined on a warm stage, it is seen to send out processes,and, as in other amoebae, vacuoles may be seen as clear spaceslying in the granular and darker-coloured inner protoplasm. Inthe small vacuoles a deeply stained point may be seen. Thesevacuoles may be extruded through the ectoplasm. In somecases the vacuoles are so numerous that they occupy the wholeof the space usually occupied by the granular protoplasm, and aremerely surrounded by a zone of variable thickness, which " hasthe appearance of finely granular glass of a distinctly pale greentint" (Lafleur). In the cystic stage a nucleus which appearsamongst the vacuoles may be made out, usually towards one sideof the amoeba. This nucleus is of considerable size, i.e. nearlyas large as a red blood corpuscle, and is readily distinguishablefrom the surrounding protoplasm. When stained by the Bendamethod (safranin and light green) a more deeply staining nucleolusmay be seen in the nucleus. The nucleus is perhaps bestseen when stained by this method, but it is always difficult toobtain well-stained specimens of this organism. If these amoebaecan be kept under observation for some time evidence of amitoticdivision may sometimes be seen. Red blood corpuscles areoften englobed by this amoeba, as are also micro cocci and bacilli.The movements of the amoebae are most active at a temperatureof about 90° to 98° F. From the fact that pigment is containedin these organisms, it is supposed that they take in the red bloodcorpuscles as nutritive material, and that other substances maybe taken in to serve a similar purpose. Nothing is known of themethod of multiphcation of the amoeba., but it is supposed that itmay be both by fission and by spore formation. These organismsare present in the early stage of the acute disease, and disappearat the later stages. Perhaps of some importance is thefact that the abscesses found in the liver and lung, which occurso frequently in cases of dysentery, usually contain, especiallyin the portions immediately adjoining the suppurating mass, a

considerable number of these amoebae. In the very smallabscesses the amoebae are numerous and active, and occupy thecapillaries in the tissues. It is quite possible that this pluggingof the capillaries with amoebae is the cause both of the hemorrhage'sand of the small areas of necrosed tissue, the supply ofnutriment being cut off from the liver cells and from the lungtissues, and that suppuration occurs only as a secondary process,though Councilman and Lalleur maintain that the amoeba itselfis the primary cause of suppuration. It is possible, of course, thatthe suppuration is due to the action of pus-forming organismsconveyed along with, or following, the amoeba, as we know thatthe growth of suppurating organisms can go on in dead tissueswhen these organisms have no chance of surviving in the healthytissues and fluids of the body. Lafleur holds that the amoebaforms a toxic substance which exerts a direct devitalizing effecton the liver cells, and that the amoeba itself causes suppuration.The abscesses in the lung, which invariably extend directly fromthe liver and occur at the base of the right lung, also contain theseamoebae. For these reasons this organism is looked upon as thecause of dysentery and of certain forms of dysenteric abscess.

They differ from the Entamoeba coli — often met with in theintestine — which has a more distinct nucleus containing largerchromatin masses and is surrounded by a highly refractivenuclear membrane. Further, in the Entamoeba coli the cytoplasmis of the same character throughout, there being nodifferentiation into ectoplasm and endoplasm. The Amoebahistolytica is often met with in a " resting phase, " in which thenucleus is less distinctly marked, and may consist of smallmasses of chromatin distributed throughout the cell or penetratingsmall buds formed on the surface. Around each of thesebuds, three, four or more, a highly refractive cyst wall is formed,the cysts becoming separated from the rest of the cell, theremnant of which undergoes disintegration. These cysts areextremely resistant, and probably maintain the continuity ofthe species outside the body.

In the active phase, the amoeboid form appears able by itstough membranous pseudopodia to push its way into the mucousmembrane of the large intestine, especially the rectum, the lowerpart of the ileum and the flexures. Once it is ensconced in thesetissues, small soft oedematous looking swellings soon appear onthe mucous surface. Marshall points out that the amoebaeprobably reach the liver by the portal circulation from the dysentericlesions in which the amoebae are found. Other observersmaintain that the amoebae may pass through the walls of theintestine, through the peritoneal cavity, and so on to the liverwhere they give rise to typical abscesses.

Syphilis. — It has long been recognized that syphilis is a specificinfective disease, but although characterized by fever, anaemia,and increased growths of tissue followed by rapid degenerationand ulceration of tissue, it is only within quite recent years thata definite parasitic organism, present in all cases of typicalsyphilis, has been isolated and studied. Schaudinn and Hoffmann,foUowed by Metchnikoff and others, have described as ofconstant occurrence a spiral or screw-shaped organism in whichare seen from half a dozen to a dozen well-defined, short,regular, almost semicircular curves. This organism, whenexamined fresh, in normal or physiological salt solution,exhibits active screw-like movements as it rotates along itslong axis; from time to time it becomes more or less bow shapedand then straightens out, the while moving about frompoint to point in the field of the microscope. It is not verystrongly refractive, and can only be examined properly with theaid of special central illumination and in the presence of minuteparticles, by the movements of which the organism is morereadily traced.

In order to obtain this organism for demonstration it is a goodplan to wash the primary or secondary syphilitic sore thoroughlywith alcohol; some of the clear fluid is then collected on a cover glass;or, perhaps better still, the lymphatic gland nearest to oneof these sores may be punctured with a hypodermic needle, thefluid being driven out on to a slide on which some normal salinesolution has been placed. When the organism has been examinedalive the film may be carefully dried and then stained by Giemsa's ​modification of the Romanowsky stain (see Plate I., fig. i). Thisstain, which may be obtained ready prepared from Griibler, ofLeipzig, under the name of " Giemsa'sche Losung für die RomanowskyFarbung, " is made as follows: Azur Il.-eosin compound, 3grnis. and Azur II. o-8 grm. are mixed and dried thoroughly inthe desiccator over sulphuric acid; this mixture is then very finelypulverised, passed through a fine-meshed silk sie'e and dissolvedat 60° C. in Merck's glycerin, 250 grms., the mixture being wellshaken; 250 grms. of methyl-alcohol (Kahlbaum I.), which hasbeen previously heated to 60° C, is then added. The whole, afterbeing well shaken, is allowed to stand for twenty-four hours andfiltered. The solution, now ready for use, should be kept in ayellow glass bottle. To i c.c. of ammonia-free distilled water addI drop of this stain. Stain for from a quarter to three-quarters ofan hour. Wash in running water, blot, drj', and mount in Canadabalsam. Longer exposure to the action of a more dilute Giemsafluid often gives excellent results.

The stained organisms may be seen as delicate, reddish, regularspirals with pointed extremities. They usually measure from 4to 14/1 in length, though they may reach 18 or 22/1; the breadthis about 0-25JJ. In a section of the liver from a case of congenitalsyphilis an enormous number of these spirochaetes may be found.

Stain by Levaditi's method as follows: Fix fragments of tissuenot more than i mm. thick in 10% formol solution for twenty fourhours. Rinse in distilled water and harden in 96% alcoholfor twenty-four hours. Then wash in distilled water for someminutes, i.e. until the pieces fall to the bottom of the vessel, andtransfer to a 1*5-3% solution of nitrate of silver (3% is preferablewhen the tissues have been obtained from the living patient).This impregnation should be carried on at a temperature of 38° C.for from three to five days, according to the nature of the tissue."Reduce" the silver in the following solution: Pyrogallic acid,2-4%, Formol, 5 c.c, Aq. dest., 100 c.c. Allow this solution to acton the tissues for from twenty-four to forty-eight hours at roomtemperature. Again wash in distilled water, dehydrate withalcohol, clear with xylol and cedar-oil, and embed in paraffin.The sections should not be more than 5^1 thick. In a section sostained the spirochaetes are seen as dark spirals standing out againsta pale yellow background. On staining with a weak counter stainmany of the spirals may be seen actually within the liver cells.

