Every practitioner in Tropical Countries knows how frequently cases of fever occur in which it is impossible to arrive at a definite diagnosis.

Much light has been thrown on the subject of long-continued fevers by the researches of Leishman, Donovan, Manson, Rogers, etc., especially with regard to Kala-azar. Moreover, the work of Wright, Lamb, and others, has shown that some other forms of long-continued tropical fevers represent cases of Malta fever.

The history of the study by modern methods of the epidemiology of plague may be said to date from the discovery of B. pestis by Yersin and Kitasato in 1894. The severe outbreaks which since then have yearly recurred, notably in Bombay and Hongkong, have offered a wide field for investigation. That the opportunities thus afforded have not been neglected is sufficiently shown in the statement that in Bombay alone no fewer than six scientific commissions devoted their attention to various aspects of the disease within a few years. In addition, epidemics have been investigated in many places throughout the world.

1. Numerical counts on gelatin media are of very limited value for surface well examinations and are quite useless for open draw-wells. The blood-heat enumeration is of use, but still of but limited value.

2. The influence of rainfall and local conditions generally is marked for this class of waters with regard to their bacterial content.

Whether the well is uncovered, or covered and provided with a pump has a very important influence upon the bacteriological results. For a good many wells which show very bad bacteriological findings the cause of pollution is frequently due to surface pollution rather than to pollution of the ground water through the soil. If these wells are properly protected they will become suitable sources of drinking supply.

3. The results obtained confirm the value of B. coli and streptococci estimations as the best tests by which to judge the freedom from pollution of such waters.

The streptococci results are of great value, only second in importance to the B. coli determinations. In numerical distribution these two organisms closely agree. The presence of streptococci is more reliable as evidence to deduce pollution than their absence is to exclude it.

4. An opinion regarding the freedom of surface wells from pollution is best formed on the basis of combined topographical and bacteriological investigation.

5. Inspection alone is frequently quite insufficient for the purpose of determining if a well is contaminated and if it should be closed.

Of the 50 wells examined no less than 31 had to be classed as doubtful (Series C), topographical examination alone affording insufficient data for the expression of a decided opinion.

In view of the fact that pure water supplies are not easy to obtain in many rural districts, a water supply, which may have been in use for many years, cannot be condemned in the absence of clear evidence that it is unsatisfactory and dangerous.

6. In surface well waters a large proportion of the coli-like organisms isolated are atypical in one or more particulars.

7. Typical B. coli implanted into soil showed some alteration of character, but the changes were not extensive and no evidence was obtained that the widely aberrant organisms met with in different soils and waters ever represent typical B. coli altered by unfavourable environment.

8. Organisms closely allied to B. coli, but differing in one or more characters, possess significance as indicators of faecal contamination.

The more nearly the organism isolated resembles an “excretal” B. coli the greater is its significance as an indicator of pollution. Consequently the fewer the number required to condemn a sample water in which they occur. Stated as a working proposition, the more the characters of the coli-like organisms deviate from that which for convenience may be spoken of as the typical form, the greater the proportionate number of them required to condemn the water.

9. The presence of ‘excretal’ B. coli in 10 c.c. or less of a surface well water points to undesirable pollution and is sufficient to condemn the water.

Many writers having observed that cases of acute rheumatism are not distributed evenly throughout the year, much study has been devoted to the possible relationship between these variations and meteorological conditions.

In the following paper an attempt will be made to give a description of certain characteristic features which we have observed on postmortem examination of a large number of plague rats in the course of the daily routine rat investigation in Bombay. An account of the diagnosis of rat plague may appear at first sight to cover well-known ground and to be consequently unnecessary. Having regard however to its importance the subject seems to have received remarkably little attention, judging from the scattered references to it in the literature.

(1) On the macroscopical alterations in the tissues of guinea-pigs which had been fed exclusively on bread, groats, and unpeeled grain.

By experimenting with the “one-sided” diets which were used in the experiments, mentioned in the foregoing paper on polyneuritis in poultry, we found that guinea-pigs also contract a disease, and that this disease is accompanied by very characteristic changes.

