Parasitic Diseases

Medical warning! This article is from the 1911 Encyclopaedia Britannica. Medical science has made many leaps forward since it has been written. This is not a site for medical advice, when you need information on a medical condition, consult a professional instead.

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 animal parasites has been more widely and more thoroughly investigated (see Bacteriology). The knowledge gained has not only modified our conception of the pathology of these diseases, but has had a most important influence upon our methods of treatment of sufferers, both as individuals and as members of communities. For clinical and other details of the diseases mentioned in the following classification, see the separate articles on them; the present article is concerned mainly with important modern discoveries as regards aetiology and pathology. In certain cases indeed the aetiology is still obscure. Thus, according to Guarnieri, and Councilman & Calkins, there is associated with vaccinia and with small-pox a Protozoan parasite, Cytoryctes variolae, Guar. This parasite is described as present in the cytoplasm of the stratified epithelium of the skin and mucous membranes in cases of vaccinia, but in the nuclei of the same cells in cases of variola or small-pox, whilst it is suggested that. there may be a third phase of existence, not yet demonstrated, in which it occurs as minute spores or germs which are very readily carried in dust and by air currents from point to point. In certain other conditions, such as mumps, dengue, epidemic dropsy, oriental sore - with which the Leishman-Donovan bodies (Helcosoma tropicum, Wright) are supposed to be closely associated (see also Kdla-azar below) - verruga, framboesia or yaws - with which is commonly associated a spirochaete (Castellani) and a special micrococcus (Pierez, Nicholls) - and beri-beri, the disease may be the result of the action of specific micro-organisms, though as yet it has not been possible to demonstrate any aetiologica relationship between any microorganisms found and the special disease. Such diseases as haemoglobinuric fever or black-water fever, which are also presumably parasitic diseases, are probably associated directly with malaria; this supposition is the more probable in that both of these are recognized as occurring specially in those patients who have been weakened by malaria.

The following classification is based partly upon the biological relations of the parasites and partly on the pathological phenomena of individual diseases: A. - Diseases due to Vegetable Parasites.

Table of contents

1 I 2 II 3 I 4 II 5 2 6 C 7 'D 8 Infective Endocarditis 9 Erysipelas 10 Gonorrhoea 11 Relapsing Fever 12 Plague 13 Pneumonia 14 Influenza 15 Diphtheria 16 Leprosy 17 Glanders 18 II 19 'B 20 Amoebic Dysentery 21 Syphilis 22 Tsetse-Fly Disease (Trypanosomiasis) 23 Sleeping Sickness (Trypanosomiasis) 24 II 25 'C 26 Scarlet Fever 27 'D 28 Measles 29 Mumps 30 Whooping-Cough 31 Authorities

I

To Schizomycetes, Bacteria Or Fission Fungi. I. Caused by the Pyogenetic Micrococci. Suppuration and Septicaemia. Erysipelas.

Infective Endocarditis. Gonorrhoea.

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

Influenza.

Yellow Fever and Weil's Disease. Diphtheria.

Tetanus.

Tuberculosis. Glanders. Leprosy.

II

To Higher Vegetable Parasites.

Actinomycosis, Madura Foot, Aspergillosis and other Mycoses. B. - Diseases due to Animal Parasites.

I

To Protozoa.

Malaria. Kala-Azar.

Amoebic Dysentery. Tsetse-fly Disease.

Haemoglobinuric Fever. Sleeping Sickness. Syphilis.

II

To Other Animal Parasites. Filariasis, &c.

Cholera. Typhoid Fever. Malta Fever. Relapsing Fever. Plague.

Pneumonia.

FIG. I.

FIG. 3.

FIG. 4.

FIG. 5.

FIG. 7.

FIG. 9.

FIG. I. - Spirochaeta pallida of Schaudinn (Spironema pallidum), the organism found in the early sores of syphilis; stained by Giemsa's stain, x 1000 diam.

2

Preparation of the Glanders bacillus (B. mallei), from a 12hours' agar-agar culture. X 1000 diam.

" 3. - Negri bodies (red with blue points) in and around the nerve cells of the corns: ammonis of a dog suffering from rabies. x Boo diam.

" 4. - Staphylococcus pyogenes aureus from a 12-hours' agar culture. x woo diam.

" 5. - Malaria. Life cycle, in the blood, of the Tertian malarial parasite commencing with the small amoebulae and passing through the spore-bearing stages. x Iwo diam.

" 6. - Section of gland from a guinea-pig inoculated with the Glanders bacillus (B. mallet). x woo diam.

" 7. - Leishman-Donovan bodies found in the scraping made from the cut surface of the spleen from a case of Kala-Azar. x 1000 diam.

" 8. - Branched hyphal threads of the Ray fungus (Actinotnyces, clubbed through thickening of the sheath.) x 1000 diam. " 9. - The Trypanosoma Gambiense, seen in a blood film taken from a case of sleeping sickness. x woo diam.

C

Infective Diseases in which an organism has been found, but has not finally been connected with the disease. Hydrophobia. Scarlet Fever.

'D

Infective Diseases not yet proved to be due to micro-organisms. Small-pox. Mumps.

Typhus Fever. Whooping Cough, &c. Measles A. - Diseases due to Vegetable Parasites. I. - To Schizomycetes, Bacteria Or Fission Fungi. I. Caused by the Pyogenetic Micrococci. Suppuration and Septicaemia. - It is now recognized that although nitrate of silver, turpentine, castor oil, perchloride of mercury and certain other chemical substances are capable of producing suppuration, the most common causes of this condition are undoubtedly the so-called pus-producing bacteria. Of these perhaps the most important are the staphylococci (cocci arranged like bunches of grapes), streptococci (cocci arranged in chains), and pneumococci, though certain other organisms not usually associated with pus-formation are undoubtedly capable of setting up this condition, e.g. Bacillus pyocyaneus, Bacillus coli communis, and the typhoid bacillus. These organisms (the products of which, by chemical irritation, stimulate the leucocytes to emigration) bring about the death and digestion of the tissues and fluids (which no longer " clot ") with which they come in contact, pus (matter) being thus formed: 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 from the original site of infection, or pyaemia, with the formation of secondary abscesses, may thus be set up.

In septicaemia the pus-forming organisms grow at the seat of 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 may be swept away either by the lymph or by the blood, and carried to positions in which they set up further inflammatory or suppurative changes. In the streptococcal inflammations spreading 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 powerful bactericidal action; should they escape, however, they are carried without multiplication into the capillaries of the general circulation, of the lung, or of the liver, where, being stopped, they may give rise to a second focus of infection, especially if at the point of impaction the vitality of the tissues is in any way lowered. Unless the blood is very much impoverished, its bactericidal action is usually sufficiently powerful to bring about the destruction of anything but comparatively large masses of pyogenetic organisms. This bactericidal power, however, may be lost; in such case the pus-forming organisms may actually multiply, a general haemic infection resulting. Should microorganisms be conveyed by the veins to the heart, and there be deposited on an injured valve, an infective endocarditis is the result; from such a deposit numerous organisms may be continuously poured into the circulation. Simple thrombi or clots may also become infected with micro-organisms. Fragments of these, washed away, may form septic plugs in the vessels and give rise to abscesses at the points where they become impacted. A distinction must be drawn between sapraemia and septicaemia. In sapraemia the toxic products of saprophytic organisms are absorbed from a gangrenous or necrotic mass, from an ulcerating surface, or from a large surface on which saprophytic organisms are living and feeding on dead tissues: for example, we may have such a condition in the clots that sometimes remain after childbirth on the inner surface of the wall of the womb. So long as no micro-organisms follow the toxins, the condition is purely sapraemic, but should any organisms make their way into and multiply in the blood, the condition becomes one of septicaemia. The term pyaemia is usually associated with the formation of fresh secondary foci of suppuration in distant parts of the body. If the primary abscess occurs in the lungs, the secondary or metastatic abscesses usually occur in the vessels of the general or systemic circulation, and less frequently in other vessels of the lung. When the primary abscess occurs in the systemic area, the secondary abscess occurs first in the lung, and less frequently in the systemic vessels; whilst if the primary abscess be in the portal area (the veins of the digestive tract), the secondary abscesses are usually distributed over the same area, the lungs and systemic vessels being more rarely affected.

Infective Endocarditis

Acute malignant or ulcerative endocarditis occurs in certain forms of septicaemia or of pyaemia. It is brought about by the Streptococcus pyogenes (see Plate II. fig. 2), the pneumococcus, or the Staphylococcus pyogenes aureus (see Plate I. fig. 4), or, more rarely, by the gonococcus, the typhoid bacillus or the tubercle bacillus, as they gain access to acute or chronic valvular lesions of the heart. The aortic and mitral valves are usually affected, the pulmonary and tricuspid valves much more rarely, though Washbourn states that the infective form occurs on the right side more frequently than does simple endocarditis. A rapid necrosis of the surface of the valve is early followed by a deposition of fibrin and leucocytes on the necrosed tissue; the bacteria, though not present in the circulating blood during life, are found in these vegetations which break down very rapidly; ulcerative lesions are thus formed, and fragments of the septic clot (i.e. the fibrinous vegetations with their enclosed bacteria) are carried in the circulating blood to different parts of the body, and, becoming impacted in the smaller vessels, give rise to septic infarcts and abscesses. The ulceration of the valves, or in the first part of the aorta, may be so extensive that aneurysm, or even perforation, may ensue.