This organism may be found in the lung, spleen and other visceralorgans, and even in the heart of a patient suffering from syphilis.It has also been found in syphilitic lesions produced experimentallyin the higher apes, especially the chimpanzee. As a result ofthese observations it is now generally accepted as being the primarycause of syphilitic lesions in the human subject. It is certainlypresent in the lesions usually met with in cases of primary andsecondary syphilis of the human subject, and by its action on theblood and tissues of the body produces an antigen, a specific (?)substance, the presence of which has been utilized by Wassermannin the diagnosis of syphilis. He uses the m.ethod of deviation ofcomplement by the antigen substances contained in the syphiliticfluid blood or cerebro spinal fluid — by which the lytic action ofa haemolysing fluid is prevented.

Kdla-dzar. — The non-malarial remit tent fever, met with inChina, known as dum-dum fever in India and as kala-azar inAssam, fs associated with peculiar parasitic bodies described byDonovan and Leishman {Herpetomonas Dotwvani) (? Helcosomairopiciim, Wright). This fever is characterized by its greatchronicity, associated with very profound, and ultimately fatal,bloodlessness, in which there is not only a fall in the number of redblood corpuscles, but a marked diminution in the number ofwhite blood corpuscles. Ulceration of the skin and mucousmembrane, especially of the lower parts of the small intestineand of the first part of the colon is often present, this beingaccompanied by dropsy and by distinct enlargement of the liverand spleen. Leonard Rogers, who has given an excellentaccount of this condition, points out that there is a markedincrease in the number of cells in the bone-marrow.

The Leishman-Donovan bodies have been found in largenumbers, especially in the spleen (see Plate I., fig. 7); they mayalso be found in the ulcerating surfaces and wherever the cellularproliferation is marked. These organisms may be found insections, or they may be demonstrated in film preparationsmade from the material scraped from the freshly-cut surface ofthe spleen.

The films are best stained by Leishman's method: Solution A.-Medicinalmethylene-blue (Griibler), i part; distilled water, 100parts; sodium carbonate, 1-5 parts. This mixture is heated to 65° C.for twelve hours and then allowed to stand at room temperaturefor ten days. Solution B. — Eosin extra B.A. (Griibler), i part;distilled water, 1000 parts. Mix equal parts of solutions A and Bin a large open vessel and allow to stand for from six to twelvehours, stirring from time to time wi^h a glass rod. Filter, and wash

the precipitate which remains on the paper with a large volume oi:distilled water until the washings are colourless or only tinged apale blue. Collect the insoluble residue, dry and pulverize.

Make a 0-15 "/o solution of the powder (which may also be obtainedfrom Grubler & Co., Leipzig) in absolute methyl alcohol (Merck's" for analysis ), and transfer to a clean, dry, well stopperedbottle. Pour three or four drops of this stain on to the preparedfilm (blood, bone, marrow, &c.) and run from side to side. Afterabout half a minute add six or eight drops of distilled water, andmix thoroughly by moving the slide or cover-glass. Allow the stain 1to act for five minutes longer or, if the film be thick, for ten. Washwith distilled w'ater, leaving a drop or two on the glass for about aminute. Examine at once or after drying without heat and mountingin xylol balsam. 1

These peculiar parasitic bodies appear as deeply stained points,;,rounded, oval or co*ckle-shaped, lying free or grouped in the,large endothelial cells of the spleen. Examined under a magnifi-cation of 1000 diameters they are found to measure from 3-5 to,2-5/i, or even less, in diameter. Their protoplasm is stained,somewhat unequally, light blue; and from this light blue backgroundtwo very deeply stained violet corpuscles of unequal jsize stand out prominently; the smaller of these is more deeply jstained than the larger, is thinner, somewhat more elongated or, ^rod-shaped, and parallel or running at right angles to the large .corpuscle or obliquely from it. The larger corpuscle is roundedor oval, conical, or sometimes almost dumb-bell shaped. These,bodies may appear to touch one another, though usually theyare disconnected. Most of these Donovan-Leishman bodies areembedded in the protoplasm of the large endothelial or mono nuclearsplenic cells, of similar cells in the bone marrow, or ofcertain lymphatic glands. They may also be seen lying in theprotoplasm of the endothelial cells lining the capillary vesselsand lymphatics. They are considered by Leishman and LeonardRogers to be organisms in an intermediate stage of developmentof either a Trypanosome or some form of Herpetomonas. Rogers,who succeeded in cultivating them outside the body, describedchanges which he considers are associated with this latter germ.Patton goes further than this, and states that the LeishmaniadoKovani Lav. et Mesn. taken up by the bed bug closely resemblesin its life cycle that of the Herpetomonas of the common housefly.It is thought that the Leishman-Donovan bodies are thetissue parasite stage, and that the herpetomonas stage is probablyto be sought for in the blood of the patient.

Tsetse-Fly Disease (Trypanosomiasis) . — The interesting observationscarried out by Sir David Bruce have invested the tsetse flywith an entirely new significance and importance. In 1895Bruce first observed that in the tsetse disease — n'gana — theremay be found a flagellated haematozoon closely resembling theTrypanosoma Evansii found in Surra. This, like the Surraorganism, is very similar in appearance to, but considerablysmaller than, the haematozoon often found in the blood of thehealthy rat. It has, however, as a rule a single flagellum only.A small quantity of blood, taken from an affected buffalo, wildebeest,koodoo, bushbuck or hyaena — in all of which animalsit was found by Bruce — when inoculated into a horse, mule,donkey, cow, dog, cat, rabbit, guinea-pig, rat or mouse, produces asimilar disease, the organisms being found sometimes in enormousnumbers in the blood of the inoculated animal, especially in thedog and in the rat. He then found that the tsetse-fly can produce,the disease in a healthy animal only when it has first chargeditself with blood from a diseased animal, and he producedevidence that Clossina morsitans is not capable of producing thedisease except by carrying the parasites from one animal toanother in the blood that it takes through its proboscis into itsstomach. The parasites taken in along with such blood mayremain in the stomach and alive for a period of 118 hours, butshortly after that the stomach is found to be empty, and theparasites contained in the excrement no longer retain theirvitality. The mode of multiplication of these organisms hasbeen studied by Rose-Bradford and Plimmer, who maintainthat the multiplication takes place principally in the spleen andlymphatic glands. The tsetse-fly parasite, however, is stillimperfectly understood, though much attention is now beingpaid to its life-history and development. ​Sleeping Sickness (Trypanosomiasis). — To the group of diseasescaused by Trypanosomes must now be added sleeping sickness.This disease is due to the presence and action in the human bodyof a form known as T. gambicnse (Button).