Owing to the somewhat contradictory results which have been obtained by various investigators as to the nature of the Micrococcus neoformans and the relation which this organism bears to malignant disease, we have thought it advisable to place on record our observations in a large number of cases of carcinomata, sarcomata and certain cases of anaemia which are known to run a fatal course. Doyen (1886), in a preliminary note communicated to the Academy of Sciences of Paris, stated that he had found small spherical bodies in malignant and other growths which he regarded as micro-organisms. In 1902, at the Surgical Congress, at Berlin, he stated further that he had isolated a micro-organism from simple and malignant growths which, when inoculated into animals, gave rise to neoplastic formations. To this organism he gave the name M. neoformans. In his opinion new growths resulted from an infection of the body with this organism. Since then he has published a number of observations showing the beneficial effects which may be obtained by the employment of a vaccine or serum against the M. neoformans in malignant disease.

Most towns augment their water supply from wells, and in South Africa, where the rivers are said to run underground, Johannesburg is no exception.

Its chief supply is from deep wells in the dolomite some 20 miles to the south-west of the town, but one of the suburbs—Parktown—is not connected to the main supply, but at present draws its water from two wells (the property of the Rand Water Board) which will be subsequently referred to as No. 1 and No. 2, sunk in the shales of the upper Witwatersrand beds. From here the water is pumped to two Water Towers situated at the highest point of the suburb from whence it is distributed by gravitation. For various reasons, the Rand Water Board had decided on replacing the pumping machinery at these wells by electrically driven gear, and advantage was to be taken of the change to properly line and deepen the wells by a steel bore-hole.

One of the first duties which the present Commission had to undertake was to decide where the epidemiological observations which were necessary to be made should be carried out. After various parts had been visited, it was decided that the headquarters of the Commission should be in Bombay, and that Bombay City and Island should, in the first instance at least, be put under observation for epidemiological purposes.

The pathological histology of plague in man and experimental plague in animals has already been the subject of several researches, notably those of Aoyama (1896), Yamagiwa (1897), Albrecht and Gohn (1897), Dürck (1904) and Hamdi (1904) in the case of human plague, and of van der Stricht (1897), Honl (1897), Lustig and Zardo (1897), Babes and Livadite (1897), Albrecht and Gohn (1900) and Sata (1900) in the case of experimental plague.

1. It is inadmissible to study the “Danysz Effect” on tetanolysin owing to its rapid deterioration.

2. The so-called “equivalents” of toxin and antitoxin deduced by Arrhenius and Madsen are arbitrary.

3. No evidence has yet been advanced that the “Danysz Effect” has a limiting value when the time of contact of the first fraction of toxin with the antitoxin is prolonged.

4. If a limiting value of the “Danysz Effect” exist that calculated by Arrhenius is probably erroneous.

5. The monomolecular formula used by Arrhenius is merely an interpolation.

6. The “Danysz Effect” is much better represented by a bimolecular formula.

7. No confirmation of the “equivalents” of toxin and antitoxin has as yet been obtained from the “Effect.”

8. Expediency appears to be the only justification for assuming that the “Effect” is due to either a modified antitoxin or to a modified toxin, viz. epitoxonoid.

9. All the phenomena of the “Effect” hitherto advanced have their counterpart in the staining of paper, porcelain, etc., by anilin dyes.

1. The relation between lethal doses of diphtheria toxin and the times in which they kill guinea-pigs, or lethal times, is approximately such that the lethal dose multiplied by the corresponding lethal time gives a constant value—a hyperbolic relation.

2. Deductions with regard to lethal doses from deaths occurring on the first day or on any day after the sixth give such widely divergent results that, in our opinion, they are at present of negligible value.

3. Under the ordinary circumstances of standardisation of diphtheria toxin and antitoxin the relation given in conclusion No. 1 is as close an approximation as any alternative likely to prove of practical utility.

4. The graphic representation of L+ doses against lethal times gives a straight line relationship.

5. Five of the best investigated toxins confirmed Ehrlich's views in so far as that with toxicities diminishing by 50% their neutralising powers remained practically unimpaired.

6. The individual sensitivities of guinea-pigs to free diphtheria toxin render any general relation between lethal times and doses of little value when a small number, e.g. 5, of test animals is inoculated.