In certain cases of streptococcic endocarditis the use of antistreptococcic serum appears to have been attended with good results. Sir A. Wright found that the introduction of vaccines prepared from the pus-producing organisms after first lowering the opsonic index almost invariably, after a very short interval, causes it to rise. He found, too, that the vaccine is specially efficacious when it is prepared from the organisms associated with the special form of suppuration to be treated. Whenever the opsonic index becomes higher under this treatment the suppurative process gradually subsides: boils, acne, pustules, carbuncles all giving way to the vaccine treatment. The immunity so obtained is attributed to the increased activity of the serum as the result of the presence of an increased amount of opsonins. Further, Bier maintains that a passive congestion and oedema induced by constriction of a part by means of a ligature or by a modification of the old method of cupping without breaking the skin appears to have a similar effect in modifying localized suppurative processes, that is processes set up by pus-producing bacteria. Wright holds that this treatment is always more effective when the opsonic index is high and that the mere accumulation of oedematous fluid in the part is sufficient to raise the opsonic index of that fluid and therefore to bring about a greater phagocytic activity of the leucocytes that are found in such enormous numbers in the neighbourhood of suppurative organisms and their products.

Erysipelas

In 1883 Fehleisen demonstrated that in all cases of active erysipelatous inflammation a streptococcus or chain of micrococci (similar to those met with in certain forms of suppuration) may be found in the lymph spaces in the skin. The multiplying streptococci found in the lymph spaces form an active poison, which, acting on the blood-vessels, causes them to dilate; it also " attracts " leucocytes, and usually induces proliferation of the endothelial cells lining the lymphatics. These cells - perhaps by using up all available oxygen - interfere with 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 are the result of the action of this special coccus, alone, or in combination with other organisms. It has been observed that cancerous and other malignant tumours appear to recede under an attack of erysipelas, and certain cases have been recorded by both Fehleisen and Coley in which complete cessation of growth and degeneration of the tumour have followed such an attack. As the streptococcus of erysipelas can be isolated and grown in pure culture in broth, it was thought by these observers that a subcutaneous injection of such a cultivation might be of value in the treatment of cancerous tumours. No difficulty was experienced in setting up erysipelas by inoculation, but in some cases the process was so acute that the remedy was more fatal than the disease. The virulence of the streptococcus of erysipelas, as pointed out by Fehleisen and Coley, is greatly exalted when the coccus is grown alongside the Bacillus prodigiosus and certain other saprophytic organisms which flourish at the bodytemperature. It is an easier matter to control the action of a non-multiplying poison, even though exceedingly active, than of one capable, under favourable conditions, of producing an indefinite amount of even a weaker poison. The erysipelatous virus having been raised to as high a degree of activity as possible by cultivating it along with the Bacillus prodigiosus - the bacillus of " bleeding " bread - in broth, is killed by heat, and the resulting fluid, which contains a quantity of the toxic substances that set up the characteristic erysipelatous changes, is utilized for the production of an inflammatory process - which can now be accurately controlled, and which is said to be very beneficial in the treatment of certain malignant tumours. The accurate determination of the aetiology of erysipelas has led to the adoption of a scientific method of treatment of the disease. The Streptococcus erysipelatis is found, not specially in the zone in which inflammation has become evident, but in the tissues outside this zone: in fact, the streptococci appear to be most numerous in the lymphatics of the tissues in which there is little change. Before the appearance of any redness there is a dilatation of the lymph spaces with fluid, and the tissues become slightly oedematous. As soon, however, as the distension of vessels and the emigration of leucocytes, with the accompanying swelling and redness, become marked, the streptococci disappear or are imperfectly stained - they are undergoing degenerative changes - the inflammatory " reaction " apparently being sufficient to bring about this result.

If it were possible to set up the same reaction outside the advancing streptococci might not a barrier be raised against their advance? This theory was tested on animals, and it was found that the application of iodine, oil of mustard, cantharides and similar rubefacients would prevent the advance of certain micro-organisms. This treatment was applied to erysipelatous patients with the most satisfactory result, the spread of the disease being prevented whenever the zone of inflammation was extended over a sufficiently wide area. The mere " ringing " of the red patch by nitrate of silver or some other similar irritant, as at one time recommended, is not sufficient: it is necessary that the reaction should extend for some little distance beyond the zone to which the streptococci have already advanced.

Gonorrhoea

A micro-organism, the gonococcus, is the cause of gonorrhoea. It is found in the pus of the urethra and in the conjunctiva lying between the epithelial cells, where it sets up considerable irritation and exudation; it occurs in the fluid of joints of patients affected with gonorrhoeal arthritis; also in the pleuritic effusion and in the vegetations of gonorrhoeal endocarditis. It is a small diplococcus, the elements of which are flattened or slightly concave disks apposed to one another; these, dividing transversely, sometimes form tetrads. They are found in large numbers, usually in the leucocytes, adherent to the epithelial cells or lying free. They stain readily with the basic aniline dyes, but lose this stain when treated by Gram's method. The gonococcus is best grown on human blood-serum mixed with agar (Wertheim), though it grows on ordinary solidified 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-transparent disk-like growth, with somewhat irregular margins, or with small processes running out beyond the main colony. It acts by means of toxins, which have been found to set up irritative changes when injected, without the gonococci, into the anterior chamber 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 Cholera Commission in Egypt and India, brought forward overwhelming evidence in proof of his contention that a special bacterium is_ the causal agent of cholera; subsequent observers in all countries in which cholera has been met with have confirmed Koch's observation. The organism described is the " comma " bacillus. or vibrio, one of the spirilla, which usually occurs as a slightly curved rod 1 to 21./. in length and 0.5 to o. 6µ in thickness. These comma-shaped rods occur singly or in pairs; they may be joined together to form circles, half-circles, or " S "-shaped curves (see Plate II. fig. 3).

In cultivations in specially prepared media they may be so grouped as to form long wavy or spiral threads, each of which may be made up of ten, twenty, or even thirty, of the short curved vibrios; in the stools of cholera patients, especially during the earlier stages of the disease, they are found in considerable numbers; they may also be found in the contents of the lower bowel and in the substance of the mucous membrane of the lower part of the small intestine,. especially in the crypts and in and around the epithelium lining the follicles. It is sometimes difficult, in the later stages of the disease, to obtain these organisms in sufficiently large numbers to be able to distinguish them by direct microscopic examination, but by using the Dunbar-Schottelius method they can be detected even when present in small numbers. A quantity of faintly alkaline meat broth, with 2% of peptone and i % common salt, is inoculated with some of the contents of the intestine, and is placed in an incubator at a temperature of 35° C. for about twelve hours, when, if any cholera bacilli are present, a delicate pellicle, consisting almost 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 organisms being overgrown, as it were, by the other organisms. In order to obtain a pure culture of the cholera bacillus, remove a small fragment of the young film, shake it up thoroughly in a little broth, and then make gelatine-plate cultivations, when most characteristic colonies appear as small greyish or white points. Each of these, when examined under a low-power lens, has a yellow tinge; the margins are wavy or crenated; the surface is granular and has a. peculiar ground-glass appearance; around the growing colony liquefaction takes place, and the colony gradually sinks to the bottom 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 only be recognized by a faint aromatic and sweetish smell, which can scarcely 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 some time, but it appears to be less resistant than many of the putrefactive and saprophytic organisms. It grows better in a saline solution (brackish water) than in perfectly fresh water; it flourishes in serum and other albuminous fluids, especially when peptones are present. Its power of forming poisonous substances appears to vary directly with the amount and nature of the albumen present in the nutrient medium; and though it grows most readily in the presence of peptone, it appears to form the most virulent poison when grown in some form or other of crude 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 healthy stomach and intestine are not favourable breeding-grounds for the cholera bacillus. In the first place, it requires an alkaline medium for its full and active development, and the acid found in a healthy stomach seems to exert an exceedingly deleterious influence upon it. Secondly, it appears to be incapable of developing except when left at rest, so that the active peristaltic movement of the intestine interferes with its development. Moreover, it forms its poison most easily in the presence of crude albumen. It is interesting to note what an important bearing these facts have on the personal and general spread of cholera. Large quantities of the cholera bacillus may be injected into the stomach of a guinea-pig without any intoxicative or other symptoms of cholera making their appearance. Further, healthy individuals have swallowed, without any ill effect, pills containing the dejecta from cholera cases, although cases are recorded in which "artificial" infection of the human subject has undoubtedly taken place, whilst, as Metchnikoff demonstrated, very young rabbits, deriving milk from mothers whose mammary glands have been smeared with a culture of the cholera vibrio, soon succumbed, suffering from the classical symptoms of this disease.

If, however, previous to the injection of the cholera bacillus the acidity of the stomach be neutralized by an alkaline fluid, especially if at the same time the peristaltic action of the intestine be paralysed by an injection of morphia, a characteristic attack of cholera is developed, the animal is poisoned, and in the large intestine a considerable quantity of fluid faeces containing numerous cholera bacilli may be found. There appear to be slight differences in the cholera organisms found in connexion with different outbreaks, but the main characteristics are preserved throughout, and are sufficiently distinctive to mark out all these organisms as belonging to the cholera group. Amongst the known predisposing causes of cholera are the incautious use of purgative medicines, the use of unripe fruit, insufficient food and intemperance. These may be all looked upon as playing the part of the alkaline solution in altering the composition of the gastric juices, and especially as setting up alkaline fermentation in the stomach and small intestine; beyond this, however, the irritation set up may bring about an accumulation of inflammatory serous fluid, from the albumens of which, as we have seen, the cholera organism has the power, of producing very active toxins.