In order to demonstrate the parasite in the blood of a case ofsleeping sickness, where they are very scanty and difficult tofind, the best method is repeated centrifugalization of the blood(Bruce), 10 c.c. being treated at a time; then the sediment in anumber of these tubes is collected and again centrifugalized.The living trypanosome may, as a rule, be distinguished in thisfinal sediment, even under a low power of the microscope. Theorganism may be found in greater numbers in the cerebro-spinalfluid of a case in which the symptoms of sleeping sickness havebeen developed, though centrifugalization of from 10 to 15 c.c.of the cerebro-spinal fluid for half an hour may be necessarybefore they can be demonstrated. Greig and Gray, at Mott'ssuggestion, were able to find the organism in the fluid removed bymeans of a hypodermic syringe from the swollen lymph glandsthat appear as one of the earliest signs of infection. Examinedfresh and in its native fluid or in normal saline solution it is seenas an actively motile, highly refractive, somewhat spindle-shapedorganism (see Plate I., fig. 9). The anterior end is prolonged intoa pointed flagellum, the posterior end being slightly blunted orrounded. This organism darts about rapidly between the redblood corpuscles or other corpuscles or particles, and showsrapid undulations, the flagellum beating quickly and the bodyfollowing the flagellum. In this body a couple of very brightpoints may be seen. On staining by Leishman's stain (see underKdla-dzar) the general protoplasm of the body is stained blueand is somewhat granular. This trypanosome is from 15 to 25/iin length (without the flagellum, which is from 5 to 6/i) and from1-5 to 2-5/ibroad. In the centre of the spindle-shaped mass is avery distinct reddish purple oval corpuscle corresponding to thelarger of the two bright points seen in the unstained specimen;this, the nucleus or macro nucleus, is slightly granular. Near theposterior or blunt end of the organism is a second, but muchsmaller, deeply stained reddish purple point, the second of thebright spots seen in the unstained specimen; this is known as themicro-nucleus or centrosome. Around the micro-nucleus is akind of court or area of less deeply stained protoplasm, arisingfrom or near which and running along the margin of the body is anarrow band with a very sharply defined wavy free margin.This thin band of protoplasm seems to be continuous with thelarge spindle-shaped body of the trypanosome, but at the freemargin it takes on the red tint of the micro-nucleus instead ofthe blue tint of the protoplasm. The undulatory membrane,as this band is called, is narrowest at the posterior end, gettingbroader and broader until the micro-nucleus is reached, beyondwhich it tapers off irregularly until finally it merges in theflagellum. In sleeping sickness the presence of this organism isusually associated with distinct anaemia, the red cells beingdiminished in number and the haemoglobin in quantity. Alongwith this there is an increase in the number of mono nuclearleukocytes.

The trypanosome is carried to the human patient bythe Glossina palpalis, in the proboscis of which the organismsmay be seen for some short time after the insecthas sucked blood from an infected patient. These trypanosomeshave been found living and active in the stomachof this insect up to 118 hours, but after 140 hours no livingparasites can be demonstrated. They undergo no metamorphosesin this intermediate host and are simply dischargedin the intestinal excreta. It may be readily understoodthat the trypanosome under these conditions soon loses itsvirulence, and an animal cannot be infected through the biteof the Glossina for more than 48 hours after the infected bloodhas been ingested by the fly. The organism may remain latentin the human body for a considerable period. It certainly setsup very tardily any changes by which its presence can be detected.The first symptoms of its presence and activity are enlargementof the lymphatic glands, especially those behind the neck, acondition often accompanied by irregular, and intermittent fever.

After a time, in from three months to three years, accordingto Bruce, the organism gains access to the fluid in the cerebrospinalcanal. Accompanying this latter migration are languor,lassitude, a gradually increasing apathy, and finally profoundsomnolence.

The incubation period, or that between the time of infectionand the appearance of the symptoms associated with trypanosomiasismay be as short as four weeks, or it may extend overseveral years. The inhabitants of the island of Senegal who havelived in Casamance do not consider themselves safe from thedisease until at least seven years after they have left an infectedarea. At first, amongst negroes, according to Button and Todd,there is no external clinical sign of disease except glandularenlargement; in mulattoes and whites an irregular and intermittentfever may be the chief sign of infection, " the temperaturebeing raised for two to four days, then falling to normal orbelow normal for four or five days." In other cases the fever isof the septic type, the temperature being normal in the morningbut rising in the evening to ioi-3°or 102-2° F., rarely to 104° F.,the curve differing from that characteristic of malaria in whichthe rise usually takes place in the morning. Moreover, in sleepingsickness there are no rigors before the rise of temperatureand but slight sweating, such as there is usually occurring at theend of the rise. Here again we have a distinction between themalarial condition and that of sleeping sickness. The respirationand the pulse rate are increased both during the febrile and thenon-febrile attacks; the respiration is from 29 t030 a minute, andthe pulse rises to 90, and even up to 140, a minute, according tothe degree of cardiac excitability which appears to be constantlypresent. The localized swelling and redness are seen as puffinessof the face, oedema of the eyelids and ankles and feet, congestederythematous patches on the face, trunk or limbs. Anaemia,general weakness and wasting, at first very slightly marked,gradually become prominent features, and headache is oftenpresent. The enlargement of the spleen appears to go on concurrentlywith enlargement of the lymphatic glands. Mansonpoints out that trypanosomiasismay terminate fatally without theappearance of any characteristic symptoms of sleeping sickness,but as a rule the " sleeping " or second stage supervenes. Thetemperature now becomes of the hectic type, rising to 102-2° F.in the evening and falling to 98-6° F. in the morning. Hereagain there are no rigors or sweating. Buring the last stages ofthe disease the rectal temperature may fall as low as 95° and forthe last day or two to 92° F., the pulse and respiration fallingwith the temperature. The irritability of the heart is still marked.Headache in the supra orbital region, and pain in the back, andeven in the feet, have been described. Activity and intelligencegive place to laziness, apathy and dullness; the face loses itsbrightness, the eyelids approximate, and the muscles around themouth and nose become flabby and flaccid, the patient becomesdrowsy, and when questioned replies only after a marked interval.Fibrillary tremors of the tongue and shaking of the hands andarms, distinct even during rest, become increased when anyvoluntary movement is attempted. These tremors may extendto the lower limbs and trunk. Epileptiform convulsions, generalweakness and progressive emaciation come on, and shortly beforedeath there is incontinence of urine and faeces. " The intellectualfaculties gradually become impaired, the patient has acertain amount of difficulty in understanding what is said to him,and becomes emotional, often crying for no reason whatever;delirium is usually absent, the drowsiness increases and thepatient's attitude becomes characteristic, the head falls forwardon the chest and the eyelids are closed. At first the patient iseasily aroused from this drowsy condition, but soon he reaches astage in which he falls sound asleep almost in any attitude andunder any conditions, especially after meals. These periods ofsleep, which become gradually longer and more profound, leadeventually to a comatose condition from which the patient can bearoused only with the greatest difficulty. It is at this stage thatthe temperature becomes normal and death occurs." Nabarropoints out, however, that this condition of drowsiness and sleep,leading eventually to coma, is by no means invariably present. ​In the early part of the sleeping-sickness stage patients oftensleep more than usual, but later do not sleep excessively. Theybecome lethargic and indifferent to their surroundings, however,and often lie with their eyes closed. When spoken to they hearand understand what is said to them and after a longer or shorterinterval give a very brief reply.

