PART II EXPERIMENTS IN PATHOLOGY, MATERIA MEDICA, AND THERAPEUTICS (continued 3)

"The annual admissions per mille for enteric fever amongst British troops in India have risen from 18.5 in 1890 to 32.4 in 1897, while the death-rate has increased from 4.01 to 9.01; and we are of opinion that every practicable means should be tried to guard against the ravages made by this disease. The anti-typhoid inoculations have been, we believe, on a sufficiently large scale to show the actual value of the treatment, while the results appear to afford satisfactory proof that the inoculations, when properly carried out, afford an immunity equal to or greater than that obtained by a person who has undergone an attack of the disease; further, the operation is one which does not cause any risk to health. In these circumstances, we are very strongly of opinion that a more extended trial should be made of the treatment; and we trust that your Lordship will permit us to approve the inoculation, at the public expense, of all British officers and soldiers who may voluntarily submit themselves to the operation."

On 1st August, the Secretary of State for India announced in Parliament that this treatment, at the public expense, had been sanctioned.

On 20th January 1900, Professor Wright published in the British Medical Journal an account of these 1898-99 inoculations in India. "They were undertaken under conditions which were very far from ideal. In particular, there is reason to suppose that the results obtained may have been unfavourably influenced by a weakening of the vaccine, brought about by repeated re-sterilisation." In no case was reinoculation done. The statistics were compiled from information furnished by officers of the Royal Army Medical Corps actually in charge of troops in the various stations; and were supplemented by reports received from the commanding officers of the various inoculated regiments. They are as follows:—

Numbers under Observation. Cases. Deaths. Percentage of Cases. Percentage of Deaths.

Inoculated 2835 27 5 0.95 0.2

Uninoculated 8460 213 23 2.5 0.34

If the inoculated had been attacked equally with the uninoculated throughout the period of observation, they would have had 71 cases instead of 27.

These inoculations belong to the early part of 1899. During the rest of the year, inoculations were made in India, Egypt, and Malta: the results are given in an appendix to the Report of the Royal Army Medical Department, 1899. (See British Medical Journal, 21st September 1901.) The great majority of the troops tabulated were in India. Of the troops stationed at Malta, 61 were inoculated, 2456 not inoculated; among the former there were no cases, among the latter there were 17 cases and 5 deaths. In Egypt, of 4835 troops, 461 were inoculated; among these there were no cases, among the uninoculated there were 30 cases and 7 deaths. In India, of 30,353 troops, 4502 were inoculated, leaving 25,851 not inoculated; among the inoculated there were 44 cases and 9 deaths, among the non-inoculated 657 cases and 146 deaths. Taking the Indian statistics, and estimating percentage to strength, we find, amongst the inoculated, admissions 0.98, deaths 0.2; amongst the non-inoculated, admissions 2.5, deaths 0.56. The cases which occurred amongst the inoculated men were in the majority of instances of a mild character. Taking Malta, Egypt, and India together, it appears that the inoculated, if they had suffered equally with the non-inoculated, would have had 108 cases and 24 deaths, instead of 44 cases and 9 deaths.

At the end of 1899, this treatment, only just out of the hands of science, was suddenly demanded for the protection of a huge army at war in a country saturated with typhoid. Still, the South African results, and other results during 1899 to 1901, show a good balance of lives saved. The following paragraphs give all results published from the beginning of 1900 to May 1902. They are put in order of publication. Doubtless a few other reports have been overlooked in compilation; but the list includes all that were easily accessible.

1. Manchester, England. The British Medical Journal, 28th April 1900, contains a note by Dr. Marsden, Medical Superintendent of the Monsall Fever Hospital, Manchester, on the inoculation of 14 out of 22 nurses engaged in nursing typhoid patients. Of the remaining 8, 4 had already had typhoid. The inoculations were made in October 1899. The following table shows the subsequent freedom from typhoid of the nursing staff:—

Year. Number of Typhoid Patients. Cases among Nursing Staff.

1895 229 3

1896 238 3

1897 302 4

1898 426 8

To end of September 1899 163 5

From October 1899 to March 1900 146 0

2. Ladysmith, South Africa. The Lancet, 14th July 1900, contains a short note by Professor Wright, on the distribution of typhoid among the officers and men of the military garrison, during the siege of Ladysmith. The figures are as follows:—

Number. No. of Cases. Proportion of Cases. No. of Deaths. Proportion of Deaths. Case- mortality.

Not inoculated 10,529 1489 1 in 7.07 329 1 in 32 1 in 4.52

Inoculated 1,705 35 1 in 48.7 8 1 in 213 1 in 4.4

The wide difference between the two groups, as regards the incidence of the disease, is well marked; but the case-mortality is practically the same in each group. (The statistics of the General Hospital, Ladysmith, also tell in favour of the preventive treatment: see Surgeon-Major Westcott's letter, British Medical Journal, 20th July 1901, in answer to Dr. Melville's letter, British Medical Journal, 20th April 1901.)

3. The Portland Hospital: Modder River and Bloemfontein. The British Medical Journal, 10th November 1900, contains an account by Dr. Tooth of the cases of typhoid in this hospital. Concerning the preventive treatment, he says: "The experience of my colleague Dr. Calverley and myself may be of interest, though we fear that the numbers are too few for safe generalisation.

"Personnel of the Portland Hospital. We take first the relation of disease and inoculation among the personnel of the hospital. Twenty-four non-commissioned officers, orderlies, and servants of the Portland Hospital, and 4 of the medical staff, were inoculated on the voyage out. All these showed the local symptoms at the time; that is, pain, stiffness, and local erythema; 17 also presented well-marked constitutional symptoms—general feeling of illness, fever, and headache. Of the orderlies, 9 had enteric fever subsequently. Two had refused inoculation, and both of these had the disease very severely; in fact one died. Of the inoculated cases, 5 had the disease lightly, and 2 fairly severely. One of the sisters had the disease rather severely, and she had not been inoculated.

"Officers and men admitted to the Portland Hospital. We had under treatment at the Portland Hospital 231 cases of enteric fever, most of which came under our care at Bloemfontein. We have not included in these figures a number of patients who came in convalescent for a short time only, and on their way to the base, and who would therefore appear in the admission and discharge book of the hospital. If we did so, of course our percentages would be lower. Of these 231 patients, 53 had been inoculated at home or on the voyage out, and of them 3 died, making a percentage of deaths among the inoculated of 5.6 per cent.; 178 had not been inoculated, of whom 25 died; that is, a mortality among the non-inoculated of 14 per cent. The general mortality in enteric fever with us was 28 deaths out of 231 cases; that is, 12.1 per cent., which seems to compare favourably with the experience of the London hospitals.

"It is interesting to record our experience among the officers taken separately. Thirty-three officers were admitted with enteric fever; 21 had been inoculated; that is, 63.6 per cent.; a much larger percentage than among the men. Only one of these officers died, and he had not been inoculated.

"These figures are small, but such as they are they are significant, and they dispose us to look with favour upon inoculation. So also does our clinical experience with our patients, for among the inoculated the disease seemed to run a milder course."

4. No. 9 General Hospital, Bloemfontein. The Medical Chronicle for January 1901 contains an account, by Dr. J. W. Smith, of the work of this hospital. He says: "The general impression amongst the medical officers in our hospital was that a single inoculation probably did not confer an immunity lasting very long—the lapse of time differing in individuals—and also that there was a tendency in the cases of enteric in inoculated patients to abort at the end of ten or fourteen days. I should say, however, that a very considerable number of our detachment who had been inoculated suffered from enteric, of whom 4 at least died. Of the medical staff, the only member of the junior staff who had not been inoculated died of enteric."

5. Scottish National Red Cross Hospital, Kroonstadt. The British Medical Journal, 12th January 1901, contains an account of the work of this hospital by Surgeon-Colonel Cayley, Officer in Charge. He says: "The first section of the hospital, consisting of 61 persons—officers, nursing sisters, and establishment—left Southampton on 21st April 1900. During the voyage out, all except 4 were inoculated twice, at an interval of about ten days; 2 were inoculated once; and 2 (who had had typhoid) were not inoculated. Immediately we reached the Cape, the hospital was sent up to Kroonstadt in the Orange River Colony, and remained there as a stationary hospital till the middle of October. During this period there were always many cases of enteric under treatment in hospital. Further, some of the medical officers and student orderlies had charge of the Kroonstadt Hotel temporary hospital, which was crowded up with enteric cases; and the nursing sisters, for three weeks, did duty in the military hospitals at Bloemfontein in May and June, when enteric fever was at its worst. There was not a single case of enteric among the personnel of this first section of the hospital.

"The second section of the hospital—medical officers, nurses, and establishment, 82 in all—left Southampton in May 1900. On board ship nearly all of them were inoculated, but many of them only once. The material for inoculation had been on board for some time, and was not so fresh as in the first instance. Of this second section, 1 nurse had enteric at Kroonstadt. She was the only one, out of a total of 36 nurses, who suffered from enteric; and she was the only nurse who was not inoculated, excepting the 2 who were protected by a previous attack of enteric. A third section of the hospital, consisting of 4 medical officers and 16 nurses, went out in July; they were all inoculated, and none of them had enteric.

"Of the second section, 5 orderlies had enteric fever at Kroonstadt, of whom 2 died. Of these 5, there were 2 inoculated (once) and 3 non-inoculated. Of the 2 who died, 1 had been once inoculated, the other had not been inoculated."

6. Meerut, India. The British Medical Journal, 9th February 1901, gives a short note by Professor Wright on inoculations in the 15th Hussars. He says: "Through the kindness of Lieutenant-General Sir George Luck, commanding the Bengal Army, I am permitted to publish the following officially compiled statistics, dealing with the effects of anti-typhoid inoculations in the case of the 15th Hussars:—

From 22nd October 1899 to 22nd October 1900.

Strength. Inoculated. Cases. Deaths. Not Inoculated. Cases. Deaths.