The part played by want of personal cleanliness, overcrowding and unfavourable hygienic conditions may be readily understood if it be remembered that the cholera bacillus may grow outside the body. The number of cases in which epidemics of cholera have been traced to the use of drinking-water contaminated with the discharges from cholera patients is now considerable. The more organic matter present the greater is the virulence of water so contaminated; and the addition of such water to milk has, in one instance at least, led to an outbreak. If cholera dejecta be sprinkled on moist soil or damp linen, and kept at blood-heat, the bacillus multiplies at an enormous rate in the first twenty-four or thirty-six hours; but, as seen in the Dunbar-Schottelius method, at the end of three or four days it 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 propagation of the disease can scarcely be over-estimated. Water which contains an ordinary amount of organic and inorganic matter in solution does not allow of the multiplication of this organism, which may soon die out; but when organic matter is present in excess, as at the margin of stagnant pools and tanks, development occurs, especially on the floating solid particles. This bacillus grows at a temperature of 30° C. on meat, eggs, vegetables and moistened bread; also on cheese, coffee, chocolate and dilute sugar solutions. In some experiments carried out by Cartwright Wood and the writer in connexion with the passage of the cholera organism through filters it remained alive in the charcoal filtering medium for a period of at least forty-two days, and probably for a couple of months. It must be remembered that cholera bacilli are gradually overcome or overgrown by other organisms, as only on this supposition can the immunity enjoyed by certain regions, even after the water and soil have been contaminated, provided that no fresh supply is brought in " to relight the torch," be explained. In most of the regions in which cholera remains endemic the wells are merely dug-out pits beneath the slightly raised houses, and are open for the reception of sewage and excreta at all times. These dejecta contain organic material which serves as a nutriment on which infective organisms, derived from the soil and ground-water, may flourish. Not only dejecta, but also the rinsings from soiled linen and utensils used by cholera patients should be removed as soon as possible, "without allowing them to come into contact with the surface of the soil, with wells," or with vegetables and the like. The discovery of Koch's comma bacillus has so altered our conceptions of the aetiology of this disease that we now study the conditions under which the bacillus can multiply and be disseminated, instead of concerning ourselves with the cholera itself as some definite entity. Telluric agencies become merely secondary factors, the dissemination of the disease by winds from country to country is no longer regarded as being possible, whilst the spread of cholera epidemics along the lines of human intercourse and travel is now recognized. The virulent bacillus requires the human organism to carry it from those localities in which it is endemic to those in which epidemics occur. The epidemiologist has come to look upon the study of the cholera organism and the conditions under which it exists as of more importance than mere local conditions, which are only important in so far as they contribute to the propagation and distribution of the cholera bacillus, and he knows that the only means of preventing its spread is the careful inspection of everything coming from cholera-stricken regions. He also recognizes that the herding together of people of depressed vitality, under unhygienic and often filthy conditions, in quarantine stations or ships, is one of the surest means of promoting an epidemic of the disease; that attention should be confined to the careful isolation of all patients, and to the disinfection of articles of clothing, feeding utensils, and the like; that the comma bacillus can only be driven out of rooms by means of light and fresh air; that thorough personal, culinary and household cleanliness is necessary; that all water except that known to be pure should be carefully boiled; and that all excess, both in eating and drinking, should be avoided. The object of the physician in such cases must be first to isolate as completely as possible all his cholera patients, and then to get rid of all predisposing causes in the patients themselves, causes which have already been indicated in connexion with the aetiology of the disease.

Attention has frequently been drawn to the fact that patients who have lived for some time in a cholera region, or who have already suffered from an attack of cholera, appear to enjoy a partial immunity against the disease. Haffkine, working on the assumption that the symptoms of cholera are produced by a toxin formed by the cholera organism, came to the conclusion that, by introducing first a modified and then a more virulent poison directly into the tissues under the skin, and not into the alimentary canal, it would be possible to obtain a certain insusceptibility to the action of this poison. He found that for this purpose the cholera bacillus, as ordinarily obtained in pure culture from the intestinal canal, is too potent for the preliminary inoculation, but is not sufficiently active for the second, if any marked protection is to be obtained. By allowing the organism to grow in a well-aerated culture the virulence is gradually diminished, and this virulence, once abolished, does not return even when numerous successive cultures are made on agar or other nutrient media. On the other hand, by passing the cholera bacillus successively through the peritoneal cavities of a series of about thirty guinea-pigs, he obtains a virus of great activity; this activity is soon lost on agar cultivations, and i t is necessary, from time to time, again to pass the bacillus through guinea-pigs, three or four passages now being sufficient to reinforce the activity.

From these two cultures the vaccines are prepared as follows: The surface of a slant agar tube is smeared with the modified cholera organism. After this has been allowed to grow for twentyfour hours, a small quantity of sterile water is poured into the tube, and the surface-growth is carefully scraped off and made into an emulsion in the water; this is then poured off, and the process is repeated until the whole of the growth has been removed. The mixture is made up with water to a bulk of 8 c.c., so that if i c.c. is injected the patient receives a of a surface-growth; it is found that this quantity, when injected subcutaneously into a guinea-pig, gives a distinct reaction, but does not cause necrosis of the tissues. If the vaccine is to be kept for any length of time, the emulsion is made with o 5% carbolic acid solution, prepared with carefully sterilized water, and the mixture is made up to 6 c.c. instead of 8 c.c., since the carbolic acid appears to interfere slightly with the activity of the virus. The stronger virus is prepared in exactly the same way. The preliminary injection, which is made in the left flank, is followed by a rise in temperature and by local reaction.

After three or four hours there is noticeable swelling and some pain; and after ten hours a rise in temperature, usually not very marked, occurs. These signs soon disappear, and at the end of three or four days the second injection is made, usually on the opposite side. This is also followed by a rise of temperature, by swelling, pain and local redness: these, however, as before, soon pass off, and leave no ill effects behind. A guinea-pig treated in this fashion is now immune against some eight or ten times the lethal dose of cholera poison, and, from all statistics that can be obtained, a similar protection is conferred upon the human being.

Pfeiffer found that when a small quantity of the cholera vibrio is injected into the peritoneal cavity of a guinea-pig highly immunized against cholera by Haffkine's or a similar method, these vibrios rapidly become motionless and granular, then very much swollen and finally " dissolve." This is known as Pfeiffer's reaction. A similar reaction may be obtained when a quantity of a culture of the cholera vibrio mixed with the serum derived from a guinea-pig immunized against the cholera vibrio, or from a patient convalescent from the disease, is injected into the peritoneal cavity of a guinea-pig not subjected to any preliminary treatment; and, going a step further, it was found that the dissolution of the cholera vibrio is brought about even when the mixture of vibrio and serum is made in a test tube. On this series of experiments as a foundation, the theory of acquired immunity has been reared.

Evidence has been collected that spirilla, almost identical in appearance with the cholera bacillus, may be present in water and in healthy stools, and that it is in many cases almost impossible to diagnose between these and the cholera bacillus; but although these spirilla may interfere with the diagnosis, they do not invalidate Koch's main contention, that a special form of the comma bacillus, which gives a complete group of reactions, is the cause of this disease, especially when these reactions are met with in an organism that comes from the human intestine. Typhoid Fever. - Our information concerning the aetiology of typhoid fever was largely increased during the last twenty years of the 19th century. In 1880 Eberth and Klebs independently, and in 1882 Coats, described a bacillus which has since been found to be intimately associated with typhoid fever. This organism (Plate II. fig. 4) usually appears in the form of a short bacillus from 2 to 3µ in length and 0.3 to o 5,u in breadth; it has slightly rounded ends and is stained at the poles; it may also occur as a somewhat longer rod more equally stained throughout. Surrounding the young organism are numerous long and well-formed flagella, which give it a very characteristic appearance under the microscope. At present there is no evidence that the typhoid bacillus forms spores. These bacilli are found in the adenoid follicles or lymphatic tissues of the intestine, in the mesenteric glands, in the spleen, liver and kidneys, and may also be detected even in the small lymphoid masses in the lung and in the post-typhoid abscesses formed in the bones, kidneys, or other parts of the body; indeed, it is probable that they were first seen by von Recklinghausen in 1871 in such abscesses. They undoubtedly occur in the dejecta of patients suffering from typhoid fever, whilst in recent years it has been demonstrated that they may also be found in the urine. It is evident, therefore, that the urine, as well as the faeces, may be the vehicle by means of which the disease has been unwittingly spread in certain otherwise inexplicable outbreaks of typhoid fever, especially as the bacillus may be present in the urine when the acute stage of the disease has gone by, and when it has been assumed that, as the patient is convalescent, he is no longer a focus from which the infection may be spread. Easton and Knox found typhoid bacilli in the urine of 21% of a series of their typhoid patients.

In 1906 Kayser demonstrated what had previously been suspected, that the typhoid bacilli may persist for considerable periods in the bile duct and gall bladder, whence they pass into the intestinal tract and are discharged with the evacuations. Patients in whom this occurs are spoken of as " typhoid carriers." They become convalescent and except that now and again they suffer from slight attacks of diarrhoea they appear to be perfectly healthy. It has been observed, however, especially during these attacks of diarrhoea, that typhoid bacilli may be found in the faeces. Curiously enough the bacilli are as virulent as are those isolated when the disease is at its height. Hence these typhoid carriers are exceedingly dangerous centres of infection, and as women act as " carriers " much more frequently than do men, although, as is well known, typhoid fever attacks men much more frequently than women, the facilities for the distribution of the disease are great, as women so frequently act as laundresses, cooks, housemaids, nurses and the like. Frosch states that out of 6708 typhoid patients 310 excreted bacilli for more than io weeks after convalescence; 144 of these were no longer infective at the end of three months; 64 had ceased to be infective at 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, but from a critical examination of the histories of 25 such carrier cases he was convinced that 14 had been continuously infective for from four to nine years. Dr Donald Greig, in 1908, reported a case in which the patient appears to have been a typhoid carrier for fiftytwo years from the time of convalescence. Frosch pointed out, what has now been fully confirmed, that the bacilli in these cases though often present in the faeces in enormous numbers may disappear and again reappear from time to time, and that a continuous series° of examinations is necessary before a convalescent patient can be acquitted of being a " typhoid carrier." In this connexion it is interesting to note that Blumenthal and Kayser have discovered typhoid bacilli in the interior of gall-stones. Drs Alexander and J. C. G. Ledingham, examining the 90 female patients and attendants in a Scottish asylum in which, during some four or five years, 31 cases of typhoid had occurred in small groups in which the source of infection could not be traced to any recognized channel, found amongst them three " typhoid carriers." The importance of such a discovery amongst asylum patients may be readily understood when the careless and uncleanly habits of insane patients are borne in mind. As it has been demonstrated that the typhoid bacillus is found, not merely in the lymphatic tissue but, in 75% of the cases, actually circulating in the blood, the appearance of the bacillus in the secretions and excretions may be readily understood.