The leucocytosis that occurs during the course of this form oftrypanosomiasis is due, apparently, to secondary or terminalbacterial infections so frequently associated with the disease inits later stages. The first stage of the disease, that of fever,may last for several years; the second or nervous stage withtremors, &c., for from four to eight months. It is quite exceptionalfor the disease to be prolonged for more than a year fromthe time that the nervous symptoms become manifest, though aEuropean who contracted trypanosomiasis in Uganda, havingdelusions and becoming drowsy within the year, did not die ofsleeping sickness untU more than eighteen months from the onsetof the nervous symptoms.

The Glossina palpalis is not found in swamps. It affects abelt of from ten to thirty yards broad along banks boundingwater shaded by scrub and Underwood. It may, however,follow or be carried by the animal or human subject it is attackingfor a distance of, say, three hundred yards, but unless carriedit will not cross an artificial clearing of more than thirty yardsmade in the natural fly belt. The authorities in the plague strickenareas recommend, therefore, the clearance of belts thirtyyards in width along portions of the lake side, at fords and in suchother places as are frequented by natives. No infected personshould be allowed to enter a " fly area, " so that they may notact as centres from which the flies, acting as carriers, mayconvey infection. The provision of clothing for natives who arecompelled to work in fly areas is an important precautionarymeasure.

There seems to be some doubt as to whether Trypanosomagambicnse of Dutton is the same organism and produces the sameconditions as the Trypanosoma of Bruce and Nabarro from Uganda,but most observers seem to think that the two species are the sameand yield the same results when inoculated into animals. It issupposed that this trypanosome may pass through certain stagesof metamorphosis in the human or animal body, and differentdrugs have been recommended as trjpanocides during these variousstages, an arsenic preparation (atoxyl) first being given, and then,when the organisms have disappeared, injections of bi chloride ofmercury, this salt appearing to prevent the relapses which occurwhen atoxyl only is given over a prolonged period. Ehrlich,treating animals suffering from trypanosomiasis with parafuchsin,found that although the parasites disappeared from the bloodthey soon recurred. On the exhibition of another dose of parafuchsinthey again disappeared. This was repeated for a considerablenumber of times, but after a time the parafuchsin lostit* effect, the trj-panosome having acquired an immunity againstthis substance; they had in fact become " fuchsin-fast." Suchfuchsin-fast organisms injected into animals still retain their immunityagainst parafuchsin and may transmit it through morethan 100 generations. Nevertheless, they cannot withstand theaction of other trypanocidal drugs. The outcome of all this isthat large doses of the trypanocidal drug should be given at once,and that the same drug should never be given over too long a period,a fresh drug often being effective even when the first drug has lostaction.

II. — To OTHER Animal Par.4Sites

Filariasis. — Since Bancroft and Manson first described Filarianocturna and its relation to the common form of filariasis, themost important contribution to our knowledge has been made, atthe suggestion of the younger Bancroft, by Dr G. C. Low, who hasdemonstrated that the embryos of the filaria may be found in theproboscis of the mosquito [Culex ciliaris), whence they probablyfind their way into the circulating blood of the human subject.It appears that the filaria embryo after being taken, with theblood of the patient, into the stomach of the mosquito, loses itssheath; after which, leaving the stomach, it passes into thethoracic muscles of its intermediate host, and becomes morefully developed, increasing considerably in size and attaininga mouth, an alimentary canal, and the characteristic trilobedcaudal appendage. It now leaves the thoracic muscles, and,passing towards the head, makes its way " into the loose cellulartissue which abounds in the pro thorax in the neighbourhood of

the salivary glands." Most of them then " pass along the neck,enter the lower part of the head, " whence they may pass intothe proboscis. Although it has never been demonstrated thatthe filaria is directly inoculated into the human subject from theproboscis of the mosquito, it seems impossible to doubt that whenthe mosquito " strikes, " the filaria makes its way into the circulationdirectly from the proboscis. It is important to note thatthe mosquito, when fed on banana pulp, does not eject the filariafrom its proboscis. This, however, is not to be wondered at,as the filaria is apparently unable to live on the juices of thebanana; moreover, the consistence of the banana is very differentfrom that of the human skin. The importance of this observation,as affording an additional reason for taking measuresto get rid of the mosquito in districts in which filariasis is rife,can scarcely be over-estimated.

C . — Infective Diseases in which an Organism has been found,but has not finally been connected with the Disease.

Hydrophobia is usually contracted by man through inoculationof an abraded surface with the saliva of an animal affected withrabies — through the bite of a dog, the animal in which theso-called rabies of the streets occurs. The puppy is speciallydangerous, as, although it may be suffering from rabies when thesaliva contains an extremely exalted virus, the animal mayexhibit no signs of the disease almost up to the time of its death.The other animals that may be affected " naturally " are wolves,cats, foxes, horses, cows and deer; but all warm-blooded animalsmay be successfully inoculated with the disease. The principalchanges met with are found in the nervous system, and includedistension of the perivascular lymphatic sheaths, congestionand oedema of the brain and spinal cord and of the meninges.Hæmorrhages occur into the cerebral ventricles of the brain,especially in the floor of the fourth, and on the surface and in thesubstance of the medulla oblongata, and the spinal cord.

In addition to these small hemorrhage's, collections ofleukocytes are met with in hyperaemic areas in the medullaoblongata and pons, sometimes in the cortical cerebral tissueand in the spinal cord, in the perivascular lymphatics of the greymatter of the anterior horns and in the white matter of thepostero-internal and postero-external columns. Here also thenerve cells are seen to be vacuolated, hyahne and granular, andoften pigmented; thrombi may be present in some of the smallervessels, and the collections of leukocytes may be so prominent,especially in the medulla, that they have been described asmiliary abscesses. Hæmorrhages are also common in thevarious mucous and serous membranes; hyaline changes in andaround the walls of blood-vessels; proliferation of the endothelium;swelling and vacuolation of nerve cells; pericellularinfiltration with leukocytes, and infiltration of the salivaryglands with leukocytes (Coats). An increased number of leukocytesand microcytes in the blood has also been made out. Thevirus, whatever it may be, has a power of multiplying in thetissues, and of producing a toxic substance which, as in thecase of tetanus to.xin, appears to act specially on the centralnervous system.

In recent years fresh interest has been aroused in the morbidhistology of the brain and cord in hydrophobia by the appearanceof Negri's description of " bodies " which he claims arefound in the central nervous system only in hydrophobia orrabies (see Plate I., fig. 3). These bodies, which are rounded,oval, triangular, or slightly spindle- or sausage-shaped, whenspecially stained consist of a red (acidophiles) basis in which standout small blue (basophile) granules, rods and circles, oftensituated within vacuoles. A small central point which is surroundedby no clear space is supposed to correspond to thenucleus of a protozoan. But this can be little more than a suggestion.The Negri bodies are certainly present in the centralnervous system in cases of hydrophobia, and have not been foundin similar positions in any other disease. They are present inlarge numbers, even at an early stage of the disease, althoughthey are then so small that they may easily escape detection, sosmall indeed that they may pass through the pores of a Berkefeld ​filter, the filtrate in such cases being capable of acting as arabic virus. In the more chronic cases and in the later stages ofthe disease the Negri bodies may attain a considerable size andmay be easily seen under the microscope. They are from o-5/xto 20IX in diameter — the longer the course of the disease the largerthe bodies, these larger forms seldom if ever being met with inspecially susceptible animals, which soon succumb to the disease.The Negri bodies may be constricted in the middle, or, if somewhatelongated, there may be two or three constrictions whichgive it the appearance of a string of sausages. They may be metwith in almost all the nerve cells of the central nervous systemin well-developed cases of hydrophobia, but they are most numerousand are found most readily in the cells of the cornu ammonis,and then in the Purkinje cells of the cerebellum.

