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Originally appearing in Volume V28, Page 164 of the 1911 Encyclopedia Britannica.
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VACCINATION AGAINST ROUGET (FRANCE) Years. .L ,,; -o 03 Mortality. m ° w wj 0 o 0 a ° 0 ,.. .a C v 0 G' No E 0 o m > '.~ .0 isa oa'n c°a E 5> .4c m 0, u c,) m C ar ~.° o ° ~m o c e ~+ a'Z ~.v. VI.V au, ~b'o^w 5'-' 5 C ro' < 1886 For these 7,087 91 24 56 171 2.41 20 % 1887 years two France and other countries 49 7,467 57 10 23 90 1.21 es 1888 are put 31 6,968 31 25 38 94 I *35 „ together. 15,958 1889 19,338 41 11,257 92 12 40 144 1.28 1890 17,658 41 14,992 118 64 72 254 1.70 „ 1891 20,583 47 17,556 102 34 70 206 1.17 1892 37,900 38 10,128 43 19 46 108 1.07 „ Total: 111,437 2961 75,455 534 188 345 1067 1.45 „ 4. Tubercle.-Laennec, who in 1816 invented the stethoscope, recognized the fact that tubercle is a specific disease, not a simple degeneration of the affected tissues. Villemin, in 1865, communicated to the Academie des Sciences the fact that he had produced the disease in rabbits by inoculating them with tuberculous-natter; and he appealed to these inoculations-en voici les preuves-to show that La tuberculose est une affection specifique: Sa cause reside dans un agent inoculable: L'inoculation se fait tres-bien de l'homnie au lapin: La tuberculose appartient donc a la classe des maladies virulentes. In 1868 Chauveau produced the disease not by inoculation but by admixture of tuberculous matter with the animals' food. In 188o, after a period of some uncertainty and confusion of doctrines, Cohnheim reaffirmed the infectivity of the disease, and even made the proof of tubercle depend on inoculation alone: " everything is tuberculous that can produce tuberculous disease by inoculation in animals that are susceptible to the disease; and nothing is tuberculous that cannot do this." In 1881 Koch discovered the tubercle bacillus, and, in spite of the tragic failure of his tuberculin in 1890-91, a vast amount of practical advantage has already issued out of Koch's discovery, both by way of cure and by way of prevention. It has been proved, by experiment on animals, that the sputa of phthisical patients are infective; and this and the like facts have profoundly influenced the nursing and general care of such cases. Bacteriology has brought about (under the safe-guard of modern methods of surgery) a thorough and early surgical treatment of all primary tuberculous sores or deposits—the excision of tuberculous ulcers, the removal of tuberculous glands and the like. It has helped us to make an early diagnosis, in obscure cases, by finding tubercle bacilli in the sputa, or in the discharges, or in a particle of the tissues. It has proved, past all reasonable doubt, that tabes mesenterica, a disease that kills every year in England alone many thousands of children, may arise from infection of the bowels by the milk of tuberculous cows. And it has helped to bring about the present rigorous control of the milk trade and the meat trade. The " new tuberculin," now that the use of the opsonic index has guided physicians to a better understanding of the tuberculin treatment, has been found of great value, and is giving excellent results in suitable cases. Moreover, tuberculin is used, because of the reaction that it causes in tuberculous animals, as a test for the detection of latent tuberculosis in cattle. An injection of one to two cubic centimetres under the skin of the neck is followed by a high temperature if the animal he tuberculous. If it be not, there is no rise of temperature, or only a very slight rise. For example, in 1899 this test was applied to 270 cows on farms in Lancashire: 18o reacted to the test, 85 did not, 5 were " doubtful." Tuberculous disease was actually found in 175 out of the 180. Eber of Dresden used the test on 174 animals, of whom 136 reacted. 32 did not react and 6 were doubtful. Of the 136, 22 were slaughtered, and were all found to have tubercle; of the 32, 3 were slaughtered, and were found free. The opinion of Professor M'Fadyean, one of the highest authorities on the subject, is as follows: " I have most implicit faith in tuberculin as a test for tuberculosis when it is used on animals standing in their own premises and undisturbed. It is not reliable when used on animals in a market or slaughter-house. A considerable number of errors at first were found when I examined animals in slaughter-houses after they had been conveyed there by rail, &c. Since that, using it on animals in their own premises, I have found that it is practically infallible. I have notes of one particula- case where 25 animals in one dairy were tested, and after-wards all were killed. There was only one animal which did not react, and it was the only animal not found to be tuberculous when killed." This test has now been in regular use for many years in many countries, and it is accepted everywhere as of national importance. 5. Diphtheria.—The Bacillus diphtheriae (Klebs-Loffler bacillus) was described by Klebs in 1875, and obtained in pure culture by Loffler in 1884. Behring and Kitasato, in 1890, succeeded in immunizing animals against the disease. The first cases treated with diphtheria antitoxin were published in 1893 by Behring, Kossel and Hubner. In England the antitoxin treatment was begun in the latter part of 1894. Besides its curative use, the antitoxin has also been used as a preventive, to stop an outbreak of diphtheria in a school or institute or hospital or village, and with admirable success. (See DIPHTHERIA.) 