7. Even with a dose of toxin which would, in any ordinary series of tests, be regarded as an L+ dose, 5 out of 33 guinea-pigs survived the sixth day or 15%1, and the m.l.d. of a well-investigated toxin showed similar variations; consequently both the L+ and m.l.d. values of a toxin are not those amounts which kill with certainty in a fixed time, but those which will cause death in that time with the greatest probability.

8. After inoculation, guinea-pigs unless suffering from the consequent “shock,” continue to increase in weight throughout the first day, even with doses that may subsequently prove lethal, and with highly toxic doses the variation in weight during this time is of little significance.

9. The greater the amount of free toxin injected, the more rapid is the increment in weight followed by a decrement.

10. The weight of a test animal at the end of 24 hours after inoculation forms a better normal or origin with which to compare the subsequent time-weight relations than the initial weight before injection.

11. On the basis of Conclusion 10 the general connection is found that with increasing amounts of free toxin the position of the maximum loss of weight is gradually transferred from the second to the fifth day for guinea-pigs which survive over six days.

12. The time-weight ratios for almost certainly lethal doses give straight line connections, corresponding probably to starvation curves of the guinea-pig.

1. It is possible to infect wild rats of Bombay with plague by feeding them with the viscera of dead plague rats, 21·4% being susceptible to this method of infection. Bombay rats show a greater immunity to infection by feeding than rats of the same species, which have not been subjected to a plague epizootic.

A series of experiments were also done with Mus rattus caught in the Punjab. Of these rats 67·8% were susceptible. In this series a considerably larger dose of infected material was given.

We have infected a large number (38%) of wild Bombay rats by feeding them on the whole carcases of their plague-infected comrades. No difference as regards the post-mortem appearances or the distribution of the primary bubo was found between rats infected in this way and rats infected by feeding on soft viscera.

2. The general pathological lesions found in all rats infected by feeding are, in the main, the same as those found in rats naturally infected. There are, however, two striking differences:—

(a) The distribution of the primary bubo is different. The common site in naturally infected plague rats is in the neck, no mesenteric bubo having been seen out of 5000 post-mortems. In the case of fed rats the common site is the mesentery.

(b) In the case of naturally infected rats the stomach and intestines show no marked pathological change. In the case of fed rats well marked pathological lesions are found in the intestines.

3. It would appear that in nature intestinal infection rarely or never takes place, and that in consequence rats do not become infected by eating the carcases of their comrades.

4. A large series of rats were fed on the urine of plague cases. None of these contracted the disease.

(1) Worli village is badly infested with rats, practically all M. rattus.

(2) Persistent trapping for one year appeared to reduce the rat population to approximately one quarter of the original number.

(3) Three cases of plague which occurred in the village were investigated. It is probable that these three cases all contracted the infection outside the village.

(4) In two instances there is evidence which points to infection having been introduced in the clothing or persons of people, and of this spreading in one instance to a guinea-pig, and in the other instance to rats.

These animal experiments corroborate the findings in the blood of anilin and nitro-benzine workers and enable us to follow the sequence of events, which appear to be the same in cases of poisoning by either of these bodies, though they are much more marked in the case of the latter.

These bodies may gain access to the body either by (1) inhalation of their vapours; (2) absorption through the skin; (3) absorption from the alimentary canal after being swallowed.

Probably the first method occurs most commonly, since cases of poisoning are much more frequent in hot close weather than during the colder seasons of the year. No matter how they are absorbed these bodies appear to have the same action on the blood, which is as follows:

They first convert the oxy-haemoglobin of the red corpuscles into met-haemoglobin, this is followed by haemolysis, degeneration of cytoplasm and escape of haemoglobin into the plasma.

If a considerable amount of met-haemoglobin is present in the blood, the respiratory capacity of the red corpuscles is diminished, the patient becomes cyanosed and the colour of the blood is changed to a chocolate brown. This fact renders the estimation of haemoglobin by the ordinary colour standards impossible, as they are based on the colour of pure oxy-haemoglobin, which is quite different from that of met-haemoglobin.

In the less severe cases of poisoning in which met-haemoglobin is not present in sufficient amount to be detected spectroscopically, the changes which may be found in the blood are sufficiently characteristic to enable a diagnosis of anilin or nitro-benzine poisoning to be made.