Officers 22 19 0 0 3 0 0

N.C.O. and Men 481 317 2 1 164 11 6

Women 36 24 0 0 12 0 0

It would thus appear that the incidence of enteric in the inoculated was represented by 0.55 per cent., and the mortality by 0.27 per cent.; while the incidence in the uninoculated was 6.14 per cent., and the death-rate 3.35 per cent."

If the inoculated had suffered equally with the uninoculated, they would have had 22 cases with 11 deaths, instead of 2 cases with 1 death.

7. The Edinburgh Hospital, South Africa. The Scottish Medical and Surgical Journal, March 1901, contains an account of the work of the Edinburgh Hospital, by Dr. Francis Boyd. Of the staff, 58 were inoculated (27 once, and 31 twice). Among these 58, there were 9 cases of typhoid fever, with I death, in a patient who had old mitral disease. "Our experience has been that, while inoculation appears to modify the disease, completely modified attacks are met with in the uninoculated. Again, very severe attacks, with complications and relapse, occur in those who have been inoculated. One cannot from this conclude that inoculation has been valueless, for had not the patient been inoculated, the attack might have been still more severe."

8. Egypt and Cyprus. The British Medical Journal, 4th May 1901, gives a short note by Professor Wright on inoculations during 1901 in Egypt and Cyprus. He says: "I am indebted to the kindness of Colonel W. J. Fawcett, R.A.M.C., Principal Medical Officer in Egypt, for the following statistics dealing with the incidence of enteric fever, and the mortality from the disease, for the year 1900, in the inoculated and uninoculated among the British troops in Egypt and Cyprus:—

Average Annual Strength. Cases. Deaths. Percentage of Cases. Percentage of Deaths.

Uninoculated 2669 68 10 2.50 0.40

Inoculated 720 1 1 0.14 0.14

These figures testify to a nineteen-fold reduction in the number of attacks of enteric fever, and to a threefold reduction in the number of deaths from that disease, among the inoculated.... The only case which occurred among the inoculated was that of a patient admitted to hospital on the thirty-third day after inoculation. It would seem that the disease was in this case contracted before anything in the nature of protection had been established by the inoculation."

9. Imperial Yeomanry Hospital, Pretoria. Dr. Rolleston, Consulting Physician to this hospital, writes in the British Medical Journal, 5th October 1901: "Among the personnel of the hospital (17 medical officers, 50 nursing sisters, 83 orderlies, etc.), total, 150, there were 22 cases of enteric fever, or an incidence of 14.6 per cent. Of the 150, 35 were inoculated, and of these, 6, or 17 per cent., suffered from enteric; while, of 115 non-inoculated members of the personnel, 16, or 13.9 per cent., suffered from enteric fever; the percentage is therefore higher among the inoculated. There were 2 deaths, both in non-inoculated patients. In 100 cases of enteric fever among non-commissioned officers and men, taken mainly from convalescent patients, only 8 had been previously inoculated; there were 3 fatal cases, all among non-inoculated patients. Among 42 officers who had enteric, no fewer than 19 had been previously inoculated; 6 of these 19 cases were severe in character, but none were fatal; of the 23 non-inoculated cases, 7 were severe, and of these 7, 3 ended fatally. The interval between inoculation and the subsequent incidence of enteric fever varied between one and twenty-one months, but in only four instances was the interval less than six months. The average interval between inoculation and the onset of enteric fever in these 19 cases was thirty-eight weeks.

"As far as these scanty figures go, they point to the conclusion (1) that anti-typhoid inoculation does not absolutely protect against a future attack of typhoid fever; (2) that when enteric occurs in an inoculated person, there is, as a rule, an interval of about six months; (3) that inoculation protects against a fatal termination to the disease."

10. Richmond Asylum, Dublin. The British Medical Journal, 26th October 1901, contains a note by Professor Wright on an outbreak of typhoid in this asylum during August to December 1900. Inoculations were begun on 6th September, by Dr. Cullinan, and by 30th November 511 persons were inoculated. After careful criticism of all doubtful cases, Professor Wright gives the following figures:—

Comparative Incidence of Typhoid Fever in Inoculated and Non-Inoculated, calculated upon the average strength of the representative groups during the period intervening between the commencement of the inoculations and the termination of the epidemic.

Average Strength. Cases. Deaths. Percentage of Cases. Percentage of Deaths.

Uninoculated 298 30(-1?) 4 10.1 1.3

Inoculated 339 5(+1?) 1 1.3 0.3

"It may be noted," he says, "that the result is in conformity with that of all the statistical returns of anti-typhoid inoculation which have reached me."

11. Deelfontein. The Lancet, 18th January 1902, contains a paper by Dr. Washbourn and Dr. Andrew Elliot, on 262 cases of typhoid fever in the Imperial Yeomanry Hospital at Deelfontein during the year March 1900 to March 1901. (See Dr. Washbourn's earlier letter, Brit. Med. Jour., 16th June 1900.) They say: "In 211 of our cases, it was definitely recorded whether the patient had been inoculated or not: 186 of these cases had not been inoculated, with 20 deaths, or a mortality of 10.7 per cent.; 25 had been inoculated, with 4 deaths, or a mortality of 16 per cent. The mortality was thus higher among the inoculated than among the non-inoculated." Of the personnel of the hospital, there were 59 inoculated, with 4 cases, and 25 not inoculated, with 4 cases.

12. Winburg. The Lancet, 5th April 1902, contains a short note by Professor Wright, on the 5th Battalion, Manchester Regiment. He says: "In view of the dearth of statistics bearing on the incidence of typhoid fever in South Africa in inoculated and uninoculated persons respectively, the following, for which I am indebted to Lieutenant J. W. West, R.A.M.C., Winburg, Orange River Colony, may not be entirely without interest. The statistics here in question give the results obtained in the case of the 5th Battalion, Manchester Regiment, for the six months which have elapsed since their landing in South Africa. The figures, which relate to a total strength of 747 men and officers under observation, are as follows:—

Number. Cases. Deaths. Percentage of Cases. Percentage of Deaths.

Uninoculated 547 23 7 4.2 1 in 3.3

Inoculated 200 3 0 1.5 0

"The three attacks in the inoculated are reported to have been of exceptionally mild type, contrasting in a striking manner with the severe attacks which occurred in the uninoculated. At the time of sending in the report, some of the uninoculated patients were 'not yet out of danger.'"

Certainly, these instances show a good balance of lives saved, not only under the adverse conditions of the war, but also in Egypt, India, and the United Kingdom. But the bacteriological work on typhoid fever has been directed also to the working out of a very different problem: and that is the method of diagnosis which is called "Widal's reaction." The practical uses of this reaction are of the utmost importance. It is the outcome of work in different parts of the world—by Wright and Semple and Durham in England, Chantemesse and Widal in France, Pfeiffer and Kolle and Grüber in Germany, and many more. The first systematic study of it was made by Durham and Pfeiffer; and Widal's name is especially associated with the application of their work to the uses of practice. Admirable accounts of the whole subject are given by Dr. Cabot in his book, The Serum-Diagnosis of Disease (Longmans, 1899), and by Mr. Foulerton in the Middlesex Hospital Journal, October 1899 and July 1901.

Widal's reaction is surely one of the fairy tales of science. The bacteriologist works not with anything so gross as a drop of blood, but with a drop of blood fifty or more times diluted; one drop of this dilution is enough for his purpose. Take, for instance, an obscure case suspected to be typhoid fever: a drop of blood taken from the finger is diluted fifty or more times, that the perfect delicacy of the test may be ensured; a drop of this dilution is mixed with a drop of nutrient fluid containing living typhoid bacilli, and a drop of this mixture of blood and bacilli is watched under the microscope:—

"The motility of the bacilli is instantaneously or very quickly arrested, and in a few minutes the bacilli begin to aggregate together into clumps, and by the end of the half-hour there will be very few isolated bacilli visible. In less marked cases, the motility of the bacilli does not cease for some minutes; while in the least marked ones the motility of the bacilli may never be completely arrested, but they are always more or less sluggish, while clumping ought to be quite distinct by the end of the half-hour."

The result of this clumping is also plainly visible to the naked eye, by the subsidence of the agglutinated bacteria to the bottom of the containing vessel: and thus an easy practical mode of diagnosis is afforded by it.

As with typhoid, so with Malta fever, cholera, and some other infective diseases. And the unimaginable fineness of this reaction goes far beyond the time of the disease. Months, even years, after recovery from typhoid, a fiftieth part of a drop of the blood will still give Widal's reaction: and it has been obtained in an infant whose mother had typhoid before it was born. A drop of dried blood, from a case suspected to be typhoid, may be sent a hundred miles by post to be tested; and typhoid, like diphtheria, may now be submitted to the judgment of an expert far away, and the answer telegraphed back. It would be difficult to exaggerate the practical importance of this reaction for the early diagnosis of cases of typhoid fever, especially those cases that appear, at the onset, not severe.

Malta Fever

The specific organism of Malta fever (Mediterranean fever), the bacillus Melitensis, was discovered in 1887 by Surgeon-Major David Bruce, of the Army Medical Staff. Its nature and action were proved by the inoculation of monkeys. The use of Widal's reaction is of great value in this disease:—

"The diagnosis of Malta fever from typhoid is, of course, a highly important practical matter. It is exceedingly difficult in the early stages." (Manson, loc. cit.)

As with typhoid, so with Malta fever, Netley led the way to the discovery of an immunising serum. In the course of the work, one of the discoverers was by accident infected with the disease:—

"He was indisposed when he went to Maidstone to undertake anti-typhoid vaccination, and after fighting against his illness for some days, he was obliged to return to Netley on 9th October. Examination of blood-serum (Widal's reaction) showed that he was suffering from Malta fever. It appears that he had scratched his hand with a hypodermic needle on 17th September, when immunising a horse for the preparation of serum-protective against Malta fever; and his blood, when examined, had a typical reaction on the micrococcus of Malta fever in 1000-fold dilution. The horse, which has been immunised for Malta fever for the last eight months, was immediately bled, and we are informed that the patient has now had two injections, each of 30 cub. cm. of the serum. He is doing well, and it is hoped that the attack has been cut short." (British Medical Journal, 16th October 1897.)