There can be little doubt that typhoid bacilli are not, as is very frequently assumed, present merely in the lymphatic glands and in the spleen (see Plate II. fig. 5): they may be found in almost any part of the lymphatic system, in lymph spaces, in the connective tissues, where they appear to give rise to marked proliferation of the endothelial cells, and especially in the various secreting organs. It is probable that the proliferation often noticed in the minute portal spaces in the liver, in cases of typhoid fever, is simply a type of a similar proliferation going on in other parts and tissues of the body. It was for long assumed 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 present than is usually met with in water. The fact, however, that the organism may remain alive in water is of great importance; and, as in the case of cholera, it must be recognized that certain of the great epidemics of typhoid or enteric fever have been the result of " water-borne infection." The bacillus, a facultative parasite, grows outside the body, with somewhat characteristic appearances and reactions: it flourishes specially well on a slightly acid medium; in the presence of putrefactive organisms which develop strongly alkaline products it may gradually die out, but it appears to retain its vitality longer in the presence of acid-forming organisms. It may, however, be stated generally that after a time the typhoid bacillus becomes weakened, and may even die out, in the presence of rapidly growing putrefactive organisms. In distilled water it may remain alive for a considerable period - five or six weeks, or even longer. It grows on all the ordinary nutrient media. It does not coagulate milk; hence it may grow luxuriantly in that medium without giving rise to any alteration in its physical characters; contaminated milk, therefore, is specially dangerous affording as it does an excellent vehicle for the dissemination of the typhoid bacillus which may also be conveyed by food and even by water. To food the bacillus is readily conveyed by flies, on their limbs or by the proboscis, which become infected by the excrement on which they crawl and feed. The observations of physicians working amongst the British troops in South Africa afford abundant evidence that the typhoid bacillus may also be carried along with dust from excreta to fresh patients, for although these bacilli die very rapidly when they are desiccated, they remain alive sufficiently long to enable them to multiply and flourish when again brought into contact with moist food, milk, &c.

When inoculated on potato, careful examination will reveal the 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. 3.

FIG. 4.

FIG. 2.

FIG. 5.

v

FIG. 7.

FIG. 9.

FIG. IO.

FIG. I I.

FIG. 12.

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 woo diams.) FIG. 3. - Cholera spirillum, from eight days' agar culture, showing many involution forms. Flagella well stained. (X woo.) FIG. 4. - Bacillus typhi abdominalis (typhoid bacillus), with well-stained flagella. Young agar cultivation. (X 1000.) FIG. 5. - Group of typhoid bacilli, in a section of spleen. (X woo.) FIG. 7. - Preparation from young cultivation of Bacillus pestis (plague bacillus). Flagella well stained (x 1000.) FIG. 9. - Bacillus diphtheriae, from twenty-four hours' culture. (X moo.) FIG. I o. - Free edge of false membrane from case of diphtheria containing numerous diphtheria bacilli. (X woo.) FIG. II. - Bacillus tetani, with well-stained flagella. Twenty-four hours' culture. (X woo.) FIG. 12. - Scraping from a wound in a case of tetanus, showing several spore-bearing and a few nonspore-bearing tetanus bacilli. (X woo.) FIG. 15. - Bacillus tuberculosis. Bacilli in a giant-cell in the human liver in a case of acute tuberculosis. (X moo.) FIG. 16. - Bacillus leprae. Bacilli in endothelial cells of splenic tissue. (X woo.) FIG. 19. - Amoebae in 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 less luxuriant growth. This organism, when taken from young broth cultures twelve to twenty-four hours old - during the period at which flagella are best seen - and examined microscopically, exhibits very lively movements. When, as pointed out 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 formed which is found to be made up of masses or clumps of typhoid bacilli which have lost their motility. This reaction is so characteristic and definite, that when the mixture is kept under examination under the microscope, it is quite possible to follow the slowing-down movement and massing together of the organisms. It is found, moreover, that normal diluted bloodserum has no such effect on the bacilli. This property of the blood-serum is acquired at such an early date of the disease - sometimes even at the end of the first week - and occurs with such regularity, that typhoid fever may now actually be diagnosed by the presence or absence of this " agglutinating " property in the blood. If serum taken from a patient supposed to be suffering from typhoid fever, and diluted with saline solution to i in io, to 1 in 50, or in still greater dilution, causes the bacilli to lose their motility and to become aggregated into clumps within an hour, it may be concluded that the patient is suffering from typhoid fever; if this agglutination be not obtained with a dilution of 1 in io, in from 15 to 30 minutes, experience has shown that the patient is not suffering from this disease. Certain other diseases, such as cholera, give a similar specific serum reaction with their specific organisms. These sera have, in addition, a slight common action - a general agglutinating power - which, however, is not manifested except in concentrated solutions, the higher dilutions failing to give any clumping action at all, except with the specific bacillus associated with the disease from which the patient, from whom the serum is taken, is suffering.

Wright and Semple, working on Haffkine's lines, introduced a method of vaccination against typhoid, corresponding somewhat to that devised by Haffkine to protect against cholera. They first obtained a typhoid bacillus of fairly constant virulence and of such strength and power of multiplication that an agar culture of 24 hours growth when divided into four, and injected hypodermically, will kill four fairly large guinea-pigs, each weighing 350 to 400 grammes. A similar culture emulsified in bouillon or saline solution and killed by heating for five minutes at 60° C. is a vaccine sufficient for from four to twenty doses. In place of the agar culture a bouillon culture heated for the same period may be used as the vaccine. In either case the vaccine is injected under the skin of the loin well above the crest of the ileum. This injection is usually followed by local tenderness and swelling within three or four hours, and swelling and tenderness in the position of the nearest lymphatic glands, marked malaise, headache, a general feeling of restlessness and discomfort and a rise of temperature. The blood of a patient so treated early causes agglutination of typhoid bacilli and acts on these bacilli much as does cholera serum in Pfeiffer's reaction. At the end of ten days a second and stronger dose is given. After each injection there is, according to Wright, a " negative phase " during which the patient is somewhat more susceptible to the attacks of the typhoid bacillus. This negative phase soon passes off and a distinct positive or protected phase appears. The practical outcome of this is that wherever possible a, patient who is going into a typhoid infected 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 agglutinative and lytic powers of the serum continue to rise and the patient so vaccinated is far less susceptible to the action of the typhoid bacillus. It is recorded in favour of this method of treatment that of 4502 soldiers of the Indian army inoculated 0.98% contracted typhoid, while of 25,851 soldiers of the same army who were not inoculated over 21% (2.54) contracted typhoid. Similarly, at Ladysmith, of the whole of the besieged soldiers only 1705 had been inoculated, but of these only 2% contracted typhoid, whilst of 10,529 uninoculated men 14% were attacked. Wright, who has been indefatigable in carrying out and watching this method of treatment, has been able to accumulate statistics dealing with 49,600 individuals - of these 8600 were inoculated, and 24% contracted typhoid, 12% of these succumbing to the disease. Of the 41,000 uninoculated men 54% contracted the disease, 21% of those attacked succumbing.

Mediterranean or Malta Fever. - Until comparatively recently, Mediterranean fever was looked upon as a form of typhoid fever, which in certain respects it resembles; the temperature curve, however, has a more undulatory character, except in the malignant type, where the temperature remains high throughout the course of the attack. According to Hughes, this disease is widely distributed in the countries bordering upon the Mediterranean south of latitude 46° N., and along the Red Sea littoral. Analogous forms of fever giving a " specific " serum reaction with the micrococcus of this disease are also met with in parts of India, China, Africa and America.

The Micrococcus melitensis vel Brucei ( 1887), which is found most abundantly in the enlarged spleen of the patient suffering from Malta fever, is a very minute organism (o 33µ in diameter), ovoid or nearly round, arranged in pairs or in very short chains. If a drop of the blood taken directly from the spleen be smeared over the surface of agar nutrient medium, minute transparent colourless colonies appear; in thirty-six hours these have a slight amber tinge, and in four or five days from their first appearance they become opaque. These colonies, which flourish at the temperature of the human blood, cease to grow at the room-temperature except in summer, and if kept moist, soon die at anything below 60° F., though when dried they retain their vitality for some time. As the organism grows and multiplies in broth there is opacity of the medium at the end of five or six days, this being followed by precipitation, so that a comparatively clear supernatant fluid remains. It grows best on media slightly less alkaline than human blood; it is very vigorous and may resist desiccation for several weeks.