These consist in:

(1) A decrease in the percentage of haemoglobin as estimated from the specific gravity of the blood of from 5% to 50%.

(2) A decrease in the number of red corpuscles if the amount of poison absorbed is considerable; if the dose is very small this decrease is not found, blood formation apparently keeping pace with blood destruction.

(3) Degeneration and imperfect development of the red corpuscles as shown by the occurrence of basophil granulations, polychromasia, poikilocytosis, and variations in size.

(4) The presence of nucleated red corpuscles in severe cases.

(5) A decrease in leucocytes rapidly followed by an increase; the increase being principally due to the number of lymphocytes.

The simultaneous occurrence of all or several of these signs in the blood enables a diagnosis of poisoning by anilin or nitro-benzine to be made in quite mild cases.

Cessation from work for a short time enables the blood to recover rapidly from the effects of poisoning.

The best treatment in any severe case of poisoning by these bodies appears to be inhalation of oxygen.

Haldane, Makgill, and Mavrogordato found that mice could be kept alive in oxygen at a pressure of two atmospheres even when 90% of their blood had been converted into met-haemoglobin by injection of sodium nitrite. They also showed that animals showing severe symptoms of di-nitro-benzol poisoning recovered rapidly when placed in oxygen, and that as other substances besides met-haemoglobin are produced by the decomposition of the haemoglobin, the absence of a met-haemoglobin band is no evidence that the symptoms are not due to oxygen asphyxia.

Permission to publish this paper has kindly been given by Mr H. L. Samuel, Chairman of the Home Office Committee on Industrial Diseases.

In view of the importance of a pure milk supply, we considered that it might be of interest to examine chemically, microscopically, and bacteriologically, a number of specimens of milk coming into the Metropolis for which purpose we decided to select samples from the various counties, the milk of which is consigned to London. We found that milk so consigned comes from about twenty-six counties extending from Derby in the North, to Hampshire and Devonshire in the South and South-West, and from Hereford in the West, to Norfolk in the East.

Weichselbaum (1887) first described his Diplococcus intracellularis meningitidis (meningococcus) as having been cultivated within a few hours after death from the brain or meninges of six cases of acute cerebro-spinal meningitis. These cases occurred during the years 1885—1887 at Vienna, when no regular epidemic existed. Cases had however occurred from time to time, and there was an epidemic in part of Lower Austria in 1886. The youngest case was 14 years old. He described the micrococcus as being of a wide gonococcus-like shape, occurring in pairs or fours, not in chains, negative to Gram's stain. It failed to grow at 20° C., but grew well on agar at 37° C. almost exclusively on the surface. The growth was viscid, the colonies were often confluent and appeared finely granular when slightly magnified. The organisms required sub-culture every few days to ensure success, were easily killed by drying, and showed very little growth in broth.

1. Nickel carbonyl is a highly toxic compound.

2. Dissociation of nickel carbonyl takes place rapidly at the temperature of the body in the presence of air, moisture and carbon dioxide.

Nickel carbonyl also dissociates at the temperature of the body in the absence of air, moisture and carbon dioxide, but not to the same extent as in the presence of these owing to the fact that a reversible action occurs between the nickel and the dissociated carbon monoxide.

3. Nickel carbonyl is soluble in water to the amount of 2·36 c.cm. of vapour (i.e. 6·43 mgrs. of nickel) per 100 grs. at 9·8° C.

The amount dissolved in water is directly proportional to the pressure, when the temperature is constant.

The solubility in water diminishes as the temperature is raised.

4. The solubility of nickel carbonyl in serum and in blood is about 2½ times greater than that in water. At 10° C. 100 grs. of serum dissolves 5·98 c.cm. of nickel carbonyl vapour (i.e. 15·71 mgrs. of nickel).

5. When nickel carbonyl is brought into contact with water, serum, blood and other liquids, if oxygen and carbon dioxide are present, dissociation occurs and a substance is formed, probably a hydrated basic carbonate of nickel, which is slightly soluble, but also forms a very fine precipitate, which renders the liquid turbid. The liquid can only be cleared of the turbidity by passing it through a Berkefeld filter.