About fifty cases had up to September 1899 been treated at Netley "with marked benefit: whereas they found that all drug-treatment failed, the antitoxin treatment had been generally successful."[36] A good instance of the value of the serum-treatment of Malta fever is published in the Lancet, 15th April 1899. For a later account of this treatment and of its efficacy, see the Philadelphia Medical Journal, 24th November 1900.

Another point is noted by Sir Patrick Manson, in his recent Lane Lectures (Constable, 1905). "For some time back," he says, "a commission of experts, working under the direction of the Royal Society, has been studying this disease in Malta. The commission has accumulated much detailed information; but the most important observation it has published is the fact that a large percentage of the goats in Malta are infected with Micrococcus melitensis, and that the milk of the infected goats contains the bacterium. May not this account for the great prevalence of Mediterranean fever there and in other places having perhaps a similar milk-supply?"

X THE MOSQUITO: MALARIA, YELLOW FEVER, FILARIASIS

Within the last few years, it has been proved that the mosquito is an intermediate host, between man and man, of malaria, yellow fever, and filariasis (elephantiasis).[37] Just as the grosser parasites, the tapeworms, must alternate between man and certain animals, and cannot otherwise go through their own life-changes and reproduce their kind, so the micro-parasites that are the cause of malaria alternate between man and the mosquito, having the mosquito as an intermediate host. These organisms, once they get into the mosquito, pick out certain structures, and there carry out a definite cyclical phase of their lives, whereby their progeny make their way into the stylets of the mosquito, and so get back to man, who is their "definite host." Thus, malaria is not, strictly speaking, a disease of man; it is one phase in man of micro-organisms that have another phase in mosquitoes. So also with filariasis; the filariæ in man, their ova, and their embryo-worms, are one phase of filariasis; and the embryo-worms in certain structures of the mosquito are another phase. The plasmodium malariæ and the filaria are instances of a law of animal life that holds good also of plant life:—

"All plants and animals possess parasites, and thousands of different species of parasites have been closely studied by science; we therefore know much about their general ways of life. As a rule, a particular species of parasite can live only in the particular species of animal in which, by the evolution of ages, it has acquired the power of living. It is therefore not enough for the parasites of an individual animal—say a man—to be able to multiply within that individual, but they must also make arrangements, so to speak, for their progeny to enter into and infect other individuals of the same species. They cannot live for ever in one individual; they must spread in some way or other to other individuals.

"The shifts made by parasites to meet this requirement of their nature are many and various, and constitute one of the wonders of nature. Some scatter their spores and eggs broadcast in the soil, water, or air, as it were in the hope that some of them will alight by accident on a plant or animal suitable for their future growth. Many parasites employ, in various ways, a second species of animal as a go-between. Thus, some tapeworms, and the worms which cause trichinosis, spend a part of their lives in the flesh of swine, and transfer themselves to human beings when the latter eat this flesh. To complete the cycle, the parasites return to swine from human offal; so that they propagate alternately from men to swine, and from swine to men. The blood-parasites which cause the deadly tsetse-fly disease among cattle in South Africa are transferred from one ox to another on the proboscis of the ox-biting or tsetse-fly. The progeny of the flukes of sheep enter a kind of snail, which spreads the parasites upon grass. The progeny of the guinea-worm of man enter a water-flea. The progeny of the parasites which cause Texas cattle-fever, and which are very like the malarial parasites, live in cattle-ticks, and are transferred by the young of these ticks into healthy cattle." (Ross, Malarial Fever, 1902.)

1. Malaria

The plasmodium malariæ was discovered by Laveran in 1880, in the blood of malarial patients. For many years his work stopped there, because it was impossible to find the plasmodium in animals: "the difficulties surrounding the subject were so great that this discovery seemed to be almost hopeless." In 1894, Sir Patrick Manson—who had proved mosquitoes to be the intermediate host in the case of the parasitic nematode filaria—suggested, as a working theory of malaria, that the plasmodium was carried by mosquitoes. This belief, not itself new, he made current coin. He observed that there is a flagellate form of the plasmodium, which only comes into existence after the blood has left the body: and he suggested that the flagella might develop in the mosquito as an intermediate host, a halfway-house between man and man. Then, in 1895, Ross set to work in India, keeping and feeding vast numbers of mosquitoes on malarial blood; and for two years without any conclusive result. About this time came MacCallum's observations, at the Johns Hopkins University, on a parasitic organism, halteridium, closely allied to the plasmodium malariæ; he showed that the flagella of the halteridium are organs of impregnation, having observed that the non-flagellated form, which he regarded as the female, after receiving one of the flagella, changed shape, and became motile. In August 1897, Ross found bodies, containing pigment like that of the malarial parasite, in the outer coat of the stomach of one kind of mosquito, the grey or dapple-winged mosquito, Anopheles maculipennis, that had been fed on malarial blood. In February 1898, he was put on special duty under the Sanitary Commissioner with the Government of India, to study malaria, and started work again in Calcutta:—

"Arriving there at a non-fever season, he took up the study of what may be called 'bird malaria.' In birds, two parasites have become well known—(1) the halteridium, (2) the proteosoma of Labbé. Both have flagellated forms, and both are closely allied to the plasmodium malariæ. Using grey mosquitoes and proteosoma-infected birds, Ross showed by a large number of observations that it was only from blood containing the proteosoma that pigmented cells in the grey mosquito could be got; therefore that this cell is derived from the proteosoma, and is an evolutionary stage of that parasite. Next, Ross proceeded to find out its exact location, and found that it lay among the muscular fibres of the wall of the mosquito's stomach. It grows large (40-70 micro-millimetres) and protrudes from the external surface of the stomach, which under the microscope appears as if covered with minute warts." (Manson, at Edinburgh meeting of British Medical Association, 1898.)

These pigmented spherical cells give issue to innumerable swarms of spindle-shaped bodies, "germinal rods"; and in infected mosquitoes Ross found these rods, in the glands that communicate with the proboscis. Thus the evidence was complete, that the plasmodium malariæ, like many other parasites, has a special intermediate host for its intermediate stage of development; and that this host is the dapple-winged mosquito. It is impossible to over-estimate the infinite delicacy and difficulty of Ross's work; for instance, in his "Abstract of Recent Experiments with Grey Mosquitoes," he says that "out of 245 grey mosquitoes fed on birds with proteosoma, 178, or 72 per cent., contained pigmented cells; out of 249 fed on blood containing halteridium, immature proteosoma, &c., not one contained a single pigmented cell." Another time (April 1898) he counted these pigment-cells under the microscope:—

"Ten mosquitoes fed on the sparrow with numerous proteosoma contained 1009 pigmented cells, or an average of 101 each. Ten mosquitoes fed on the sparrow with moderate proteosoma contained 292 pigmented cells, or an average of 29 each. The mosquitoes fed on the sparrow with no proteosoma contained no pigmented cells."

Finally, he completed the circle of development by infecting healthy sparrows by causing mosquitoes to bite them.

In 1899, there went out a German Commission to German East Africa, a Royal Society's Commission to British Central Africa, and an expedition from the Liverpool School of Tropical Medicine; in 1900, another German Commission, this time to the East Indies, and another expedition from the Liverpool School; by July 1901, the Liverpool School was organising its seventh expedition. Italy, of course, has given infinite study to the disease:—

"It has been decided that, in addition to the stations of observation and experiment in the provinces of Rome, Milan, Cremona, Mantua, Gercara, Foggia, Lecce, others shall be established in the provinces of Udine, Verona, Vicenza, Padua, Ravenna, Pisa, Basilicata, and Syracuse. Besides epidemiological researches, applications on a large scale will be made of preventive measures for the protection of the agricultural population against the scourge. Another extensive experiment on the prophylaxis of malaria will be made on the Emilian littoral. Moreover, in all the malarious regions of the Italian peninsula the provincial and communal administrations and many private persons will co-operate in the application of preventive measures. From all this it may be gathered that during the summer and autumn the war against malaria will be carried on in Italy with great vigour and thoroughness." (British Medical Journal, 6th July 1901.)

In India, the work started in 1900 by the Royal Society Commissioners, and by the Nagpur Conference, has been widely extended; especially by such researches as those of Major Buchanan, I.M.S., Superintendent of the Central Jail, Nagpur. The following paragraph, from the report of the Sanitary Commissioner with the Government of India, refers to Major Buchanan's published work, Malarial Fevers and Malarial Parasites in India:—

"A remarkable note is struck at the outset, in the acknowledgment made, by the author, of the capable assistance rendered in these researches by several of his Burmese prisoners, whom he trained to the use of the microscope, and who soon became expert in detecting and distinguishing the various kinds of parasites.... Besides a systematic clinical account of the different forms of fever and the associated parasites, which is the first attempt of the kind in India, there are a summary of the facts showing the relation of the seasonal prevalence of Anopheles to the incidence of attacks; experiments exhibiting the protective effects of mosquito-curtains; inoculation-experiments; researches on the blood-parasites of birds; and many other points.... Nor can we pause to notice the many attempts now being made by health officers and others to pursue the methods of prophylaxis indicated; these efforts are necessarily in the tentative stage, but, so far, and especially where carried out in connection with small communities and institutions, they are giving promise of gratifying success."

The famous experiment made by Dr. Sambon and Dr. Low in 1900, must be recalled here:—

"Dr. Luigi Sambon and Dr. G. C. Low, both connected with the London School of Tropical Medicine, volunteered to live from June till October, that is to say, through what may be called the height of the malaria season, in a part of the Campagna near Ostia, which is so infested by the disease that no one who spends a night there under ordinary conditions escapes the effect of the poison. Dr. Sambon, Dr. Low, Signor Terzi, and their servants, have now exposed themselves to the pestilential influence of this valley of the shadow of death for over two months. They live in a mosquito-proof hut; they take no quinine or other drug which might be regarded as prophylactic. Not one of the experimenting party has the least sign of infection.[38] ...