Although there are several methods of preparing these organismsfor microscopical examination, the following is perhaps the simplest.A fragment of the grey substance, say from the cornu ammonis,is taken from a section made at right angles to the surface and placedon a slide about one inch from the end. A cover slip is now " pressedupon it until it is spread out in a moderately thin layer; then thecover slip is moved slowly and evenly over the slide, " leaving thefirst three-quarters of an inch of the slide clear. In makingthe smear only slight pressure is used, the pressure beginning onthe edge of the cover slip away from the end of the slide towardswhich the cover slip is travelling, thus driving more of the nervetissues along the smear " and producing more well-spread nervecells." The smears are then air-dried, placed in methyl-alcoholfor one minute, and then in a freshly-prepared mixture of lo c.c.of distilled water, three drops of a saturated alcoholic solutionof rose anilin violet, and six drops of Loeffler's alkaline methyleneblue, which is warmed until steam rises; the stain is then pouredfrom the specimen, which after being rinsed in water is allowed todry and is then mounted in Canada balsam.

The nature of the disease produced by the inoculation of salivafrom a rabid animal appears to depend upon (i) the quantityof the rabic virus introduced; (2) the point of its introduction;(3) the activity of the virus. Thus by diluting the poison withdistilled water or saline solution and injecting small quantities,the period of incubation may be prolonged. Slight wounds ofthe skin, of the limbs and of the back are followed by a longincubation period; but when the inoculation takes place in thetips of the fingers or in the skin of the face, where nerves arenumerous, and especially where the wound is lacerated or deep,the incubation period is much shorter and the attack usuallymore severe. This, as in tetanus, is accounted for by the factthat the lymphatics of the nerves are much more directly continuouswith the central nervous system than are any other setof lymphatics. The poison appears to act directly upon thecells of the central nervous system.

Arising out of recent researches on hydrophobia, two methodsof treatment — one of which, at any rate, has been attended byconspicuous success — have been put into practice. The first ofthese, Pasteur's, is based upon the fact that rabic virus may beintensified or attenuated at will. Pasteur found that althoughthe virus taken from the cerebrospinal fluid of the dog alwaysproduces death in the same period when inoculated into the sameanimal, virus taken from other animals has not the same activity.If passed through a succession of monkeys it may become soattenuated that it is no longer lethal. If either the " monkeyvirus, " which is not fatal to the rabbit, or the " dog virus, "which kills in twelve to fourteen days, be passed through a seriesof rabbits, the virulence may be so exalted that it may kill inabout six days: its activity cannot be increased beyond thispoint by any means at present at our disposal. This intensifiedvirus was therefore named virus fixe by Pasteur, and it forms astandard from which to work. He found, too, that under certainconditions of temperature the virus may be readily attenuated,one hour at 50° or half an hour at 60° C. completely destroyingit. A 5% solution of carbolic acid acting for half an hour, or aI per 1000 solution of bi chloride of mercury or acetic acid orpermanganate of potash, brings about the same result, as do alsoexposure to air and sunHght. The poison contained in the spinalcord of the rabbit exposed to dry air and not allowed to undergoputrefactive changes gradually loses its activity, and at the endof fourteen to fifteen days is incapable of setting up rabic symptoms.A series of cords from rabbits inoculated with the virus,fixe are cut into short segments, which, held in series by the duramater, are suspended in sterile glass flasks plugged with cotton wooland containing a quantity of potassium hydrate— a powerfulabsorbent of water. At the end of twenty-four hours the activityof the virus is found to have fallen but slightly; at the end offorty-eight hours there is a still further falling off, until on thefourteenth or fifteenth day the virus is no longer lethal. Withmaterial so prepared Pasteur treated patients who had been bittenby mad dogs. On the first day of treatment small quantitiesof an emulsion of the cord exposed for thirteen or fourteen daysin saline solution are injected subcutaneously, and the treatmentis continued for from fifteen to twenty-one days, according tothe severity of the bite, a stronger emulsion — i.e. an emulsionmade of a cord that has been desiccated for a shorter period beingused for each succeeding injection, until at last the patientis injected with an emulsion which has been exposed to the airfor only three days. In the human subject the period of incubationof the disease is comparatively prolonged, owing to thein susceptibility of the tissues to the action of this poison; thereis therefore some chance of obtaining a complete protection oracclimatization of the tissues before the incubation period iscompleted. The virus introduced at the bite has then no morechance of affecting the nerve centres than has the strong virusinjected in the late stages of the protective inoculation: the nervecentres, having become gradually acclimatized to the poisonsof the rabic virus, are able to carry on their proper functionsin its presence, until in time, as in the case of microbial poisons,the virus is gradually neutralized and eliminated from the body.Various modifications and improvements of this method havefrom time to time been devised, but all are based on, and aremerely extensions of, Pasteur's original work and method. Assoon as it was found that antitoxins were formed in the tissuesin the case of an attack of tetanus, attention was drawn tothe necessity of determining whether something similar mightnot be done in the production of an antirabic scrum for the treatmentof rabies. Babes and Lepp, and then Tizzoni and hiscolleagues Schwarz and Centanni, starting from vims fixe,obtained a series of weaker inoculating materials by submittingit for different periods to the action of gastric juice. Beginningwith a weak virus so prepared, and from time to time injectingsuccessively stronger emulsions (seventeen injections in twentydays) into a sheep, they succeeded in obtaining a serum of suchantirabic power that if injected in the proportion of i to 25,000of body- weight, an animal is protected against a lethal dose ofvirus fixe. The activity of this serum is still further reinforcedif a fresh series of injections is made at intervals varying from twoto five months, according to the condition of the animal, eachseries occupying twelve days. This antirabic substance storedin the blood has not only the power of anticipating (neutralizing?)the action of the poison, but also of acting as a direct curativeagent; as a prophylactic agent, readily kept in stock and easilyand rapidly exhibited, it possesses very great advantages overthe inoculation method. It must be borne in mind that thelonger the period after the infection the greater must be theamount of serum used to obtain a successful result.

As regards the necessity for any treatment it may be pointedout that although the saliva of a rabid dog may be infective threedays before the manifestation of any symptoms of the diseasedeath takes place almost invariably within six days of the firstsymptom. If therefore the animal remains alive for ten daysafter the patient is bitten, there is no necessity for the antirabictreatment to be applied and the patient need fear no evil resultsfrom the bite.

There can be little doubt that hydrophobia is a specific diseasedue to a multiplication of some virus in the nervous system, in theelements of which it is ultimately fLxed; that it passes from thewound to the central nervous system by the lymphatics; andthat, as in tetanus, the muscular spasms are the result of theaction of some special poison on the central nervous system.