This organism is distinctly pathogenetic to monkeys, and its virulence may be so increased that other animals may be affected by it. Though unable to live in clean or virgin soil, it may lead a saprophytic existence in soil polluted with faecal matter. Hughes maintains that the " virus " leaves the body of goats and of man along with the faeces and urine. The importance of this in ambulatory cases is very evident, especially when it is remembered that goats feeding on grass, &c. which has come in contact with such urine are readily infected. It seldom appears to be carried for any considerable distance. Infection is not conveyed by the sputum, sweat, breath or scraping of the skin of patients, and infected dust does not seem to play a very important part in producing the disease. Hughes divides the fever into three types. In the malignant form the onset is sudden, there are headache, racking pain over the whole body, nausea and sometimes vomiting; the tongue is foul, coated and swollen, and the breath very offensive; the temperature may continue for some time at 103° to 105° F. The stools in the diarrhoea 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 periods in which the patient appears to be improving. These pyrexial curves, from one to seven in number, average about ten days each, the first being the longest, - eighteen to twenty-three days. In an intermittent type, in which the temperature-curve closely resembles the hectic pyrexial curve of phthisis or suppuration, the " undulatory " character is also marked. A considerable number of toxic symptoms make their appearance - localized neuritis, synovitis, anaemia, emaciation, bronchial catarrh, weakness of the heart, neuralgia, profuse night-sweats and similar conditions. Patients otherwise healthy usually recover, even after prolonged attacks of the disease, but the mortality amongst patients suffering from organic mischief of any kind may be comparatively high. The diagnosis from malaria, phthisis, rheumatic affections and pneumonia may, in most cases, be made fairly easily, but the serum agglutinating reaction (first demonstrated by Wright in 1897) with cultures of the Micrococcus melitensis, corresponding to the typhoid reaction with the typhoid bacillus, is sometimes the only trustworthy feature by which a diagnosis may be made between this fever and the above-mentioned diseases. About 50% of the goats in Malta give a positive agglutinative reaction and about io % excrete milk which contains the micrococcus.

Sir David Bruce, in his investigations on the tsetse fly disease, pointed out that certain wild animals although apparently in 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, manifestations of Malta fever. Indications as to the direction in which to look were given in the following fashion. There was a strike amongst the dairymen supplying the barracks in Malta and it became necessary to replace the goat's milk in the dietary of the troops by condensed milk. What followed ? In the first half of the year 1906 there had been 144 cases (in 1905 there had been 750 cases), in the second half after the alteration of the milk supply, only 32 cases were recorded and in 1907, 7 cases during the whole year. In the navy during the same period there were, in 1905, 498 cases, in 1906, 248 cases and, from January to September 1907, not a single case.

The most common method of infection is by the ingestion of milk, but the milk when handled may also give rise to infection through finding its way into cuts, bruises, &c. In the goat the disease is of an extremely mild character, the clinical symptoms, which are present for two or three days only, being easily overlooked. In spite of this the goat is highly susceptible to the infection either by the various methods of inoculation or as the result of feeding with contaminated or infected material. The micrococcus is often found in the circulating blood from which it may be excreted along with the urine and faeces. In time, however, it disappears, first from the general circulation and most of the viscera, persisting longest in the spleen, kidneys and lymphatic glands. In the later stages of the disease the micrococcus is found in the milk even after it has disappeared from the above glands. It is during this stage that the milk of the goat is so dangerous, as now and again it may contain an enormous number of the specific micrococcus varying " within wide limits from day to day," although bearing " no relationship to. the severity of the infection, air temperature, &c.; the presence of the Micrococcus melitensis in the milk appears to be merely the result of a mechanical flushing of the mammary glands by means of which the cocci multiplying therein are removed." As pointed out by the Mediterranean Fever Commission the micrococcus of Malta fever from its vantage ground in the milk may make its way to ordinary ice-creams and to native cheeses, in which it appears to retain its full virulence. Monkeys are especially susceptible to this disease, contracting it readily when they are fed with milk from an infected goat. In 1905 an interesting experiment was, unintentionally, carried out. An official of the United States Bureau of Animal Industry visiting Malta in the summer of that year purchased a herd of 61 milch-goats and four billy goats. These were shipped via Antwerp to the United States. On arrival at Antwerp the goats were transferred to a quarantine station, where they remained for five days and were then consigned by steamer to New York. On board the SS. " Joshua Nicholson," which took the goats from Malta to Antwerp, were twenty-three officers and men; ten out of the twenty-three were afterwards traced. One was found to have been infected by M. melitensis at an unknown date, and eight had subsequently suffered from febrile attacks, five yielding conclusive evidence of infection by M. melitensis. It is interesting to note, however, that two men who boiled the milk before drinking it, and an officer and a cabin-boy who disliked the milk and did not drink it at all, came off scot free.

These cases taken by themselves might leave the question somewhat open, as there was a possibility that the men attacked might have been in contact with infected patients in Malta. A far more conclusive case was the following. A woman at the quarantine station at Athenia, N. J., U.S.A., who partook freely of the mixed milk from several goats, over a considerable period, suffered from a typical attack of Mediterranean fever some nine or ten weeks after the goats had been landed in America. In this case " contact " with and other modes of exposure to infection by human patients could all be eliminated.

It may be held then that the M. melitensis leads a more or less passive existence in the body of the Maltese goat, only exercising its full pathogenic action when it gains entrance to the human body. There is some slight evidence that the Micrococcus melitensis may remain alive with its virulence unimpaired even when taken up by the mosquitoes Acartomyia and Stegomyia, and again in the common blood-sucking fly, Stomoxys, for a short period, four or five days. It can be recovered for a longer period and still in a fairly virulent condition from the excreta of these insects. In spite of this, transmission of the disease by these insects, though apparently possible, does not appear to be of very frequent occurrence. Inoculation with a vaccine prepared from the Micrococcus melitensis appears to exert a protective influence for a period of about four months, after which time there is a marked diminution in the immunity conferred by this vaccination.

Relapsing Fever

The specific cause of relapsing fever (famine fever) appears to be the Spirillum Obermeieri, an organism which occurs in the blood (during the febrile stages) of patients suffering from this disease. Between the febrile stages are periods of intermission, during which the spirillum disappears from the blood and, apparently, retires to the spleen. This disease, in epidemic form, follows in the footsteps of famine and destitution, specially affecting young people between the ages of fifteen and twenty; it seldom attacks children under five years of age, but when it attacks patients over thirty it assumes a very virulent form. In monkeys inoculated with blood containing the Spirillum Obermeieri the first symptoms appear between the second and sixth days. In the human subject this incubation period may last as long as three weeks; then comes 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 long as the first. The spirilla, the cause of this disease, are fine spirals with pointed ends, three or four times as long as the diameter of a red blood corpuscle. Although it has as yet been found impossible to cultivate these spirilla outside the body, human beings, and monkeys injected with blood containing them, contract the disease; and in monkeys it has been found that during the period before the relapse the spirilla have made their way into the cells of the spleen. As yet little is known as to the mode of development of these organisms, and of the method of their transmission from one patient to another, but it is thought that, as in the case of malaria and the tsetse-fly disease, they may be carried by bloodsucking insects. Relapsing fever is distinguished from typhoid fever by its sudden onset, and by the distinct intermissions; and from influenza by the enlargement of the spleen and liver. The most satisfactory method of diagnosis is the examination of the blood for the presence of the spirillum during the febrile stage. The postmortem 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 degeneration of the heart and voluntary muscles may also be met with.

Plague

During recent years opportunities for the study of 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 Plate II., 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, pearshaped 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 time apparently almost insuperable, has at last been overcome, as it has been found that although the acute pneumonic plague is undoubtedly highly contagious, the spread of the bubonic and septicaemic forms could not be explained on the same hypothesis. As the pneumonic form is met with in only about 2 . 5% of the whole of the cases, transmission by direct contagion seems to be an utterly inadequate explanation. In the autumn of 1896, when the plague broke out in India, and those dealing with the outbreak came to the conclusion that certain houses were centres of infection, it was noticed that these houses were most infective at night, and that they might actually be centres of infection although uninhabited; indeed the infection seemed to spread to houses between which and the infected house there appeared to be no intercommunication of any kind. This seemed to be inexplicable except on the assumption that the infective agent, the Bacillus pestis, was, in some way or other, carried by animals. It had already been noted that rats disappeared from plague-stricken houses, many dying before the appearance of the plague in the human population. Simond, noting these conditions, suggested that the plague bacillus might be transmitted by the flea from rat to rat and from rat to man. Although he was not able to demonstrate this connexion he indicated a line of research to other observers, who, as knowledge accumulated, were able to complete each link in the chain of infection. The plague bacillus having been found in the rat, the next step was to demonstrate its presence in the flea, and living plague germs were found in the stomachs of fleas inhabiting plague-infected houses. Several species seem to be able to transmit this germ, but in none of them does the plague bacillus appear to undergo any special development - alternation of generations or the like - as in the case of the protozoon of malaria in its passage from and to the mosquito and the human subject - it simply passes unchanged through the alimentary canal of the flea, is excreted in the faeces, and is carried into the wound made by the epipharynx-mandibles of the flea.