"What for practical purposes may be regarded as an experiment of the same kind is being conducted in West Africa. Dr. Elliot, a member of the Liverpool expedition sent to Nigeria some time ago to investigate the subject of malarial fever, has recently returned to this country. He reports that the members of the expedition have been perfectly well, although they have spent four months in some of the most malarious spots. They lived practically amongst marshes and other places hitherto supposed to be the most deadly. They have not kept the fever off by the use of quinine, and they attribute their immunity to the careful use of mosquito-nets at night." (British Medical Journal, 22nd September 1900.)

A similar "experiment," of the utmost importance, was made in 1900 by Professor Grassi. It concerned the workmen and their families along the Battipaglia-Reggio railway, 104 in all, including 33 children. The great majority of them had suffered from malaria in the preceding year; and only 11, including 4 children, had never suffered from it. Pending the arrival of the malarial season, quinine was given to all who needed it. The first Anopheles with its salivary glands infected was found on 14th June. Twelve days later came a case of malaria outside the "zone of experiment," in a person who had never had malaria before. The twelve days correspond to the incubation-period after infection. Anopheles having come, and the malarial season with him, the experiment was begun. The houses were carefully protected with wire netting, chimneys and all; the siesta was taken under wire netting; the workmen, if they were out in the evening or at night, wore veils and gloves; and Anopheles was to be killed wherever he was found. Quinine was altogether given up and forbidden, except for three workmen who had escaped or evaded its use before June, and had, indeed, never before been treated with quinine; one of them, moreover, had been sleeping outside the zone of experiment in July. Except these three, all the 104 and their doctors remained absolutely free from malaria up to 16th September, the date of Professor Grassi's report:—

"Rightly to estimate the value of these facts, it is necessary briefly to describe the surroundings of the protected area. Towards the north, coming from Battipaglia, three railway cottages are situated, at a distance of 1, 2, and 3 kilometres respectively. The 25 inhabitants of these cottages, although they were put under the tonic and quinine treatment in the non-malarial season, all without exception were taken ill with malarial fevers, in many cases obstinate."

Experiments of voluntary exposure to bite from an infected mosquito were made at or about this time, in London, New York, Italy, and India. The London "consignment" of mosquitoes had been allowed to bite a malaria-patient in Rome. The experiment had to be very carefully planned:—

"To have sent mosquitoes infected with malignant tertian parasites might have endangered the life of the subject of the experiment; and quartan-infected insects might have conferred a type of disease which, though not endangering life, is extremely difficult to eradicate. The cases, therefore, on which the experimental insects were fed had to be examples of pure benign tertian—a type of case not readily met with in Rome during the height of the malarial season; the absolute purity of the infection could be ascertained only by repeated and careful microscopic examination of the blood of the patient." (British Medical Journal, 29th September 1900.)

The mosquitoes were forwarded, through the British Embassy in Rome, to the London School of Tropical Medicine. The two brave gentlemen who let themselves be bitten by some thirty of the mosquitoes were in due time attacked by malaria, and the tertian forms of the parasite were found in their blood. Nine months later, one of them had a relapse, and the parasite was again found in his blood.

It is not possible to sum up the wealth of work on malaria published in 1900-1901. Good accounts of it are in the Transactions of the Section of Tropical Diseases, at the Annual Meeting of the British Medical Association (Cheltenham, 1901), and in the Thompson Yates Laboratories Reports, vol. iii., pt. 2, 1901. Everything had to be studied: not only the nature and action of the plasmodium in all its phases, but also the whole natural history and habits of the Anopheles of different countries; and, above all, the incidence of the disease on natives and on Europeans in China, India, and Africa. All that can be done here is to try to indicate the principal lines followed in the present world-wide campaign against malaria. The following paragraphs are taken mostly from the accounts given by Dr. Christophers and Dr. Annett, in the Thompson Yates Laboratories Report, 1901:—

1. Elimination of the Infection at its Source. This is the method employed with success by Professor Koch in New Guinea, viz., to search out all cases of malaria (the concealed ones in particular), and to render them harmless by curing them with quinine. At Stephansort, by thus hunting up all infected cases, and as it were, sterilising them by the systematic administration of quinine, he was able to achieve a great reduction of the disease in the next malarial season, even under adverse conditions. He says, in his report to the German Government: "The results of our experiment, which has lasted nearly six months, have been so uniform and unequivocal that they cannot be regarded as accidental. We may assume that it is directly owing to the measures we have adopted that malaria here has, in a comparatively short time, almost disappeared."

This method, of course, is applicable only in small communities; and, within these limits, it may become one of the most valuable of all methods, being, like the quality of mercy, a blessing both to him who gives and to him who taketh. But it cannot be practised on a vast scale. This difficulty is well put by Sir William MacGregor, K.C.M.G., Governor of Lagos, West Africa:—

"In all probability, the day will come before long, when newly-appointed officers for places like Lagos will have to undergo a test as to whether they can tolerate quinine or not. A man that cannot, or a man that will not, take quinine, should not be sent to or remain in a malarial country, as he will be doing so at the risk of his own life, and to the danger of others.... The great difficulty is how to extend this treatment beyond the service, more particularly to the uneducated masses of the natives. It is simply impossible to protect the whole population by quinine administered as a prophylactic. In the first place, the great mass of natives would not take the medicine; and, in the second place, the Government could not afford to pay for the 70 tons of quinine a year that would be required to give even a daily grain dose to each of 3,000,000 of people."

2. Segregation of Europeans from Natives. This method is strongly advocated by the members of the Nigeria Expedition of the Liverpool School (1900). The distance of removal to half a mile is considered sufficient: "Considerable evidence has now been accumulated to prove that the distance which is traversed by a mosquito is never very great, and extremely rarely reaches so much as half a mile." The arguments in favour of this method of "segregation" are of so great interest that they must be put here at some length. The drawback is that the method cannot be followed everywhere to its logical issue without some risk of giving offence, of seeming to abandon the native, of damaging commerce, and so forth. But, short of this, much might be done for the protection of Europeans in Africa:—

"This method is a corollary of the discovery that native children in Africa practically all contain the malaria parasite, and are the source from which Europeans derive malaria. Koch showed in New Guinea that in most places infection was very prevalent in native children, so much so that in some villages 100 per cent. of those examined contained parasites. He also showed that, as the children increased in age, immunity was produced, so that in the case of adults a marked immunity was present, and malarial infection was absent. The Malaria Commission showed, independently, that a condition of universal infection existed among the children of tropical Africa, associated with an immunity of the adults. This infection in children had many remarkable characteristics. The children were in apparent health, but often contained large numbers of parasites, and a small proportion only of the children failed to show some degree of infection.... The Liverpool School Expedition found a similar condition of a

ffairs in all parts of Nigeria visited by them.

"With a knowledge of the ubiquity of native malaria, the method of infection of Europeans becomes abundantly clear. The reputed unhealthiness or healthiness of stations is seen at once to be dependent on the proximity or non-proximity of native huts. The attack of malaria after a tour up-country, the malaria at military stations like Prah-su, the abundance of malaria on railways, are all explicable when the extraordinary condition of universal native infection is appreciated. It is evident that, could Europeans avoid the close proximity of native huts, they would do away with a very obvious and great source of infection.... When it is understood that each of these huts certainly contains many children with parasites in their blood, and also scores or hundreds of Anopheles to carry the infection, then the frequency with which Europeans suffer from malaria is scarcely to be wondered at.... The accompanying plan is that of a new railway settlement on the Sierra Leone Railway. Miles of land free from huts exist along the line, but the close neighbourhood of native huts has been selected. At the time of building of these quarters, it lay in the power of the engineers to have a malaria-free settlement; instead of which, by the non-observance of a simple fact, the station is most malarious: in this particular instance, much ingenuity has been shown in providing each set of European quarters with plenty of malarial infection. In towns only is there any difficulty in carrying out the principle of segregation. In two instances, however, this has been carried out in towns, with the result that the segregated communities of Europeans are notoriously the most healthy on the West Coast. Even when no scheme of complete segregation can be carried out, the principle should always be borne in mind, and, whenever opportunity offers, huts should be removed, and European houses built in the open.... It is almost universally the rule in West Africa to find European houses built round by native quarters, a practice which long experience in India has taught Europeans to avoid carefully. At Old Calabar, many of the factories are almost surrounded, except in front, by native habitations; similarly, at Egwanga, the small native town is built by the side and back of one of the factories. Also at the Niger Company's factory at Lokoja, the native houses are very close up to the Company's boundary railings. Akassa engineers' quarters may be, again, mentioned as an example where the engineering artisans, chiefly natives of Lagos, Accra, and Sierra Leone, are housed with their families alongside the European house. A large proportion of these native children were found by us to contain malarial parasites. Similarly also at Asaba, the proximity of the barracks of the Hausa soldiers, who have their wives and children with them, is a dangerous menace to the officers at the Force House.

"Examples of the opposite condition of affairs might also be given. For instance, at Old Calabar, the Government offices and Consulate, Vice-Consulate, and medical house, are comparatively free from malarial fever; it having been established that the natives shall not build on the European side of the creek separating the two slopes on which the native town and European quarters are built. This creek is at a distance of about half a mile from the houses mentioned."

It is plain, from these and other instances given by the members of the Nigeria Expedition, that a modified sort of "segregation" can be effected in many places, without any injury either to native feelings, or to politics, or to commerce; and that by such segregation the risk of malaria among Europeans in Africa would be diminished.