Scarlet Fever. — In scarlet fever recent observations have beencomparatively few and unimportant. Crooke, and later Klein, ​and others have, however, shown that in the glands and throatsof scarlet fever patients a streptococcus, to which is assigned thechief etiological role in connexion with this disease, is present.On the other hand, it is maintained by many observers that thesestreptococci are nothing more than the streptococci found inpuerperal fever, erysipelas, and similar infective conditions, andcertainly the organisms described closely resemble Streptococcuspyogenes. In 1904 Mallory described certain " bodies " whichhe considers may be associated with scarlet fever, and whichwere sufficiently distinctive to justify him in suggesting that hewas dealing with the " various stages in the developmental cycleof a protozoan." These bodies, which were demonstrated infour cases of scarlet fever, " occur in and between the epithelialcells of the epidermis and free in the superficial lymph vesselsand spaces of the corium." They are small, varying from thesize of a blood platelet to that of a red blood corpuscle, and" stained deUcately but sharply with methylene blue." Wellformed rosettes with numerous segments may be seen, formswhich MaUory thinks may correspond to the phase of asexualdevelopment of the malarial parasite. He also describes" coarsely reticulated forms which may represent stages insporogony or be due to degeneration of the other forms." Hegives beautiful illustrations, both drawings and photographs, ofthese organisms, and without claiming that he has proved anyetiological relation between these bodies and scarlet fever, statesthat his personal opinion is that such relation exists.

D. — Infective Diseases not yet proved to be due toMicro-organisms.

Small-pox. — ^There have been few recent additions to ourknowledge of the aetiology of small-pox, though Dr MoncktonCopeman now holds that the smaU-pox organism, like that ofvaccine, is probably a very minute bacillus, which, from itsbehaviour in the presence of glycerin, is possessed of the power offorming spores. If vaccine lymph, taken from the calf, be protectedfrom all extraneous spore bearing organisms and treatedwith 50% solution of glycerin, it, in time, becomes absolutelysterile as regards ordinary non-spore bearing organisms. Eventhe staphylococci and streptococci, usually found in calf lymph,cannot withstand the prolonged action of this substance, but spore bearingorganisms still remain alive and active. Moreover, thelymph still retains its power of producing vaccine vesicles, so that thevaccine organism, in its powers of resistance, resembles the spore bearing,and not the non-spore bearing, organisms with which weare acquainted. This vaccine organism must be very minute; itis stated that it can be cultivated only on special media, though itmultiplies freely in the superficial cutaneous tissues of the calf,the monkey and the human subject. Perhaps the most importantoutcome of Dr Monckton Copeman's work on this subjectis that he has obtained a vaccine lymph from which are ehminatedall streptococci and staphylococci, and, if the lymph betaken with reasonable care, any other organisms which couldpossibly give rise to untoward results.

Typhus Fever. — Although it is fuUy recognized that typhusmust be one of the specific infective fevers brought about by theaction of a special micro-organism, no definite information as tothe bacterial aetiology of this condition has been obtained. It isalways looked upon as a " filth " disease; and from the frequencyof minute hemorrhage's, and from the resemblance to thehemorrhagic septicaemia's in other respects, it appears probablethat the bacillus of typhus is the organism described by Mott in1883 as an actively motile dumb-beU coccus, and ten years laterby Dubieff and Bruhl as the Diplococcus typhosus exanthematicus;the polar staining and general resemblance to thediplococcus of fowl cholera, the plague bacillus, the diplococcus of" WUdseuche, " certain forms of swine fever and hog cholera, andothers of the hemorrhagic septicaemia's, are sufficient to suggestthe generic affinity of this organism to this septicaemic group.We have as yet, however (1910), no absolute proof of the etiologicalrelation of the bacillus to this disease.

Measles. — In measles, as in scarlet fever, micro cocci have hadascribed to them the power of setting up the specific disease.

Canon and Pielicke have, however, described minute bacillisomewhat resembling those described as occurring in vaccinelymph. These are found in the blood in the early stages of thedisease, and also in the profuse catarrhal secretions so characteristicof this condition. There are no records of the successfulinoculation of this minute bacillus, and until such evidence isforthcoming this organism must be looked upon as being anaccessory, possibly, but not the prime cause, of measles.

Mumps. — It is generally accepted that mumps is probablycaused by a specific micro-organism, the infective materialmaking its way in the first instance through the ducts to theparotid and other sahvary glands. It appears to bring about apeculiar oedematous inflammation of the interstitial tissue of theglands, but slight parenchymatous changes may also be observed.The virus is present in the tissues for some days before there isany manifestation of parotid sweUing, but during this period it isextremely active, and the disease may be readily transmitted frompatient to patient. The infectivity continues for some time,probably for nearly a week after naked-eye manifestations of thediseased condition have disappeared.

Whooping-Cottgh. — A diplococcus, a streptococcus, and varioushigher fungi have in turn been put down as the cause of thisdisease. It must, from its resemblance to the other specificinfective fevers, be considered as an infective disease of microbicorigin, which goes through a regular period of incubation andinvasion, and in which true nervous lesions, especially of thepneumogastric and superior laryngeal nerves, are somewhatcommon.

Affanassieff, and later KopUck, have described a minutebacillus, with rounded ends and bi-polar staining, which occurs inthe mucus discharged at the end of a paroxysm of whooping cough.KopUck examined sixteen cases, and found this organismin thirteen of them. There can be little doubt that the infectivematerial is contained in the expectoration. It may remain activefor a considerable period, but is then usually attached tosolid particles. It is not readily carried by the breath,and multiplies specially in the mucous membranes, setting upinflammation, probably through its toxic products, which appearto be absorbed, and, as in the case of the tetanus poison, to travelspecially along the lymphatics of the local nerves. Affections ofthe lung — bronchitis and broncho-pneumonia — may be directlyassociated with the disease, but it is much more hkely that theseaffections are the result of secondary infection of tissues alreadyin a weakened condition.