6. Tetanus (lock-jaw).—Experiments on animals have taught us the true nature of this disease, and have led to the discovery of an antitoxin which has given fairly good results. We possess, moreover, a preventive treatment against the disease; though, unfortunately, the time of latency, when the antitoxin is most needed, cannot be recognized. The old, mischievous doctrine that tetanus was due to acute inflammation of a nerve, tracking up from a wound to the central nervous system, was abolished once and for ever by Sternberg (188o), Carle and Rattone (1884) and Nicolaier (1884), who proved that the disease is due to infection by a specific flagellate organism in superficial soil. " It is said to be present in almost all rich garden soils, and that the presence of horse-dung favours its occurrence. There seems to be no doubt as to the ubiquity of the tetanus germ " (Poore, Milroy Lectures, 1899). The work of discovering and isolating the bacillus was full of difficulty. Nicolaier, starting from the familiar fact that the disease mostly comes from wounds or scratches contaminated with earth, studied the various microbes of the soil, and inoculated rabbits with garden mould. He produced the disease, and succeeded in finding and cultivating the bacillus, but failed to obtain a pure culture. Kitasato, in 1899, obtained a pure culture. Others studied the chemical products of the bacillus, and were able to produce the symptoms of the disease by injection of these chemical products obtained from cultures, or from the tissues in cases of tetanus. It has been proved that the infection tends to remain local; that the bacilli in and near the wound pour thence into the x xvrn. 6blood their chemical products, and that these have a selective action, like strychnine, on the cells of the central nervous system. There-fore the rule that the wounded tissues should be at once excised, in all cases where this can possibly be done, has received. confirmation. Before Nicolaier, while men were still free to believe that tetanus was the result of an acute ascending neuritis, this rule was neither enforced nor explained. As a preventive against tetanus, in man or in animals, the antitoxin has proved of the very utmost value. This has been shown in a striking way in America. " One of the wounds most commonly followed by lock-jaw is the blank-cartridge wound of the hand common on the glorious Fourth of July. The death-rate from these wounds is appalling. An active campaign has been conducted throughout the medical profession to reduce this mortality. All over the country, surgeons and medical journals have advised the injection of tetanus antitoxin in every case of blank-cartridge wound. The American Medical Association has compiled statistics of Fourth of July fatalities for the past six years. In 1903, the Fourth of July tetanus cases numbered 416. Then physicians began a more general use of antitoxin in all cases of blank-cartridge and common cracker wounds. As a result of this campaign of prophylaxis by antitoxin injections, from 416 cases of tetanus in 1903 the number dropped to 105 cases in 1904, 104 cases in 1905, 89 cases in 1906, 73 cases in 1907 and 55 cases in 1908. This reduction in the number of tetanus cases took place while the number of accidents remained practically the same each year, and while the number of deaths from causes other than tetanus was steadily rising from 6o in 1903 to 108 in 1908. It is thus evident that the saving of at least 300 lives from tetanus has been accomplished each year through the prophylactic use of antitoxin in the cases of Fourth of July wounds alone " (James P. Warbasse, M.D., The Conquest of Disease through Animal Experimentation, Appleton & Co., 1910). The preventive use of the serum in veterinary practice has yielded admirable results. In some parts of the world tetanus is terribly common among horses. Nocard of Lille has reported as follows: " The use of anti-tetanus serum as a preventive has been in force for some years in veterinary practice in cases of wounds or surgical procedures. To this end the Pasteur Institute has supplied 7000 doses of anti-tetanus serum, a dose being to cubic centimetres; a quantity which has sufficed to treat preventively 3100 horses in those parts of the country where tetanus is endemic. Among these there has been no death from tetanus. In the case of one horse, injected five days after receiving a wound, tetanus developed, but the attack was slight. During the same time that these animals were injected, the same veterinary surgeon observed, among animals not treated by injection, 259 cases of tetanus " (Lancet, August 7, 1897). 7. Rabies (hydrophobia).