3. Protection against Anopheles. Manson, in his Tropical Diseases (1905), says, "The question is often asked, Is there any other way by which malaria can be contracted than through a mosquito-bite? For many reasons, I believe not. It is difficult to prove a negative; but, so far, there is no observation capable of bearing investigation that would lead us to suppose that malaria can be acquired, under natural conditions, except by mosquito-bite," All authorities are agreed that, practically, the fight against malaria and the fight against Anopheles are one and the same thing; and the experiments by Sambon, Low, and Grassi, show what can be done, in this war against the mosquito, by way of defence. But what is practicable in Italy might not be generally practicable on the West African coast; as Sir William MacGregor says of Lagos:—

"It is not likely that in a place like Lagos as good results can be obtained from the use of mosquito-proof netting as in Italy. One great objection to it here is the serious and highly disagreeable way it checks ventilation. This is a difficulty that cannot be fully brought home to one in a cold climate. But, in a low-lying, hot, and moist locality like Lagos, it comes to be a choice of evils, to sit inside the netting stewed and suffocated, or to be worried and poisoned by mosquitoes outside. The netting is hardly a feasible remedy as regards native houses. It is not possible to protect even European quarters completely by it. Few officers or others are so occupied that they could spend the day in a mosquito-proof room. Certain it is that any man that suffers from the singular delusion that mosquitoes bite only during the night, would have a speedy cure by spending a few days, or even a few hours, in Lagos. Operations here (September 1901) are being limited to supplying one mosquito-proof room to the quarters of each officer. In this he will be able to spend the evening free from mosquitoes if he chooses to do so. The European wards of the hospital are similarly protected."

The European in Africa, as Ross says, is generally neglectful of his health; and the "unhealthiness" of the African coast is to some extent due to the life that men lead there:—

"Let us compare the habits of a European in a business-house in Calcutta with the habits of a European in West Africa. In Calcutta he sleeps under a punkah or mosquito-net, or both; he dresses and breakfasts under a punkah; in the evening he takes vigorous exercise, and he dines under a punkah. He wears the lightest possible clothing, he lives in a solid, cool, airy house, and he obtains very good food; once in five or six years, he returns to Europe for leave.... In Africa, the houses are frequently very bad; in Freetown, for instance, they are the same as the houses of natives, and are mingled with them. The Anglo-African seems to imagine that he can live in the tropics in the same manner as he lives in England. He seldom uses a punkah, except perhaps for an hour at dinner-time, and, not seldom, he neglects even the mosquito-net. The food is often, or generally, execrable. Owing to the frequent absence of gymkhanas and clubs, the exile obtains little suitable exercise."

But whatever risks the old resident may choose to take, the newcomer can at least use a proper and efficient mosquito-net at night, and avoid sleeping in a native house, and protect himself in these and the like ways against malaria.

4. The keeping down of Anopheles. The breeding places of Anopheles are ponds, swamps, and puddles, roadside ditches, tanks, and cisterns, old disused canoes, and the like collections of stagnant water: also the smaller receptacles that are more generally occupied by Culex, such as broken bottles, old tins, pots, and calabashes, and barrels, whatever will hold water—all the débris and broken rubbish round huts or houses. In all these places, Anopheles' eggs or larvæ are found; and, with practice, it is easy to detect them. Of course, it is not easy to wage war against the adult mosquito: the work is, Venienti occurrere morbo, to organise gangs of workmen, or of prison labour, and "mosquito brigades"; to clear the ground of cartloads of old biscuit-tins, broken gin-bottles, and other dust-heap things, in and around the place; to cover-in the cisterns, rain-barrels, and wells; to clean pools and duck-ponds of weed, and stock them with minnows; to put a film of kerosene to the puddles, or sweep them out, or fill them up and turf them over; everywhere, to drain, and level, and clean-up the surface soil; and everywhere, by these and the like methods, to break the cycle of the life of the plasmodium malariæ:—

"Draining and cultivation where the land will repay the expenditure, permanent and complete flooding where it will not, and such flooding is possible; proper paving of unhealthy towns, and the filling-in of stagnant, swampy pools; these—in other words, all measures calculated to keep down mosquitoes—are the more important things to be striven for in attempting the sanitation of malarious districts. In England, in Holland, in France, in Algeria, in America, and in many other places, enormous tracts of country, which formerly were useless and pestilential, have been rendered healthy and productive by such means." (Manson.)

And, short of such great enterprises as Government works of drainage, much has already been done, in many African towns, and in India, by the work of a few men and women: not only by practical sanitary improvements, but by insistent teaching and lecturing. For the admirable results recently obtained in Ismailia, Algeria, Formosa, and the Malay States, see the Medical Annual, 1905 and 1906.[39]

Before leaving the subject of malaria, it must be added that the discovery and study of the parasite which causes it have cleared up the mystery of the specific action of quinine upon the disease. It operates simply by its germicidal effect upon the microbe. But, beyond this, we have now a clue which we never had before to guide us to the most advantageous manner of administering the drug.

2. Yellow Fever

The specific organism of malaria may become active again and again in the blood, causing relapses twenty years or more after the original infection. The specific organism of yellow fever expends itself at once, in one acute attack; and, if the patient recovers, he is thenceforth more or less immune against infection. That the inoculation of the disease, by the application of a single mosquito recently contaminated, is calculated to produce a mild or abortive attack less dangerous than the average attack among the non-acclimatised, was known to Finlay, and was confirmed in 1899 by the Army Commission of the United States.

Of the mortality of the disease, Sir Patrick Manson, in 1900, wrote as follows:—

"It is better for women and children than for men; better for old residents than for newcomers; worst of all for the intemperate. According to a table of 293 carefully observed cases given by Sternberg, the mean mortality in the whole 293 cases was 27.7 per cent. This may be taken as a fairly representative mortality in yellow fever among the unacclimatised, something between 25 and 30 per cent., although in some epidemics it has risen as high as 50 or even 80 per cent. of those attacked.... Some of these epidemic visitations bring a heavy death-bill; thus, in New Orleans, in 1853, 7970 people died of yellow fever; in 1867, 3093; in Rio, in 1850, it claimed 4160 victims; in 1852, 1943; and in 1886, 1397. In Havana, the annual mortality from this cause ranges from 500 to 1600 or over."

The earlier attempts to reproduce the disease, by inoculation with its products, failed altogether:—

"In 1816, Dr. Chervin, of Point-à-Pitre (Antilles), drank repeatedly large quantities of black vomit without feeling the least disturbance. Some years before, other North American colleagues, Doctors Potter, Firth, Catteral, and Parker, did everything possible to inoculate themselves with yellow fever. After having uselessly attempted experiments on animals, they experimented on themselves, inoculating the black matter at the very moment in which the moribund patient rejected it, placing this matter in their eyes, or in wounds made in their arms, injecting it more than twenty times in various parts of their body ... in short, devising every sort of daring means for experimentally transmitting yellow fever. All these experiments were without result, and in the United States during many years it was believed that this terrible malady was non-contagious." (British Medical Journal, 3rd July, 1897.)

The history of the subject, from 1812 to 1880, is given by Dr. Finlay of Havana, in the New York Medical Record (9th February 1901). In 1880, two very important reports on the disease were published; one by a Havana Commission of the National Board of Health of the United States, the other by the United States Navy Department. They tended to show that yellow fever is a "germ-disease"; that it is not wind-borne; and that there may be some change, outside the body of the patient, whereby the virulence of the active principle of the disease is heightened. From these reports, Dr. Finlay advanced his doctrine that the mosquito receives and transmits the germs of the disease:—

"It was upon the above line of reasoning (in these reports), that I conceived the idea that the yellow-fever germ must be conveyed from the patient to the non-immunes by inoculation, a process which could be performed in nature only through the agency of some stinging insect whose biological conditions must be identical with those which were known to favour the transmissibility of the disease."

In 1881 he inoculated himself and six soldiers with infected mosquitoes, and obtained, as he had calculated, mild attacks and subsequent immunity. During the years 1881-1900 he inoculated by this method 104 persons:—

"In these inoculations, be it remembered, my principal object was rather to avoid than to seek the development of a severe attack; in point of fact, only seventeen showed any appreciable pathogenic effects after their inoculation. I felt sure, however, that severe or fatal result might follow an inoculation either with several mosquitoes contaminated from severe cases of the disease, or from a single insect applied several days or weeks after its contamination, having come to this last conclusion in view of the facts connected with the Anne Marie, and the epidemic of Saint Nazaire."

Dr. Finlay's discovery that the mosquito can convey yellow fever, and that the germ of the disease is more virulent after a prolonged sojourning in the mosquito, was proved beyond all question by the work of 1889-1901. But, so far as immunisation is concerned, few people would submit themselves to be bitten by an infected mosquito, even with perfect assurance that the germs contained in it were of a low degree of virulence: the urgent need, therefore, was for an immunising serum. In 1896, at Flores, Sanarelli discovered the bacillus icteroides; and by October 1897, he had prepared an immunising serum which was able to give a considerable amount of protection to animals.[40] Next year (Annales de l'Institut Pasteur, May 1898) came the news that he had advanced against yellow fever with its own weapons—Premières expériences sur l'emploi du sérum curatif et préventif de la fièvre jaune. Of the first 8 cases (Rio de Janeiro), 4 recovered. Then came the 22 cases at San Carlos do Pinhal, in Saint-Paul au Brésil (January 1898), with 16 recoveries, and only 6 deaths. And it is to be noted that he submitted his method of treatment to the utmost test that was possible; he chose the bad cases, and the country where the fever was most fatal:—

"Chaque cas était choisi de commun accord entre nous, dans le but de mettre bien en évidence l'action thérapeutique du sérum, mettant toujours de côté tous les cas qui se présentaient avec des symptômes vagues ou attenuès ou en forme légère ou fruste. On ne conservait donc que des cas oû, d'après la violence des phénomènes d'invasion, on devait considérer comme très peu probable une crise spontanée de la maladie...."