Authorities. — General: AUbutt and Rolleston, System of Medicine(2nd ed., London, 1905 et seq.); Castellani and Chalmers, Manualof Tropical Medicine (London, 1910); Fischer, The Structure andFtinctions of Bacteria, trans, by K. Coppen Jones (Oxford, 1900);Manson, Sir P., Tropical Diseases (3rd ed., London, 1903); Nuttall," On the Role of Insects, &c., as carriers in the spread of bacterialand parasitic diseases of man and animals " (Johns HopkinsHospital Reports, viii., 1899); Schneidemiihl, Lehrb. d. vergleich.Path. u. Therapie d. Menschen u. d. Hausthiere (Leipzig, 1898);Woodhead, Bacteria and their Products (London, 1891). Actinomycosis:Bostrom, Ziegler's Beitr. 2. pathol. Anatomic, Bd. ix.(1891); lUich, Beitrag z. Klinik d. Actinomykose (Vienna, 1892);M'Fadyean, Journ. Compar. Path, and Therap., vol. ii. (1899).Cerebro-Spinal Meningitis: Councilman, Mallory and Wright,Rep. Bd. Health, Mass. (Boston, 1898); E)avis, Journ. Infect. Diseases,iv. 558 (1907); Mackenzie and Martin, Journ. Path, andBacterial, xii. 539 (1908); Ruppel, Deutsche med. Wochenschr., S. 1366(1906); Shennan and Ritchie, Journ. Path, and Bacterial, xii. 456(1908); Symmers and others, Brit. Med. Journ. ii. 1334 (1908).Cholera: Dunbar, in Lubarsch u. Ostertag's Ergebn. d. allg. Pathologie,vol. i. (1896). Diphtheria: Behring, " DieGeschichted. Diphtherie "(Leipzig, 1893), and various other papers, principally in Zeits. f.Hygiene, Bd. xii. (1892) onwards; Ehrlich, " Die Werthbemessung d.Diphtherieheilserums u. d. theoret. Grundlagen, " Klinisches Jahrb.,Bd. vi. (1897); Klebs, " Ueber Diphtherie, " Verh. d. II. Congr.f.inn. Med. in Wiesbaden (1883); Loeffler, " Unters. u. d. Bcdeut. d.Mikro-org. f. d. Entst. d. Diphtheritis b. Menschen, &c., " Mitth. a.d. k. Gesundlieitsamte, Bd. ii. (1884); Martin, Sidney, GoulstonianLectures, Brit. Med. Journ. vol. i. (1892); Nuttall and Graham Smith,The Bacteriology of Diphtheria (Cambridge, 1908); Rouxand Yersin," Contrib. a T'^tude d. 1. Dipht(5rie, " Annates de I'inst. Pasteur,t. ii.-iv. (1888-1890). Dysentery: Kartulis, " Die Amoebendysenterie," in KoUe and Wassermann's Handb. d. path. Mikro-org.Ergiinz. Bd. p. 347 (1906); Osier, " On the Amoeba coli in Dysentery ​and in Dysenteric Liver Abscess, " Johns Hopkins Hasp. Bull. vol. i.(1890). Erysipelas: Coley, Proc. Roy. Soc. Med. (London, 1909), vol. iii.(Surg. Sect.), p. i; Fehleisen, Aetiologie dcr Erysipels (Berlin, 1883).Filariasis: Low, " On Filaria Nocturna in ' Cule.x, ' " Brit. Med.Journ. vol. i. (1900); Manson, Tropical Diseases (3rd cd., London,1903). Gonorrhoea: Bumm, Der Mikro-organism us d. gonorrh.Schkiinhaut-Erkrankungen (Wiesbaden, 1885); See, Le Gonocoque(Paris, 1896). Glanders: Koranyi, in Nothnagel's Specielle Pathologic,Bd. v. (1897); Loeffler and Schiitz, Deutsche nted. Wochenschr.(1882, Eng. trans., 1886); M'Fadycan, "Pulmonary Lesions ofGlanders, " Journ. Comp. Path, and Therap. vol. viii. (1895); Journ.State Medicine, pp. i, 65, 72, 125 (1905). Hydrophobia: Babes andLepp, " Rech. s. 1. vaccination antirabique, " Ann. de I'inst. Pasteur,t. lii. (1889); Hogyes, in Nothnagel's Specielle Pathologie, Bd. v.(1897); Negri, Boll. soc. nied. chir. di Pavia, Nos. 2, 4 (1903);Ztschr. j. Hyg., Bd. xliii. S. 507, Bd. xliv. S. 519 (1903); Pasteur,Traitement de la rage (Paris, 1886), and numerous papers in theCompt. rend. acad. d. sc. (Paris, from 1881 onwards), and in Ann.de I'inst. Pasteur, t. i. (1887) and t. ii. (1888); Tizzoni and Centanni,Lancet, vol. ii. (1895). Influenza: Canon, " Uebereinen Mikro-org. i.,Blute v. Influenzakranken, " Deutsche med. Wochenschr. (1892);Pfeiffer, " Vorl. Mitth. il. d. Erreger d. Influenza, " Deutsche med.Wochenschr. (1892). K&la-dzar: Laveran et Mesnil, Compt. rend,acad. d. sc. c.'cx.wii. p. 957 (Paris, 1903); Leishman, in Allbutt andRoUeston's Syst. Med. vol. ii., pt. ii. p. 226 (2nd ed., London, 1909);Patton, Scientific Memoirs Gov. India, No. 27 (1907), No. 31 (1907);Rogers, Brit. Med. Journ. i. 427, 490, 557 (1907). Leprosy: Hansenand Looft, Leprosy in its Clin, and Path. Aspects, trans, by N. Walker(Bristol, 1895); Mitth. u. Verhandl. d. internal, wissensch. Lepra-Conferenzz. Berlin (1897); Rake, Reports of the Trinidad Asylum(1886-1893); Report of the Leprosy Commission to India (1893).Mycetoma or Madura Foot: Bocarro, " Analysis of 100 Cases ofMycetoma, " Lancet, vol. ii. (1893); Boyce and Surveyor, Proc. Roy.Soc. Land. vol. liii. (1893); Vandyke Carter, Trans. Path. Soc. Lond.vol. xxiv. (1873), and " On Mycetoma or the Fungus Disease of India "(London, 1874); Kanthack, Journ. Path, and Bact. vol. i. (1892);Lewis and Cunningham, Physiol, and Pathol. Researches (1875);" Fungus Disease of India, " Quoin's Diet, of Medicine, vol. i.(1894); Unna and Delbanco, Monats. f. prakt. Derm. Bd. xxx.,S. 545 (1900); Vincent, " Et. s. 1. parasite d. pied Madure, "Ann. de I'inst. Pasteur, t. viii. (1894). Malaria: Celli, Malaria,trans, by Eyre (London, 1900); Nuttall, " Neuere Forsch. ii. d. Rolled. Mosquitos, &c., " Centralbl. f. Bact. u. Parasitenk. Abt. I. (1900),and in Journ. Trop. Med. vols, ii., iii. (1900), and Journ. Hyg. vols.i., ii. (1901); Nuttall and Shipley, Journ. Hyg. i. 4, 45, 269, 451(1901), ii. 58 (1902); Ruge in KoUe and Wassermann's Handb. d.path. Mikro-org. Erganz. Bd. (Jena, 1907). Malta Fever: Bruce," Note on the Discovery of a Micro-organism in Malta Fever, "Practitioner (1887); " Obs. on Malta Fever, " Brit. Med. Journ. vol. i.(1889); " Malta Fever, " in Davidson's Hygiene of Warm Climates(Edinburgh, 1893); Eyre, Quart. Journ. Med. i. 209 (1908); Hughes," Investig. into the Etiology of Mediterranean Fevers, " Lancet, ii.(1892); and in Ann. de I'inst. Pasteur, t. viii. (1893); Reports ofCommission on Mediterranean Fever (London, 1905 et seq.). InfectiveMeningitis: Neumann and Schafi^er, Z. Aetiol. d. eiterig. Meningitis;Virch. Archiv. Bd. cix. (1887); Weichselbaum, Fortschritte d.Medicin, Bd. v. (1887). Plague: Bannerman, Journ. Hyg. vi. 179(1906); and Edin. Med. Journ. n.s., xxiii. 417 (1908); Bitter, " Ueb.d. Haflfkine'schen Schutzimpfungen gegen Pest, " Zeits. f. Hygiene,Bd. .xx. (1899); Calmette et Salimbeni, Ann. de I'inst. Pasteur,xiii. 865 (1899); Haffkine, "Further Papers relating to theOutbreak of Plague in India, No. III." (London, 1898), and Brit.Med. Journ., i. 1461 (1897); Kitasato, The Lancet, ii. 325, 428(1894), and Brit. Med. Journ. ii. 369 (1894); Klein, Studies in theiBacteriology and Etiology of Oriental Plague (London, 1906); Lamb," Summary of Work of the Plague Commission " (Calcutta, 1908);Lowson, Lancet, ii. 325 (1894), see also Brit. Med. Journ. ii. 369(1894); Reports on Plague Investigations in India, in Journ. Hyg.vi. 421 (1906), vii. 323, 693 (1907-1908); Simond, Ann. de I'inst.Pasteur, xii. 625 (1898); Yersin, "La Peste bubonique a Hong-Kong," Ann. de I'inst. Pasteur, t. viii. (1894); also Yersin, Calmetteand Borrel, op. cit., t. ix. (1895). Relapsing Fever: Koch, Deutschemed. Wochenschr. (1879); Soudakewitch, " Recherches s. 1. fievrerecurrent, " Ann. de I'inst. Pasteur, t. v. (1891). Sleeping Sickness:Browning, Journ. Path, and Bacterial, xii. 166 (1908); Bulletin ofthe Sleeping Sickness Bureau (No. i, London, Oct. 1908 onwards);Dutton and Todd, " First Report of the Trypanosomiasis Expeditionto Senegal, 1902" (Liverpool, 1903); Dutton, Todd and Christy,Brit. Med. Journ. i. 186 (1904); Ehrlich, Berl. klin. Wochenschr.S.S. 233, 280, 310, 341 (1907); Laveran and Mensil, Trypanosomes andTrypanosomiases, trans, by Nabarro (London, 1907); Royal Society,Reports of the Sleeping Sickness Commission, No. i (London, Aug.1903 onwards). Suppuration and Septicaemia: Watson Cheyne,Suppuration and Septic Diseases (Edinburgh and London, 1889).Surra: Evans, Report on "Surra" Disease (Bombay, 1880);Lewis, Appendix, 14th Ann. Rep. of Sanit. Commission with theGovt, of India (1878); Lingard, Report on Surra in Equines, Bovines,Buffaloes and Canines (2 vols., Bombay, 1893 and 1899); Steci,Investig. into an Obscure and Fatal Disease among Transport Mulesin British Burma (1883). Syphilis: Metchnikoff, Lancet, i. 1553,