6. Water dissolves about 0·0035% of the product of dissociated nickel carbonyl (reckoned as nickel) at 18° C. About the same amount is dissolved in 10% solutions of sodium carbonate.

The solubility of this product of dissociated nickel carbonyl is greater in serum than in water. Serum dissolves about 0·0183% (reckoned as nickel). A solution of the salts of serum, under the same conditions, dissolves 0·005% (reckoned as nickel). Solutions of sodium phosphate of approximately the same strength as the phosphates in serum, dissolve 0·0025% (reckoned as nickel).

7. Nickel hydrate is insoluble in water but is soluble in serum to the extent of 0·0225 gr. nickel per 100 grs. serum, and in sodium phosphate solutions to the extent of 0·012% (reckoned as nickel).

8. Nickel carbonate is soluble in water to the extent of 0·0005% (reckoned as nickel), and in serum to an amount, corresponding to 0·016 gr.% of nickel. Salts of serum dissolve 0·0045 gr. % of nickel carbonate reckoned as nickel. Nickel carbonate is insoluble in sodium phosphate solutions.

9. Dissociation product in aqueous solution is precipitated by boiling, and to a certain extent by the addition of electrolytes. Some of it is thrown out of solution spontaneously on standing for some days, whereas solutions of nickel carbonate are not precipitated by either of the above means.

10. Solutions of dissociation product dialyse more slowly than solutions of similar strength of nickel carbonate, and at a certain stage in the dialysis the greater part of the nickel is adsorbed into the membrane.

11. No constant ratio exists between the nickel and the nitrogen contents of solutions of dissociation product in serum of different strengths.

12. When the proteids of the serum, containing the product of dissociated nickel carbonyl in solution, are precipitated by ammonium sulphate, nine-tenths of the nickel remains in solution. One-tenth is precipitated by adding sufficient ammonium sulphate to produce one-third of saturation, and about an additional one-hundredth by producing one-half of saturation.

13. The product of dissociated nickel carbonyl when dissolved in serum is only incompletely removable from solution by dialysis.

The product of dissociated nickel carbonyl is therefore not identical with nickel carbonate or nickel hydrate, and appears to exist in a condition of colloidal solution.

14. The poisonous properties of nickel carbonyl do not depend, as was at first supposed, on the carbon monoxide of the compound.

15. Nickel carbonyl when mixed with air and inhaled by an animal, cannot be absorbed as such, as it becomes split up into the nickel containing substance (? hydrated basic carbonate of nickel) and carbon monoxide, before or soon after reaching the alveoli of the lungs.

16. The poisonous effects of nickel carbonyl are entirely due to the nickel of the compound. The peculiar toxicity of the compound is due to the fact that being introduced in a gaseous form and that the nickel is deposited as a slightly soluble compound in a very fine state of subdivision over the immense area of the respiratory surface.

(1) The question of the alleged spread of infection by direct contact with a suffering case has been discussed. Our observations in a plague hospital and with material obtained from this hospital lead us to conclude that such a mode of spread does not exist. Support is given to this view by a consideration of the influence of imported cases on the spread of the epidemic and by an investigation of the relative frequency of single and multiple cases in houses and buildings. We have, further, referred to our experience that a rat epizootic is alone sufficient to account for a widespread dissemination of infection throughout a locality. A review of the whole of the evidence on this point brings us to the conclusion that contact with plague cases plays no part in the spread of the epidemic.

(2) In discussing the question of the infectivity of houses, evidence has been brought forward which points to the rat flea being the transmitting agent of infection from rat to man. Further, reasons have been given for the view that plague does not persist in a locality apart from infection amongst the rats.

(3) From arguments brought forward in the discussion of the two previous questions we conclude that the epidemic is wholly dependent upon the epizootics.

(4) It has been shown that infection may be transported to a distance by means of rat fleas in clothing or merchandise and that such infection, when imported into a hitherto uninfected locality, may give rise to an epizootic in the rats.

(5) Our observations lead us to conclude that plague in domestic animals in Bombay either does not occur or occurs so seldom that it cannot be said to possess any significance from an epidemiological standpoint.