Furthermore, Sanarelli was able to show the preventive value of the serum. At the end of February 1898, yellow fever broke out in the jail at San Carlos:—

"La première victime fut un condamné, qui vivait avec tous les autres dans une salle oû les conditions hygiéniques étaient assez mauvaises. Le lendemain, la sentinelle, qui était en rapport continuel avec la salle des condamnés, tombait malade. Quelques jours après, un autre condamné suivait le sort du premier, et bientôt un quatrième cas, mortel aussi, finit par signaler la prison comme un nouveau foyer d'infection qui venait s'allumer au centre d'un quartier de la ville encore resté indemne.

"Si on avait abandonné la chose à elle-même, on aurait vu se produire le même spectacle qu'avaient fourni, dans les conditions identiques, pendant les dernières épidémies, les prisons de Rio-Claro, de Limeira, et d'autres villes de l'État de Saint-Paul."

Every prisoner, except one who had already had the fever, was therefore given the preventive treatment. At once the outbreak stopped; no more cases occurred, though only a weak serum was used, though the state of the prison and its occupants was unhealthy, though the fever, two months later, was still raging round the prison, in the town.

In October 1900, the United States Commission on Yellow Fever published a preliminary report on 11 cases of mosquito-inoculation. Of these, the majority gave a negative result, and were found susceptible to infection, at a later date, from the blood of a yellow-fever patient. Two gave a positive result. In the course of these experiments, Dr. Lazear, a member of the Commission, died of the disease. In February 1901, and again in July, the Commission published further reports, emphasising the fact that the mosquito conveys the disease, and denying that the disease can be conveyed in clothing, bedding, and so forth:—

"Our observations appear to demonstrate that the parasite of this disease must undergo a definite cycle of development in the body of the mosquito before the latter is capable of conveying infection. This period would seem to be not less than twelve days.

"We also consider the question of house infection, and are able to show that this infection is due to the presence of mosquitoes that have previously bitten yellow-fever patients; and that the danger of contracting the disease may be avoided in the case of non-immune individuals who sleep in this building, by the use of a wire screen.

"We also demonstrate, by observations made at this camp (Fort Lazear), that clothes and bedding contaminated by contact with yellow-fever cases, or by the excreta of these cases, is absolutely without effect in conveying the disease."

In February 1901, Dr. H. E. Durham published an abstract of an interim report of the Liverpool School Yellow Fever Commission. He and Dr. Walter Myers, the two Commissioners, had both of them been attacked by the disease, and Dr. Myers had died of it. The report gives evidence that the disease is due to a bacillus which is not the bacillus icteroides; and it does not wholly favour the earlier report (1900) of the American Commission. A later Commission to New Orleans, September 1901 to January 1902, reported an extensive series of investigations, which seem rather to support the belief that the bacillus icteroides is the cause of the disease. Later still, this belief is again denied; and, as in rabies, so in yellow fever, the good work has gone on without waiting for the identity of this or that micro-organism.

Immunisation, by the direct use of an infected mosquito, may be compared with the old custom of inoculation against smallpox. The use of Sanarelli's serum-treatment has not gone far. There remains for consideration the method of keeping down infection by keeping down Culex.

Three reports, in 1901-1902, come from Dr. Guitéras (Havana), Surgeon-Major Gorgas, chief sanitary officer (Havana), and the Commission at New Orleans. Dr. Guitéras reports that 6 cases of yellow fever (inoculation) were treated in a large "mosquito-proof" building, which also contained cases of other diseases. No prophylaxis was enforced, save the exclusion of mosquitoes; non-immunes visited the yellow fever cases, non-immunes nursed them, and most of the attendants and labourers about the place were non-immunes; but not a single case of infection occurred. The New Orleans Commission reports that, of 200 cisterns, &c., examined in the city for the presence of larvæ, the larva of Culex (Stegomyia) predominated in more than 60 per cent.

The report of Surgeon-Major Gorgas is very pleasant reading. For two centuries, Cuba had been cursed with yellow fever; then, after the war with Spain, America took it over:—

"The army took charge of the health department of Havana, when deaths (from all causes) were occurring at the rate of 21,252 per year. It gives it up, with deaths occurring at the rate of 5720 per year. It took charge, with smallpox endemic for years. It gives it up, with not a case having occurred in the city for over eighteen months. It took charge, with yellow fever endemic for two centuries—the relentless foe of every foreigner who came within Havana's borders, which he could not escape, and from whose attack he well knew every fourth man must die. The army has stamped out this disease in its greatest stronghold."

Make fair allowance for the wide variation, from year to year, of the number of yellow fever cases in any town within the geographical belt of the disease; admit that a town may, in the course of nature, have many hundred cases in one year, and only half a dozen in another year. Again, make fair allowance for all other good influences of the American occupation of Cuba, beside those that were concerned with the stamping out of Culex; admit that the general death-rate of Havana, in the last February of Spanish rule (1898), was 82.32 per thousand, and in February 1901, was 19.32. Still, there is an example here, in the 1901 work in Havana, for the world to follow, wherever yellow fever exists. The following abstract of Surgeon-Major Gorgas' results was published in the Practitioner, May 1902, by Professor Hewlett, one of the foremost of English bacteriologists:—

"Commencing in February 1901, orders were issued that every suspected case of yellow fever should be screened with wire gauze at the public expense, so as to render the room or rooms mosquito-proof. All mosquitoes in the infected house and in contiguous houses were destroyed. After the middle of February, 100 men were employed in carrying out the destruction of the mosquito-larvæ in their breeding places, putting oil in the cesspools of all houses, clearing the streams, draining pools, and oiling the larger bodies of water. Up to June, quarantine was enforced, together with disinfection of the house and fomites. After that, however, rigid quarantine of the patient was stopped, and disinfection of fabrics and clothing ceased. It was merely required that the patient should be reported, his house placarded and screened, and a guard placed over each case to report how general sick-room sanitation was carried out, to see that the screen-door communicating with the screened part of the house was kept properly closed, and to see that communication with the sick-room was not too free, four or five non-immunes only being allowed in. By the end of September, the last focus of the disease had been got rid of, and since then, up to the beginning of January, there has not been a single case. Whereas, for the years since 1889, from 1st April to 1st December, yellow fever caused an average of 410.54 deaths, with a maximum of 1175 for 1896, and a minimum of 79 for 1899, it caused in 1901 5 deaths only. In the months of October and November, when the disease has hitherto been exceedingly rife in Havana, there has not been a single case. For the first time in 150 years, Havana has been free from yellow fever."

Sir Patrick Manson, lecturing in America, last year, on tropical diseases, summed up the work as follows:—

"Time will not permit—what to you is probably quite unnecessary—the recapitulation of the story of the labours of Reed and his coadjutors. I cannot pass on, however, to what I have to say in connection with this work without a word of admiration for the insight, the energy, the skill, the courage, and withal the modesty and simplicity of the leader of that remarkable band of workers. If any man deserved a monument to his memory, it was Reed. If any band of men deserve recognition at the hands of their countrymen, it is Reed's colleagues.

"The principal outcome of the labours of these men has been the demonstration, first, that the ultra-microscopic germ of yellow fever is present in the blood of the patient during the first three days of the disease. Second, that the first step in the passage of the germ from the sick to the sound is made, under natural conditions, in the stegomyia mosquito. And third, that after about twelve days and upwards in stegomyia, the yellow fever germ, when implanted by the said mosquito into another human host, is capable of reproduction, so that at the end of a further period of about three days it has established itself throughout the blood, is causing the violent reaction, the clinical manifestations of which we call yellow fever, and is once more in a condition to re-enter the mosquito.

"These are great etiological facts. They are of supreme practical and scientific value. Acting on them, the United States sanitary authorities expelled yellow fever from Havana. Acting on them, they should be able in the future to protect the United States themselves from such terrible visitations as in the past have swept through some of your cities."

3. Filariasis

These same lectures contain an admirable account of the life-history of Filaria. It is not necessary here to describe the loathsome deformities which occur in the later stages of filariasis. These deformities (elephantiasis, Barbadoes leg), which may attain colossal size, are due to the blocking of the lymphatic vessels with filarial worms. Cases of the disease are hardly ever seen in this country; but it is very frequent in some parts of the tropics. In the endemic areas, says Manson, 10 per cent. is not an uncommon proportion of the population to be found affected with filariasis. Thirty and even 50 per cent. may be affected. In many of the Pacific Islands—the Samoa group for instance—I believe that even this proportion is exceeded.

That Culex (fatigans) can carry the parasite, has been proved past all doubt. Neither does anybody doubt, that the keeping down of this mosquito would keep down filariasis. A report of great interest, from Barbadoes, was published in the British Medical Journal for 14th June 1902. It is written by Dr. Low, whose experiment on himself in the Campagna has already been noted in this chapter. Dr. Low reports that there is no indigenous malaria in the island, and that neither he nor Mr. Lefroy could find a single Anopheles larva, though they hunted diligently in the swamps and other likely places. But filariasis is terribly common, and so is Culex fatigans. Dr. Low examined the night-blood of 600 cases of all kinds in the General Hospital, the Central Almshouse, and elsewhere, and found the filaria-embryos in no less than 76 = 12.66 per cent. He caught and dissected a hundred mosquitoes (Culex fatigans) from the wards and corridors of the General Hospital, and found that no less than 23 of them were infected. If it were not for Culex, and for men's indifference and apathy, filariasis could be kept down all over the island:—

"There is a perfect water supply, and people can get their water fresh from the standpipes at their doors. Old wells ought to be filled up; no water-barrels or tubs should be allowed, or, if kept, they should be emptied every week or so. Tanks and collections of water in gardens should all be periodically treated with kerosene, or be furnished with closely-fitting covers to prevent mosquitoes getting in. These methods are simple and inexpensive, and each householder should see that they are applied in his garden and grounds. The difficulty begins when one has to take into account the inability of the negro to grasp anything of a hygienic nature. The only way to get over this, would be a system of sanitary inspection by a few competent men. For individual prophylaxis, mosquito-nets ought always to be used; but many, even educated people, still persist in sleeping without them; of course, nothing in this line can be expected of the native population.