1629 (1906); The New Hygiene (Harbcn Lectures, London, 1906);Ann. de I'inst. Pasteur, xxi. 753 (1907); Metchnikoff and Roux,Ann. de I'inst. Pasteur, t. xvii.-xx. (1903-1906); Schaudinn andHoffmann, Arb. a. d. Kaiserl Gesundheitsamte, xxii. 527 (1905);Berl. klin. Wochenschr. S. 673 (1905); Wassermann, Bsrl. klin.Wochenschr. S.S. 1599, 1634 (1907); Wassermann, Neisscr andBruck, Deutsche med. Wochenschr. S. 745 (1906). Tetanus: Behring," Die Blutscrumthcrapie, " Zeits. f. Hygiene, Bd. xii. (1892); KnudFaber, Om Tetanos som Infrktionssygdom (Copenhagen, 1890);Kitasato, Zeits. f. Hygiene, Bd. vii. (1889), and Bd. xii. (1892);Nicolaier, Beitr. z. Aetiol. d. Wundstarrkrampfes (Gottingen, 1885);Rose, Der Starrkrampf b. Menschen (Stuttgart, 1897); Roux andBorrel, " Tetanos cerebral et immunite contre le tetanos, " Ann. deI'inst. Pasteur, t. xii. (1898); Vaillard, Vaillard and Rouget, Vaillardand Vincent, various articles in the Ann. de I'inst. Pasteur, t. v.(1891), and t. vi. (1892); Wassermann and Takaki, " Ueb. tetanusantitox.Eigenschaftcn d. normalcn Centralncrvensystems, " Berl.klin. Wochenschr. (1898). Tsetse-fly Disease: Bradford and Plimmer,Proc. Roy. Soc. Lond. Ixv. 274 (1899); Bruce, Tsetse-flyDisease or Nagana, in Zidtdand (Durban, 1895); and London, 1897;Kanthack, Durham and Blandford, Proc. Roy. Soc. Lond. Ixiv. 100(1898). 'Tuberculosis: Bosanquet and Eyre, Serums, Vaccines andToxines (2nd ed., London, 1909); Calmette, Compt. rend. acad. d.sc. cxiiv. 1324 (Paris, 1907); Fortescue-Brickdale, Bristol Med.Chir. Jouryi. xxvi. 112 (1908); Koch, Deutsche med. Wochenschr.S. 1029 (1890); S. 209 (1897); Mitth. a. d. kaiserl. Gesundheitsamte,Bd. ii. (1884); von Pirquct, Deutsch. med. Wochenschr. S. 865 (1907);Report, with Appendices, of the Royal Commission on Tuberculosis(London, 1895); Reports, Royal Commission on Tuberculosis(London, 1904-1907); Wolff-Eisner, The Ophthalmic and CutaneousDiagnosis of Tuberculosis (Eng. trans., New York, 1908); Wright,Lancet, ii. 1598, 1674 (1905). Typhoid Fever: Chantemesse, inCharcot's Traite de medecine, t. i. (1891); Chantemesse and Widal,"Etude exper. s. I'exaltation, I'immuns. et 1. therap. d. I'infectiontyphique, " Ann.de I'inst. Pasteur, t. vi. (1892); Davies and WalkerHall, Proc. Roy. Soc. Med. vol. i. (London, 1908), (Epidem. Section),p. 175; Durham, "On a Special Action of the Serum of highlyimmunized Animals, " Journ. Path, and Bact. vol. iv. (1896-1897);Easton, Boston Med. and Surg. Journ. cliff. 195 (1905); Forster,Miinch. med. Wochenschr. S. i (1908); Frosch, Klin. Jahrb. xix.537 (Jena, 1908); Max Gruber, " Z. Theorie d. Agglutination, "Miinch. med. Wochenschr. (18^9); Griinbaum, Lancet, vol. ii. (1896);Kayser, Arb. a. d. kaiserl. Gesitndheitsamte, Bd. 24, S.S. 173, 176(Berlin, 1906); Bd. 25, S. 223 (1907); Ledingham and Ledinghani, Brit.Med. Journ. i. 15 (London, 1908); Sanarelli, " Etudes s. 1. Fievretyphoide experiment ale, " Ann. de I'inst. Pasteur, t. vi. (1892), andt. viii. (1894); Thomson and Ledingham, sSth Annual Report, LocalGovernment Board, p. 260 (London, 1909); Wright and Semple,British Med. Journ. (1897), i. 256; Variola: Calkins, Journ. Med.Research (1904), xi. 136; Councilman, Magrath and Brinckerhoff,Journ. Med. Research (1903), ix. 372, (1904), xi. 12; Guarnieri, Arch,per le sci. med. (1892) xxvi. 403; Centralbl. f. Bact. u. Parasitenk.,Bd. xvi. (1894), S. 299. Weil's Disease: Weil, "Ueb.eineeigenthiiml.m. Milztumor, Ikterus . . . akute Infectionskrankheit, " DeutscheArch. f. klin. Med. (1886), Bd. xxxix. Yellow Fever: Beauperthuy,Travaux scientifiques (Bordeaux, 1891); Boyce, Yellow Fever ProphylaxisinNew Orleans (1905; being Memoir XIX. Liverpool Schoolof Tropical Medicine, London, 1906); Health Progress and Administrationin the West Indies (London, 1910); Sanarelli, " Etiol. etPath. d. 1. Fievre jaune, " and other papers in Ann. de I'inst. Pasteur,(1897) t. xi., and (1898) t. xii.; Durham and Myeers, " InterimReport on Yellow Fever, " Brit. Med. Journ. (1901), i. 450.(G. S. W.)