At least three species of animals, two rats and the human subject, and three species of fleas are involved in this chain. The rat fleas are Pulex cheopis found in India, and Ceratophyllus fasciatus, the rat flea of northern Europe, and Pulex irritans, the common flea, all of which have the power of transmitting the disease. In India of course the Pulex. cheopis, usually solely associated with rats, seems to play the most prominent part. The two rats involved are the Mus decumanus, or brown rat, which is found in the sewers and develops the plague first, and the Mus rattus, the common black house-rat. From the sewer-rat the house-rat is infected, and from the house-rat man. Under ordinary conditions rat fleas do not attack the human subject, but, as the rats are attacked by plague and die, the infected fleas, starve out as it were, leave them and transfer their attentions to other animals and the human subject, infecting many of those they bite. Colonel Bannerman maintains that this infection takes place in the majority of cases, by this chain of transmission, and that there is no evidence that the excreta of these rats infect food or contaminate the soil. Colonel Lamb, summarizing the experimental evidence on this question, writes: " I. Close contact of plague-infected animals with healthy animals, if fleas are excluded, does not give rise to an epizootic among the latter. As the godowns (experimental huts) were never cleaned out, close contact includes contact with faeces and urine of infected animals, and contact with and eating of food contaminated with faeces and urine of infected animals as well as with pus from open plague ulcers; (2) close contact of young, even when suckled by plague-infected mothers, did not give the disease to the former; (3) if fleas are present, then the epizootic, once started, spreads from animal to animal, the rate of progress being in direct proportion to the number of fleas present; (4) an epizootic of plague may start without direct contact of healthy animal and infected animal; (5) the rat flea can convey plague from rat to rat; (6) infection can take place without any contact with contaminated soil; (7) aerial infection is excluded." The experiments lead to the conclusion that fleas and fleas alone, are the transmitting agents of infection. Bannerman gives in concise form similar evidence in relation to naturally infected native houses. Infection is carried from place to place by fleas, usually on the body or in the clothing of the human being. Such fleas, fed on infected blood, may remain alive for three weeks, and of this period, we are told, may remain infective for fifteen days. At the first opportunity these fleas forsake the human host and return to their natural host the rat. In most of the epidemics there is a definite sequence of events. First the brown rats are attacked, then the black rats, then the human subject, and Colonel Lamb suggests that after the rat disappears the flea starves for about three days and then attacks the human subject. Then comes the incubation period of plague, three days. Following this is the period of average duration of the disease, five or six days. This time-table, he says, corresponds to the period - when the epidemics are at their height - that intervenes between the maximum death-rate in rats and the maximum death-rate in man, about ten to fourteen 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 of modern medicine.

In India, where the notions of cleanliness are somewhat different from those recognized in Great Britain, most of the conditions favourable to the spread of the plague bacillus are of the most perfect character. This organism may pass into the soil with faeces; it may there remain for some time, and then be taken into the body of one of the lower animals, or of man, and give rise to a fresh outbreak. Kitasato and Yersin were both able to prove that soil and dust from infected houses contain the bacillus, that such bacillus is capable of inducing an attack of plague in the lower animals, and that flies fed on the dejecta or other bacillus-containing material, die, and in turn contain bacilli which are capable of setting up infection. Hankin claims that ants may carry the plague to and from rats, and so to the human being. It has already been mentioned that the organism rapidly loses its virulence when cultivated outside the body; on the other hand, on being passed through a series of animals its virulence gradually increases. Thus may be explained the fact that in most outbreaks of plague there is an early period during which the death-rate is very low; after a time the percentage mortality is enormously increased, the virulence of the disease being very great and its course rapid. There seem to be notable differences in the degree of susceptibility of different races and different individuals, and those who have passed safely through an attack appear to have acquired a marked degree of immunity. ' I Two methods of treatment, both of which seem to have been attended with a certain degree of success, are now being tried. Haffkine, who was the first to produce a vaccine for the treatment of cholera, prepared a vaccine of a somewhat similar type for the treatment of plague. For this the Bacillus pestis is cultivated in flasks of bouillon; to this small drops or particles of ghee (Indian butter) are added; these form centres around which the organisms may develop. As the organisms multiply they grow down into the broth, but gradually becoming fewer in number as the floating mass on the surface is left, they fine down to a point and so come to resemble stalactites. These are broken off, from time to time, by shaking, others immediately beginning to form in their place. This may go on for six weeks. The flask with its contents is then well shaken and heated in a water bath to 70° C. for from one to three hours. On testing by culture the fluid should now be sterile, i.e. no bacilli should remain alive, and the fluid, ready for use, may be injected into the subcutaneous tissues of the arm in a dose of from 3 cc. for a man and 2 to 22 cc. for a woman, children receiving relatively small amounts. A rise of temperature, followed by malaise and headache, which pass off in about 24 hours, is soon noted, and some local swelling and redness appear at the seat of injection. The Indian Plague Commission were satisfied that the use of this vaccine diminishes the incidence of attacks of plague, and that, although it does not confer a complete immunity against the disease, the case mortality is lowered. They are of opinion also that protection is not conferred at once, but Lieut.-Colonel Bannerman states that the protection is immediate and lasts for six or even twelve months. In the official report (Annual Report of the Sanitary Commissioner with the Government of India) for 1904 occurs the following: " That its value is great is certain, not only does it largely diminish the danger of plague being contracted, but, if it fails to prevent the attack, the probability of a fatal event is reduced by one-half." This method of treatment, however, is of no avail in the case of patients already attacked; for such cases Yersin's serum treatment must be called in. Various other vaccines have been described, but all consist of some form of killed or attenuated bacilli, and the results attained do not vary very greatly. Yersin, who first demonstrated the plague bacillus also devised the method of preparing an " antipest serum." A horse was inoculated repeatedly, at intervals, and with gradually increasing doses of living plague bacilli. It was afterwards found that cultures sterilized by heat served equally well for this inoculation of the horse and of course were much more xx. 25 a easily worked with. This process of preparation may have to be continued for from six months to a year. The horse is then bled and from the clot the serum is separated, care being taken to determine by injection of the blood into mice that no living bacilli have by accident made their way into, and remained in, the horse's blood. The serum is not considered to be sufficiently active until a drop and a half will protect the mouse against a dose of living bacilli fatal to a control mouse in from 48 to 60 hours. When this serum is injected in sufficiently large doses subcutaneously in mild cases, and subcutaneously and intravenously (Lancet, 1903, i. 1287) in more severe cases in doses of 150 to 300 cc. the results seem to be excellent, especially when the serum is injected into the tissues around the bubo or swellings formed in this disease. Calmette and Salimbeni used the serum in 142 cases in the Oporto outbreak. Amongst these they had a mortality of under 15%, whilst amongst 72 patients not so treated the death-rate was over 63%. This serum kills the bacilli and at the same time neutralizes the toxin formed during the course of the disease. The best results are obtained when large doses are given, and when the serum injected subcutaneously is thrown into the area in which the lymph flows towards the bubo. As in the case of the diphtheria antitoxic serum joint pains and rashes may follow its exhibition, but no other ill effects have been noted.

Pneumonia

The case in favour of acute lobar pneumonia being an infective disease was a very strong one, even before it was possible to show that a special organism bore any aetiological relation to it. In 1880, Friedlander claimed that he had isolated such an organism, but the pneumo-bacillus then described appears to be inactive as compared with the pneumococcus isolated by Fraenkel and Talamon. This latter organism which is usually found in the sputum, is an encapsuled diplococcus. Grown on serum or agar over which sterile blood has been smeared, it occurs as minute, glistening, rather prominent points, almost like a fine spray of water or dew. When the organism is cultivated in broth the capsule disappears, and chains of diplococci are seen. It resembles the influenza bacillus in a most remarkable manner. It may be found, in almost every case of pneumonia, in the " rusty " or " prune-juice " sputum. Injected into rabbits, it produces death with very great certainty; and by passing the organism through these animals its virulence may be markedly increased. Like the influenza bacillus and even the diphtheria bacillus, this organism may be present in the mouth and lungs of perfectly healthy individuals, and it is only when the vitality of the system is lowered by cold or other depressing influences that pneumonia is induced; two factors, the presence of the bacillus and the lowered vitality, being both necessary for the production of this disease in the human subject. It is quite possible, however, that, as in the case of cholera, a slight inflammatory exudation may supply a nutrient medium in which the bacillus rapidly acquires greatly increased virulence, and so becomes a much more active agent of infection.

It is claimed by the brothers Klemperer, by Washbourn and by others, that they have been able to produce an anti-pneumococcic serum, by means of which they are able to treat successfully severe cases of pneumonia. The catarrhal pneumonia so frequently met with during the course of whooping-cough, measles and other specific infective fevers, is also in all probability due to the action of some organism of which the influenza bacillus and the Diplococcus pneumoniae are types.

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

1. The first form, acute infective or epidemic cerebro-spinal meningitis, is usually associated with Weichselbaum's Diplococcus intracellularis meningitidis (two closely apposed disks), which is found in the exudate, especially in the leucocytes, of the meninges of the brain and cord. It grows, as transparent colonies, on blood-agar at the temperature of the body, but dies out very rapidly unless reinoculated, and has little pathogenetic effect on any of the lower animals, though under certain conditions it has been found to produce meningitis when injected under the dura mater.