"If such means were adopted for Barbadoes, the presence of filarial disease, which at present is quite alarming, could easily, with little trouble and expense, be greatly diminished, and thus save much suffering, as well as loss of time, hideous deformity, and doubtless in not a few instances loss of life."

Thus, in a few years, from experiments on mosquitoes, sparrows, and men, has come the present plan of campaign against malaria, yellow fever, and filariasis; that is, against Anopheles and Culex. He who would know what is being done to check these diseases in Italy, India, China, Africa, and America, must read Prof. Ross' Malarial Fever, its Cause, Prevention, and Treatment (1902), and Mosquito Brigades, and how to organise them (1902). There has been nothing like it since Pasteur died. Far and wide, from Staten Island to Cuba, from Hong Kong to Lagos, the work of keeping down the larvæ of Anopheles and Culex is going on. Henceforth we have to reckon not with a nameless something, but with a definite parasite, whose conditions of life are known. Before all things, we must shut off the sources of the infection. For centuries, men had believed in exhalations and miasmata lying all over the land: and, behold, the agents of malaria are in the puddles round a man's house, and the agents of yellow fever are in the water-butt and the broken bottles and old sardine-tins. Science has given the word, and now there are Anopheles brigades and Culex brigades set going; labourers with brooms and rubbish-carts, sweeping out the stagnant pools, draining the surface soil, and carrying off the odd receptacles that serve to hold mosquito eggs and larvæ. The job, like all sanitary jobs, must be steady, year in, year out: it must be limited to infected places, a whole continent cannot be treated. But there the work is, and will grow; and saves, by unskilled labour, and at a trivial expense, those "non-acclimatised" lives that have hitherto been thrown away as recklessly as the larvæ that are now swept out of the puddles and ditches round African settlements.

XI PARASITIC DISEASES

The foregoing chapters are concerned with bacteriology alone, and with those curative or preventive methods of treatment that have come out of inoculation-experiments on animals. The lives that are saved, or safeguarded, by these methods, even in one year, must be many thousands in each country of the civilised world. And, beside human lives, there is the protection of sheep and cattle against anthrax, swine against rouget, horses against tetanus, cattle against rinderpest. In Cape Colony alone, so far back as 1899, about half a million cattle had received preventive treatment against rinderpest; and the sum total of human and animal lives saved or safeguarded, in all parts of the world, must be reckoned in millions by this time.

The present chapter, and the next two chapters, are concerned with methods that have come out of experiments on animals, but not out of bacteriology.

It is plain that the grosser parasites of the human body, tapeworms and the like, could not be explained or understood without the help of feeding-experiments on animals. By this method, and by this alone, their life-history was discovered. They were known to Aristotle and to Hippocrates; but nothing was understood about them. They were never studied, for this among other reasons, that men believed in spontaneous generation; and the presence of lower forms of life inside human bodies was attributed to the fault of the patient, or the work of the devil. Then, at last, Redi (1712), and Swammerdam (1752) in his Bibel der Natur, struck at the doctrine of spontaneous generation, saying that it did not apply to insects; and in 1781 Pallas boldly declared that the internal parasites of man came out of eggs, like insects, and not "of themselves." It would be a good theme for an essay—The paralysing effect, on medicine and surgery, of the doctrine of spontaneous generation. Rudolphi (1808) and Bremser (1819) opposed Pallas; and von Siebold (1835) and Eschricht (1837) supported him. Then came the great students of this part of biology—Cobbold, Busk, Davaine, van Beneden, Leuckart, Küchenmeister. In 1842, Steenstrup had discovered, in certain insects, the alternation of generations; in 1852, Küchenmeister proved that the generations of internal parasites are similarly alternate. By feeding carnivorous animals with "measly" meat, he produced tapeworms in them; and by feeding herbivorous animals with the ova of tapeworms, he made their muscles "measly."

The feeding of animals was the only possible way to understand the bewildering transformations and transmigrations of the thirty or more entozoa to which flesh is heir. This chapter of pathology makes up in tragedy what it lacks in romance; for these animal parasites have killed whole hosts of people. Take, for instance, the trichina spiralis, a minute worm discovered in 1835 encysted in countless numbers in the muscles of the human body; it was studied by Virchow, Leuckart, and others, by feeding-experiments on animals, and was proved to come from infected half-cooked ham and pork, and to make its way from the alimentary canal all over the body. The name of trichiniasis or trichina-fever was given to the acute illness that came of the sudden dissemination of these myriad parasites into the tissues. Trichiniasis had killed hundreds of people by a most painful death; outbreaks of it, in Germany and elsewhere, had swept through villages like cholera or plague: then Leuckart and Virchow traced it to its source, and it was stopped there—Above all things, we must shut off the sources of the infection—the butchers' shops were kept under sanitary inspection, people were warned against half-cooked ham and pork, and there was an end of it.

Or take hydatid disease, which occurs in all parts of the world, and in some countries (Australia, Iceland) is terribly common. The nature of this disease—that it is an animal parasite transmissible between men and dogs—was proved by feeding-experiments on animals. In Iceland, where men and dogs live crowded together in huts, there is an appalling number of deaths from hydatid disease; Leuckart, in 1863, of it:—

"At present, almost the sixth part of all the inhabitants annually dying in Iceland fall victims to the echinococcus epidemic."

Before Küchenmeister's experiments in 1852, there was no general knowledge of the exact pathology of entozoic disease. The advance was not made by the experimental method alone; other things helped: but among them was neither clinical experience, nor what Sir Charles Bell called "the observation of the just facts of anatomy and of natural motions."

Beside the entozoa, there are also vegetable parasites. Of these, the most important is the streptothrix actinomyces, the cause of actinomycosis in man and cattle. Israel, in 1877, gave the first accurate account of it in man; and Böllinger, the same year, studied it in cattle. Ponfick, in 1882, recognised the identity of the disease in man and animals. In 1885, Israel published the collected records of 37 cases in man, tabulated according to the site of the primary infection. Boström, about this time, made cultures of the fungus: but all the earlier attempts at inoculation failed; and it was not till 1891 that Wolff and Israel published their successful inoculations, and thus completed the evidence that actinomycosis is a parasitic infection, a growth of vegetable threads and spores, transmissible between men and animals, and able to keep its vitality outside its host; so that men who are employed with cattle, or have the habit of chewing straws or ears of corn, incur some slight risk of infection. Before 1877, the disease was hardly suspected in man, and was not understood in cattle.

XII MYXŒDEMA

On 4th October 1873, Sir William Gull read a short paper before the Clinical Society of London, "On a Cretinoid State supervening in Adult Life in Women." This famous first account of myxœdema was based on five cases: it is less than five pages long, it does not suggest a name for the disease, and it says nothing about the thyroid gland. Four years later (23rd October 1877), Dr. Ord read a paper before the Medico-Chirurgical Society of London, "On Myxœdema; a term proposed to be applied to an essential condition in the 'Cretinoid' Affection occasionally observed in Middle-aged Women." His work had begun so far back as 1861; and in this 1877 paper he gave not only clinical observations, but also pathological and chemical facts; and he noted, as one among many changes, wasting of the thyroid gland. He also pointed out the close resemblance between cases of myxœdema and cases of sporadic cretinism.

In 1882, Reverdin stated before the Medical Society of Geneva that signs like those of myxœdema had been observed in some cases of removal of the thyroid gland on account of disease (goître). In April 1883, Kocher of Berne read a paper on this subject, before the Congress of German Surgeons; but he attributed this myxœdema after removal of the gland (cachexia strumipriva) not directly to the loss of thyroid-tissue, but rather to some sort of interference with free respiration, due to operation. On 23rd November, Sir Felix Semon brought the subject again before the Clinical Society; and on 14th December 1883, the Society appointed a Committee of Investigation to study the whole question.

Their report, 215 pages long, with tabulated records of 119 cases of myxœdema, was published in 1888. It is a monument of good work, historical, clinical, pathological, chemical, and experimental. Twenty years ago, the purpose of the thyroid gland was unknown: a few experiments had been made on it, by Sir Astley Cooper and others, and had failed; and Claude Bernard, in his Physiologie Opératoire (published in 1879, soon after his death), makes it clear that nothing was known in his time about it. He is emphasising the fact that anatomy cannot make the discoveries of physiology:—

"The descriptive anatomy, and the microscopic characters, of the thyroid gland, the facts about its blood-vessels and its lymphatics—are not all these as well known in the thyroid gland as in other organs? Is not the same thing true of the thymus gland, and the suprarenal capsules? Yet we know absolutely nothing about the functions of these organs—we have not so much as an idea what use and importance they may possess—because experiments have told us nothing about them; and anatomy, left to itself, is absolutely silent on the subject."

Therefore, in 1882-83, things stood at this point—that the removal of a diseased thyroid gland had been followed, in some cases, by a train of symptoms such as Sir William Gull had recorded in 1873. Would the same symptoms follow removal of the healthy gland? The answer was given by Sir Victor Horsley's experiments, begun in 1884. He was able, by removal of the gland, to produce in monkeys a chronic myxœdema, a cretinoid state, the facsimile of the disease in man: the same symptoms, course, tissue-changes, the same physical and mental hebetude, the same alterations of the excretions, the temperature, and the voice. It was now past doubt that myxœdema was due to want of thyroid-tissue, and to that alone; and that "cachexia strumipriva" was due to the loss, by operation, of such remnants of the gland as had not been rendered useless by disease.

The advance had still to be made from pathology to treatment. Here, so far as England is concerned, honour is again due to Sir Victor Horsley. On 8th February 1890, he published the suggestion that thyroid-tissue, from an animal just killed, should be transplanted beneath the skin of a myxœdematous patient:—

"The justification of this procedure rested on the remarkable experiments of Schiff and von Eisselsberg. I only became aware in April 1890, that this proposal had been in fact forestalled in 1889 by Dr. Bircher, in Aarau. (The date of Dr. Bircher's operation was 16th January 1889.) Kocher had tried to do the same thing in 1883, but the graft was soon absorbed; but early in 1889 he tried it again, in five cases, and one greatly improved."

The importance of this treatment, by transplantation of living thyroid-tissue, must be judged by the fact that in 1888 no practical use had yet been made of the scientific work that had been done. The Clinical Society's Report, published that year, gives but half a page to treatment, of the old-fashioned sort; and not a word of hope.

Then, at last, in 1891, came Dr. George Murray's paper in the British Medical Journal, "Note on the Treatment of Myxœdema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep." Later, hypodermic injections of thyroid-extract gave way to sandwiches, made with thyroid gland (Dr. Hector Mackenzie, and Dr. Fox of Plymouth), and these in their turn were eclipsed by tabloids.

It is a strange sequence, from 1873 onward: clinical observation, post-mortem work, calamities of surgery, experimental physiology, transplantation, hypodermic injections, sandwiches, and tabloids. And far more has been achieved than the cure of myxœdema. Even if the discovery stopped here, it would still be a miracle that little bottles of tabloids should bring men and women back from myxœdema to what they were before they became thick-witted, slow, changed almost past recognition, drifting toward idiocy. But it does not stop here. The same treatment has given good results in countless cases of sporadic cretinism, restoring growth of body and of mind to children that were hopelessly imbecile. It is of great value also for certain diseases of the skin. Moreover, physiology has gained knowledge of the purpose of the thyroid gland, and a clearer insight into the facts relating to internal secretion.

XIII THE ACTION OF DRUGS

Long after the Renaissance, the practice of medicine was still under the influence of magic. Whatever things were rare and precious were held to be good against disease—gold, amber, coral, pearls, and the dust of mummies; whatever took strange forms of life—toads, earthworms, and the like; whatever looked like the disease, after the doctrine of signatures—pulmonaria for the lungs, because the spots on its leaves were like tubercle, a kidney-shaped fruit for the kidneys, a heart-shaped fruit for the heart, and yellow carrots for the yellow jaundice. Among the drugs in the 1618 Pharmacopœia are cranium humanum, mandibula lucii, nidus hirundinum, sericum crudum, linum vivum, and pilus salamandræ. In the Pharmacopœia of 1667 are exuviæ serpentis, telæ aranearum, saliva jejuni, cranium hominis violentâ morte extincti, and worse obscenities.

Soon after the publication of this Pharmacopœia, on 14th February 1685, King Charles II. died; and in the Library of the Society of Antiquaries there is a manuscript account in Latin, by Dr. Scarbrugh, how the case was treated. The King had sixteen physicians, and nine consultations in five days; and to say "everything was done that was possible" gives no idea of the vigour of the treatment. Finally, the day he died, they gave him, eleven of them in consultation—totus medicorum chorus ab omni spe destitutus—they gave him, as more generous cardiacs, the lapis Goæ, and the Bezoar-stone. The lapis Goæ was a dust of topaz, jacinth, sapphire, ruby, pearl, emerald, bezoar, coral, musk, ambergris, and gold, all made into a pill and polished; and the bezoar is a calculus found in the intestines of herbivorous animals. Half a century later, the Pharmacopœia of 1721 still included ants' eggs, teeth, lapis nephriticus, and other horrors; and in the Pharmacopœia of 1746, though the dust of Egyptian mummies was ruled out, vipers and wood-lice were retained.

Certainly these "last enchantments of the Middle Ages" were slow to depart. Clinical observation, anatomy, and pathology, had all failed to bring about a right understanding of the actions of drugs. It was the physiologists, not the doctors, who first formulated the exact use of drugs; it was Bichat, Magendie, and Claude Bernard. That is the whole meaning of Magendie's work on the upas-poison and on strychnine, and Claude Bernard's work on curari and digitalis. Of these four substances, two only are of any use in practice; yet Magendie's study of strychnine[41] was of immeasurable value, not so much because it gave the doctors a "more generous cardiac," though that was a great gift, but because it revealed the selective action of drugs. Contrast his account of strychnine with Ambroise Paré's story how they tested the bezoar-stone on the thief instead of hanging him; contrast Bernard's chapter on curari with Dr. Scarbrugh's notes on the King's death, with all the Crown jewels inside him: you are in two different worlds. The selective action of drugs—the affinity between strychnine and the central nerve-cells, between curari and the terminal filaments of the motor nerves—that was the revolutionary teaching of science: and it came, not by experience, but by experiment.

Take Professor Fraser's address on "The Action of Remedies, and the Experimental Method" at the International Medical Congress in London, 1881:—

"The introduction of this method is due to Bichat; and, by its subsequent application by Magendie, pharmacology was originated as the science we now recognise. Bichat represents a transition state, in which metaphysical conceptions were mingled with the results of experience. Magendie more clearly recognised the danger of adopting theories, in the existing imperfections of knowledge; and devoted himself to the supplementing of these imperfections by experiments on living animals. The advantages of such experiments he early illustrated by his investigation on the upas-poison; and afterwards by a research on the then newly-discovered alkaloid, strychnia.... He demonstrated the action of this substance upon the spinal cord, by experiments upon the lower animals, so thoroughly, that subsequent investigations have added but little to his results."

Or take Professor Fraser's account of digitalis:—

"It was introduced as a remedy for dropsy; and, on the applications which were made of it for the treatment of that disease, a slowing action upon the cardiac movements was observed, which led to its acquiring the reputation of a cardiac sedative. Numerous observations were made on man by the originators of its application, by Dr. Sanders and many other physicians, in which special attention was paid to its effects upon the circulation; but no further light was thrown upon its remarkable properties, with the unimportant exception that in some cases it was found to excite the circulation. It was not until the experimental method was applied in its investigation, in the first instance by Claude Bernard, and subsequently by Dybkowsky, Pelikan, Meyer, Boehm, and Schmiedeberg, that the true action of digitalis upon the circulation was discovered. It was shown that the effects upon the circulation were not in any exact sense sedative, but, on the contrary, stimulant and tonic, rendering the action of the heart more powerful, and increasing the tension in the blood-vessels. The indications for its use in disease were thereby revolutionised, and at the same time rendered more exact; and the striking benefits which are now afforded by the use of this substance in most (cardiac) diseases were made available to humanity."

Or take Sir T. Lauder Brunton's account of the action of nitrite of amyl in angina pectoris:—

"The action of nitrite of amyl in causing flushing was first observed by Guthrie, and Sir B. W. Richardson recommended it as a remedy in spasmodic conditions, from the power he thought it to possess of paralysing motor nerves. In the spring of 1867 I had opportunities of constantly observing a patient who suffered from angina pectoris, and of obtaining from him numerous sphygmographic tracings, both during the attack and during the interval. These showed that during the attack the pulse became quicker, the blood-pressure rose, and the arterioles contracted.... It seemed probable that the great rise in tension was the cause of the pain, and it occurred to me that if it was possible to diminish the tension by drugs instead of by bleeding, the pain would be removed.

"I knew from unpublished experiments on animals by Dr. A. Gamgee that nitrite of amyl had this power, and therefore tried it on the patient. My expectations were perfectly answered. The pain usually disappeared in three-quarters of a minute after the inhalation began, and at the same time the pulse became slower and much fuller, and the tension diminished."

Of course it would be easy to lengthen out the list. Aconite, adrenalin, belladonna, calcium chloride, colchicum, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics—all these drugs, and many more, have been studied and learned by experiments on animals. Then comes the answer, that drugs act differently on animals and on men. The few instances, that give a wise air to this foolish answer, were known long ago to everybody: they do not so much as touch the facts of daily practice:—

"The action of drugs on man differs from that on the lower animals chiefly in respect to the brain, which is so much more greatly developed in man. Where the structure of an organ or tissue is nearly the same in man and in the lower animals, the action of drugs upon it is similar. Thus we find that carbonic oxide, and nitrites, produce similar changes in the blood of frogs, dogs, and man, that curare paralyses the motor nerves, alike in them all, and veratria exerts upon the muscles of each its peculiar stimulant and paralysing action. Where differences exist in the structure of the various organs, we find, as we would naturally expect, differences in their reaction to drugs. Thus the heart of the frog is simpler than that of dogs or men, and less affected by the central nervous system; we consequently find that while such a drug as digitalis has a somewhat similar action upon the hearts of frogs, dogs, and men, there are certain differences between its effect upon the heart of a frog and on that of mammals.

"Belladonna offers another example of apparent difference in action—a considerable dose of belladonna will produce almost no apparent effect upon a rabbit, while a smaller dose in a dog or a man would cause the rapidity of the pulse to be nearly doubled. Yet in all three—rabbits, dogs, and men—belladonna paralyses the power of the vagus over the heart. The difference is that in rabbits the vagus normally exerts but little action on the heart, and the effect of its paralysis is consequently slight or hardly appreciable." (Professor Fraser.)

It would be strange indeed, if experts who work in micromillimetres and decimal milligrammes, and study the vanishing-point of microscopic structures, and measure and ordain infinitesimal changes in invisible organisms, were blind to such gross and palpable differences as exist between men and pigeons in their susceptibility to a dose of opium.

Anæsthetics must be reckoned among the drugs that have been studied on animals: but, for the discovery of them, men experimented on themselves. The first use of nitrous oxide (laughing gas) in surgery was 11th December 1844, when Horace Wells, of Connecticut, had it administered to himself for the removal of a tooth. The first use of ether was made by Dr. Long, of Athens, Georgia; but he did not publish the case, or follow up the work: and the honour of the discovery of ether went to Morton, of Boston, who made repeated experiments, both on animals and on himself. The date when he first rendered himself absolutely unconscious for seven or eight minutes, is 30th September 1846; and the first operation under ether was done on 16th October, in the Massachusetts General Hospital. The first use of chloroform was 4th November 1847, that famous evening when Simpson, George Keith, and Matthews Duncan took it together. The whole history of anæsthesia is to be found in the Practitioner, Oct. 1896.