More or less successful attempts have been made to treat acute epidemic cerebro-spinal meningitis by means of antisera obtained from different sources. Flexner uses the serum of horses that have been highly immunized against numerous strains of the meningococcus, the process of immunization extending over four or five months. Meister, Lucius and Bruning supply Ruppel's antibacterial serum derived from animals immunized against several strains of meningococcus of high pathogenic activity. Both these sera may be looked upon as polyvalent sera. Ivy Mackenzie and Martin, pointing out that the cerebro-spinal fluid, even of patients who have recovered from this form of meningitis, contains no antibodies, tried and recommended injections of the patient's own blood serum into the spinal canal. In all cases the action seems to be much the same. These sera contain immune body and complement, and are distinctly bactericidal, acting on the meningococcus and rendering it much more easily taken up and digested by the white blood corpuscles. It is possible that these sera may also exert some slight antitoxic action. The serum is injected directly into the spinal canal, a corresponding quantity of the cerebro-spinal fluid having first been withdrawn by lumbar puncture. The treatment thus resembles the treatment of lockjaw, where the antitetanus serum is brought as directly as possible into contact with the nerve centres. The dose of these sera ranges from 15 to 40 cc. according to the severity of the disease. Although the general mortality of the disease is from 50 to 80%, it is stated that where Flexner's serum is used the mortality falls to 33%. The result corresponds somewhat closely to those obtained with antidiphtheria serum in diphtheria. In patients injected on the first day of the disease the mortality was only about 15%, on and from the fourth to the seventh day 22%, but after the seventh day 36%. From this it is evident that although the serum has a distinct effect in bringing about the phagocytosis of the meningococcus and the neutralization of the toxins produced, it cannot make good any damage already done to the tissues. Mackenzie and Martin treated 20 cases with the blood taken from patients suffering, or convalescent, from meningitis. Of 16 acute cases treated 14 received serum from patients who had already recovered from the disease, 8 of the patients recovered, 6 died, and 2 cases which received their own serum both recovered. In the presence of these anti-cerebro-spinal-fever sera the meningeal cocci become diminished in number and do not stain so readily, whilst, simultaneously, the polymorpho-nuclear leucocytes seem to be diminished in number. The serum should be given until the temperature becomes normal. Mackenzie and Martin assert that even normal human blood contains substances which are bactericidal to the meningeal coccus, but that these substances increase " in amount and activity in the blood serum of patients suffering from an acute or chronic meningococcic infection, and the serum of a patient recently recovered from an infection shows the evidence of the presence of these substances in a still greater degree." They were able to demonstrate, moreover, that the destructive action on the cocci depends on an immune body which requires the presence of a complement to complete the process. The cerebro-spinal fluid differs from the serum in that it does not contain substances which kill this meningeal coccus in vitro, nor are the immune body and complement present in the blood, found in this cerebro-spinal fluid. Hence the efficacy of the blood when it is called upon to replace the fluid in the cerebro-spinal canal.

2. Posterior basic meningitis, according to Dr Still, " is frequently seen during the first six months of life, a period at which tuberculous and epidemic cerebro-spinal meningitis are quite uncommon." The organism found in this disease resembles the diplococcus intracellularis meningitidis very closely, but differs from it in that it remains alive without recultivation for a considerably longer period. It is less pathogenetic than that organism, of which possibly it is simply a more highly saprophytic form. This is a somewhat important point, as it would account for the great resemblance that exists between the sporadic and the epidemic forms of meningitis.

3. In suppurative meningitis these two organisms may still be found in a certain proportion of the cases, but their place may be taken by the pneumococcus or Diplococcus pneumoniae or Fraenkel's pneumococcus - Diplococcus lanceolatus - which appears to grow in two forms. In the first it is an encapsulated organism, consisting of small oval cocci arranged in pairs or in short chains; the capsule is unstained. When the pneumococcus grows in chains - the second form - as when cultivated outside the body, on blood-serum or on agar over the surface of which a small quantity of sterile blood has been smeared, it produces very minute translucent colonies. Like Weichselbaum's bacillus, it must be recultivated every three or four days, otherwise it soon dies out. Unlike the other forms previously described, it may, when passed through animals, become extremely virulent, very small quantities being sufficient to kill a rabbit. Although the pneumococcus is found in the majority of these cases, especially in children, suppurative meningitis may also accompany or follow the various diseases that are set up by the Streptococcus pyogenes and Streptococcus erysipelatis; whilst along with it staphylococci and the Bacillus coli communis have sometimes been found. In other cases, again, there is a mixed infection of the pneumococcus and the Streptococcus pyogenes, especially in cases of disease of the middle ear. As might be expected in meningitis occurring in connexion with the specific infective diseases, e.g. influenza and typhoid fever, the presence of the specific bacilli of these diseases may 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 now generally accepted that this condition is the result of the introduction of the tubercle bacillus into the blood-vessels and lymph spaces of the meninges at the base of the brain, and along the fissures of Sylvius.

Influenza

From 1889 up to the present time, influenza has every year with unfailing regularity broken out in epidemic form in some part of the United Kingdom, and often has swept over the whole country. The fact that the period of incubation is short, and that the infective agent is extremely active at a very early stage of the disease, renders it one of the most rapidlyspreading maladies with which we have to deal. The infective agent, first observed by Pfeiffer and Canon, is a minute bacillus or diplococcus less that 1µ in length and o. 5,u in thickness; it is found in little groups or in pairs. Each diplococcus is stained at the poles, a clear band remaining in the middle; in this respect it resembles the plague bacillus. It is found in the blood - though here it seems to be comparatively inactive - and in enormous numbers in the bronchial mucus. It is not easily stained in a solution of carbol-fuchsin, but in some cases such numbers are present that a cover-glass preparation may show practically no other organisms. Agar, smeared with blood, and inoculated, gives an almost pure cultivation of very minute transparent colonies, similar to those of the Diplococcus pneumoniae, but as a rule somewhat smaller. This organism, found only in cases of influenza, appears to have the power of forming toxins which continue to act for some time after recovery seems to have taken place; it appears to exert such a general devitalizing effect on the tissues that micro-organisms which ordinarily are held in check are allowed to run riot, with the result that catarrh, pneumonia and similar conditions are developed, especially when cold and other lowering conditions co-operate with the poison. This toxin produces special results in those organs which, through over-use, impaired nutrition or disease, are already only just able to carry on their work. Hence in cases of influenza the cause of death is usually associated with the failure of some organ that had already been working up to its full capacity, and in which the margin of reserve power had been reduced to a minimum. It is for this reason that rest, nutrition, warmth and tonics are such important and successful factors in the treatment of this condition.

Yellow Fever, endemic in the West Indies and the northeastern coast of South America, may become epidemic wherever the temperature and humidity are high, especially along the seashore in the tropical Atlantic coast of North America. It appears to be one of the specific infective fevers in which the liver, kidney, and gastro-intestinal systems, and especially their blood-vessels, are affected. In 1897 Sanarelli reported, in the Annales de l'Institut Pasteur, that he had found a bacillus in the blood-vessels of the liver and kidneys, and in the cells of the peritoneal fluid, but never in the alimentary tract, of yellow fever patients. These, he maintained, were perfectly distinct from the putrefactive microbes occurring in the tissues in the later stages, their colonies not growing like those of the bacillus coli communis. They grow readily on all the ordinary artificial nutrient media, as short rods with rounded ends, usually about 2 to 4µ in length and about half as broad as they are long. They are stained by Gram's method and readily by most of the aniline dyes, are ciliated, and do not liquefy gelatine. They flourish specially 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 explanation of the special persistence of yellow fever in old, badly-ventilated ships, and in dark, dirty and insanitary sea-coast towns. Once the 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 slows down; and after some time persistent vomiting of bile comes on. At the end of three or four days the temperature and pulse fall, and there is a period during which the patient appears comparatively well; this is followed in a few hours by icterus and scanty secretion of urine. There may be actual anuria, or the small quantity of urine passed may be loaded with casts and albumen; delirium, convulsions and haemorrhages from all the mucous surfaces may now occur, or secondary infections of various kinds, boils, abscesses, suppurations and septicaemia, may result. These often prove fatal when the patient appears to be almost convalescent from the original disease. As regards prognosis, it has been found that the " lower the initial temperature the milder will the case be " (Macpherson). An initial temperature of 106° F. is an exceedingly unfavourable sign. Patients addicted to the use of alcohol are, as a rule, much more severely affected than are others. Treatment is principally directed towards prevention and towards the alleviation of symptoms, though Sanarelli has hopes that an " anti "-serum may be useful. More recently S. Flexner, working with the American Commission, isolated another organism, which, he maintains, is the pathogenetic agent in the production of yellow fever; whilst Durham and Myers maintain that a small bacillus previously observed by G. M. Sternberg and others is the true cause of this disease.

Professor Boyce, enumerating the hypotheses as to the cause of yellow fever, points out that as in the case of malaria, suspicion turned to " that form of Miasm which was supposed to arise from the mixture, in a marsh or on a mud flat, of salt with fresh water." It was early recognized that yellow fever was not carried directly from person to person, but little of definite character was known as to the poison and the method of its dissemination, and Fergusson states that " it is a terrestrial poison which high atmospheric heat generates amongst the newly arrived, and without that* heat it cannot exist." The following passage from Beauperthuy (see his collected papers published in 1891) is quoted by Boyce: " But rubbish ! the small amount of sulphuretted hydrogen or marsh gas which might arise from a marsh could not possibly hurt a fly, much less a man. It is not that, it is a mosquito called in Cumana the ` Zancudo bobo,' the striped or domestic mosquito." Beauperthuy, recently as he wrote, then stood almost alone in this opinion. Now we know that yellow fever, in common with other specific diseases, is caused by the action of an organized virus. The search for a vegetable parasite, bacillus or micrococcus, as above indicated, has been very close and strenuous, but it may now be held that up to the present no bacillus or micrococcus, well authenticated as capable of causing yellow fever, has been discovered. Latterly a search has been made for protozoal organisms, organisms similar to those present in the blood of malarious patients and like conditions, or for spirochaetes similar to those associated with relapsing fever, and Boyce draws attention to the fact that a spirochaete has recently been identified in the tissues taken from cases of yellow fever. It has however been demonstrated that the virus, whatever it may be, is carried by a species of mosquito; this seems to favour the protozoan hypothesis, especially as it is found that the Stegomyia fasciata, Fab. (or S. calopus, Meig.), after taking the blood from an infected patient is not infective immediately but only becomes capable of infecting by its bite at the end of twelve days. It would appear therefore that residence in this mosquito is necessary for the material to become fully infective. During this period some special metamorphosis may occur, and metamorphosis essential to the development of the parasite, or, on the other hand, the time may be required for it to make its way to some position from which it may emerge from the mosquito when that insect strikes." In the interval between the bite of an infected Stegomyia and the appearance of the disease (5 or 6 days) the blood of the patient contains a virus which, when taken into the mosquito, may develop into the infective material; moreover, this virus persists alive and active for three days after the disease 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 transmitted directly from the patient in secretions or in fact in anything but blood or blood-serum. The infective material, then, is present in the human subject for about eight days, during which the blood and even the blood-serum may serve as a vehicle for the infective agent. If during this period the patient is bitten by the Stegomyia the mosquito cannot distribute the infection for twelve days, but after this the power of transmitting reinfection persists for weeks and even months during cold weather when the insect is torpid. As soon, however, as the warm weather comes round and the mosquito becomes active and again begins to bite there is evidence that it still maintains its power of transmitting infection; indeed Boyce states that mosquitos infected in one year are capable of transmitting infection and starting a fresh epidemic in the following warm season. When it is remembered that a mosquito by a single bite is capable of setting up an attack of the disease, we see how important is this question.

The Stegomyia, known as the domestic or house mosquito, is spoken of as the " Tiger " mosquito, " Scots' Grey," or " Black and White Mosquito," from the fact that there is " a lyreshaped pattern in white on the back of the thorax, transverse white bands on the abdomen, and white spots on the sides of the thorax; while the legs have white bands with the last hind tarsal joint also white " (Boyce). It is also spoken of as the " cistern mosquito," as it breeds in the cisterns, barrels, water butts, &c., containing the only water-supply of many houses. It may pass through its various stages of development in any small vessels, but the larvae are not usually found in natural collections of water, such as gutters, pools or wells, if the ovipositing insect can gain access to cleaner and purer water.

The egg of the Stegomyia deposited on the water develops in from io to 20 hours into the larval form, the so-called " wigglewaggle." It remains in this stage for from 1 to 8 days, then becomes a pupa, and within 48 hours becomes a fully developed mosquito. The larvae can only develop if they are left in water, though a very small amount of water will serve to keep them alive. The eggs on the other hand are very resistant, and even when removed from water may continue viable for as long a period as three months. The Stegomyia affects clean water-butts and cisterns by preference. Consequently its presence is not confined to unhygienic districts; they may, however, " seek refuge for breeding purposes in the shallow street drains and wells in the town." The Stegomyia does not announce its advent and attack by a " ping " such as that made by the Anopheles, it works perfectly noiselessly and almost ceaselessly (from 3 p.m. to early morning) so that any human beings in its neighbourhood are not safe from its attacks either afternoon or night.

The most important prophylactic measures against the Stegomyia are ample mosquito nets " with a gauge of eighteen meshes to the inch " (Boyce), so arranged that the person sleeping may not come near the net; these nets should be used not only at night but at the afternoon siesta. Then the living room should be screened against the entrance of these pests, thorough ventilation 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 stagnant waters oiled with kerosene or petroleum, where drainage is impossible. What has been done through the carrying out of these and similar measures may be gathered from the record of the Panama Canal. In 1884 the French Panama Canal Company, employing from 15,000 to 18,000 men, lost by death 60 per 1000 annually (in 1885 over 70 per 1000). In 1904, 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, and by the end of 1907 the death-rate per annum amongst 45,000 workers was only 18 per moo, a lower death-rate than is met with in many large English towns. Similar examples might be cited from other places, but the above is sufficiently striking to carry conviction that the methods employed in carrying on the warfare against tropical diseases have been attended with unexampled success. These diseases, at one time so greatly feared, are now so much under control that some one has said " ere long we shall be sending our patients to the tropics in search of a health resort." Weil's disease, a disease which may be considered along with acute yellow atrophy and yellow fever, is one in which there is an acute febrile condition, associated with jaundice, inflammation of the kidney and enlargement of the spleen. It appears to be a toxic condition of a less acute character, however, than the other two, in which the functions and structure of the liver and kidney are specially interfered with. There is a marked affection of the gastrointestinal system, and the nervous system is also in some cases profoundly involved. Haemorrhage into the mucous and serous membranes is a marked feature. The liver cells and kidney epithelium undergo fatty changes, though in the earlier stages there is a cloudy swelling, probably also toxic in origin. Organisms of the Proteus group, which appear to have the power, in certain circumstances, of forming toxic substances in larger quantities than can be readily destroyed by the liver, and which then make their appearance in the kidney and spleen, are supposed to be the cause of this condition.

Diphtheria

In regard to no disease has medical opinion undergone greater modification than it has in respect of diphtheria. Accurately applied, bacteriology has here gained one of its greatest triumphs. Not only have the aetiology and diagnosis of this disease been made clear, but knowledge acquired in connexion with the production of the disease has been applied to a most successful method of treatment. In 1875 Klebs described a small bacillus with rounded ends, and with, here and there, small clear unstained spaces in its substance. He, however, also described streptococci as present in certain cases of diphtheria, and concluded that there must be two kinds of diphtheria, one associated with each of these organisms. In 1883 he again took up the question; and in the following year Loeffler gave a systematic description of what is now known as the Klebs-Loeffler bacillus, which was afterwards proved by Roux and Yersin and many other observers to be the causa causans of diphtheria. This bacillus is a slightly-curved rod with rounded, pointed, or club-shaped end or ends (see Plate II. fig 9). It is usually from 1 2 to 5,u or more in length and from o 3 tõ o 5,u in breadth; rarely it may be considerably larger in both dimensions. It is non-motile, and may exhibit great variety of form, according to the age of the culture and the nature of the medium upon which it is growing. It is stained by Gram's method if the decolorizing process be not too prolonged, and also by Loe$1er's methylene-blue method. Except in the very young forms, it is readily recognizable by a series of transverse alternate stained and unstained bands. The bacillus may be wedge-shaped, spindle-shaped, comma-shaped or ovoid. In the shorter forms the polar staining is usually well marked; in the longer bacilli, the transverse striation. Very characteristic club-shaped forms or branching filaments are met with in old cultures, or where there is a superabundance of nutritive material. In what may be called the handle of the club the banded appearance is specially well marked. These specific bacilli are found in large numbers on the surface of the diphtheritic membrane (Plate II. fig. 10), and may easily be detached for bacteriological examination. In certain cases they may be found by direct microscopic examination, especially when they are stained by Gram's method, but it is far more easy to demonstrate their presence by the culture method. On Loeffler's special medium the bacilli flourish so well at body-temperatureabout 37° C. - that, like the cholera bacillus, they outgrow the other organisms present, and may be obtained in comparatively pure culture. Distinct colonies may often be found as early as the eighth or twelfth hour of incubation; in from eighteen to twenty-four hours they appear as rounded, elevated, moderately translucent, greyish white colonies, with a yellow tinge, the surface 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 grow to a considerable size, 4 to 5 mm.; but when more numerous and closer together, they remain small and almost invariably discrete, with distinct intervals between them. In older growths the central opacity becomes more marked and the crenation more distinct, the moist, shiny appearance being lost. When the surface of the serum is dry, the growth, as a rule, does not attain any very large size.

These " pure " colonies, when sown in slightly alkaline broth, grow with great vigour; and if a small amount of such a 48 hours' culture be injected under the skin of a guinea-pig, the animal succumbs, with a marked local reaction and distinct symptoms of toxic poisoning very similar to those met with in cases of diphtheria of the human subject. Roux and Yersin demonstrated that the poison was not contained in the bodies of the bacilli, but that it was formed and thrown out by them from and into the nutrient medium. Moreover, they could produce all the toxic symptoms, the local reactions, and even the paralysis which often follows the disease in the human subject, by injecting the culture from which they had previously removed the whole of the diphtheria bacilli by filtration. This cultivation, then, contains a poisonous material, which, incapable of multiplying in the tissues, may be given in carefully graduated doses. If, therefore, there is anything in the theory that tissues may be gradually " acclimatized " to the poisons of these toxic substances, they saw that it should be possible to prove it in connexion with this disease. Behring, going still further, found that the tissues so acclimatized have the power of producing a substance capable of neutralizing the toxin, a substance which, at first confined to the cells, when formed in large quantities overflows into the fluids of the blood, with which it is distributed throughout the body. The bulk of this toxin-neutralizing substance remains in the blood-serum after separation of the clot. In proof of this he showed that (1) if this serum be injected into an animal before it is inoculated with even more than a lethal dose of the diphtheria bacillus or its products, the animal remains perfectly well; (2) a certain quantity of this serum, mixed with diphtheria toxin and injected into a guinea-pig, gives rise to no ill effects; and (3) that even when injected some hours after the bacillus or its toxins, the serum is still capable of neutralizing the action of these substances. In these experiments we have the germ of the present antitoxic treatment which has so materially diminished the percentage mortality in diphtheria. This serum may also be used as a prophylactic agent.

The antitoxic serum as now used is prepared by injecting into the subcutaneous tissues of a horse the products of the diphtheria bacillus. The bacillus, grown in broth containing peptone and blood-serum or blood-plasma, is filtered and heated to a temperature of 68° or 70° C. for one hour. It then contains only a small amount of active toxin, but injected into the horse it renders that animal highly insusceptible to the action of strong diphtheria toxins, and even induces the production of a considerable amount of antitoxin. This production of antitoxin, however, may be accelerated by subsequent repeated injections, with increasing doses of strong diphtheria toxin, which may be so powerful that 6 to a of a drop, or even less, is a fatal dose for a medium-sized guinea-pig. The antitoxic serum so prepared may contain 200, 400, 600 or even more " units " of antitoxin p