—The date of the first case treated by Pasteur's preventive method—Joseph Meister, an Alsatian shepherdboy—is July 1885. The existence of a specific micro-organism of rabies was a matter of inference. The incubation period of the disease is so variable that no preventive treatment was possible unless this incubation period could be regulated. Inoculations of the saliva of a rabid animal, introduced under the skin of animals, sometimes failed; and if they succeeded, the incubation period of the disease thus induced was hopelessly variable. Next, Pasteur used not saliva, but an emulsion of the brain or the spinal cord; because the central nervous system is the chief seat of the poison. But this emulsion, introduced under the skin, was also uncertain in action, and gave no fixed incubation period. Therefore, he argued, as the poison has a selective action on the nerve cells of the central nervous system, and a sort of natural affinity with them, it must be introduced directly into them, where it will have its proper environment; the emulsion must be put not under the skin, but under the dura mater (the membrane enveloping the brain). These subdural inoculations were the turning-point of his work. By transmitting the poison through a series of rabbits, by subdural inoculation of each rabbit with a minute quantity of nerve tissue from the rabbit that had died before it, he was able to intensify the poison, to shorten its period of incubation, and to fix this period at six days. Thus he obtained a poison of exact strength, a definite standard of virulence, virus fixe: the next rabbit inoculated would have the disease in six days, neither more nor less. By gradual drying, after death, of the cords of rabid animals, he was able to attenuate the poison contained in them. The spinal cord of a rabbit thathas died of rabies slowly loses virulence by simple drying. A cord dried for four days is less virulent than a cord dried for three, and more virulent than a cord dried for five. A cord dried for a fortnight has lost all virulence; even a large dose of it will not produce the disease. By this method of drying, Pasteur was able to keep going one or more series of cords, of known and exactly graduated strengths, according to the length of time they had been dried, ranging from absolute non-virulence through every shade of virulence. As with fowl cholera and anthrax, so with rabies: the poison, attenuated till it is innocuous, can yet confer immunity against a stronger dose of the same poison. A man, bitten by a rabid animal, has at least some weeks of respite before the disease can break out; and during that time of respite he can be immunized against the disease, while it is still dormant. He begins with a dose of poison attenuated past all power of doing harm, and advances day by day II to more active doses, guarded each day by the dose of the day before, till he has manufactured within himself enough antitoxin to make him roof against any outbreak of the disease. (See HYDROPHOBIA. 8. Cholera.—The specific organism of Asiatic cholera, the " comma-bacillus," was discovered by Koch in 1883; but such a multitude of difficulties arose over it that it was not universally recognized as the real cause of the disease before 1892, the year of the epidemic at Hamburg. The discovery of preventive inoculation was the work of many men, but especially of Haffkine, one of Pasteur's pupils. Ferran's earlier inoculations in Spain (1885) were a failure. Haffkine's first inoculations were made in 1893. At Agra, in April 1893, he vaccinated over 900 persons; and from Agra went to many other cities of India. Altogether, in twenty-eight months (April 1893–July 1895) no less than 42,179 persons were vaccinated (many of them twice) in towns, cantonments, gaols, tea estates, villages, schools, &c., " without having to record a single instance of mishap or accident of any kind produced by our vaccines." (See CHOLERA.) 9. Bubonic Plague.—The Bacillus pestis was discovered in 1894 by Kitasato and Yersin, working independently. The preventive treatment was worked out by Haffkine in 1896: " Twenty healthy rabbits were put in cages. Ten of them were inoculated with Haffkine's plague vaccine. Then both the vaccinated rabbits and the other ten rabbits that had not been vaccinated were infected with plague. The unprotected rabbits all died of the disease, and in their bodies innumerable quantities of the microbes were found. But the vaccinated rabbits remained in good health. Professor Haffkine then vaccinated himself and his friends. This produced some fever, from which, after a day or two, they recovered. Plague broke out in Byculla Gaol, in Bombay, in January 1897. About half the prisoners volunteered to be inoculated. Of these, 3 developed plague on the day of inoculation, and it is probable that they had already plague before the treatment was carried out. Of the remaining 148 who were inoculated,, only 2 were afterwards attacked with plague, and both of them recovered. At the same time, of the 173 who had not been vaccinated, 12 were attacked, and out of these .6 died." (See PLAGUE.) to. Typhoid Fever.—The Bacillus typhosus was discovered by Kiebs, Eberth and Koch in 188o-81. The first protective inoculations in England were made at Netley Hospital in 1896 by Sir Almroth Wright and Surgeon-Major Semple: 16 medical men and 2 others offered themselves as subjects. The first use of the vaccine during an actual outbreak of typhoid was in October 1897 at the Kent County Asylum: " All the medical staff and a number of attendants accepted the offer. Not one of those vaccinated—84 in number—contracted typhoid fever; while of those unvaccinated, and living under similar conditions, 16 were attacked. This is a significant fact, though it should in fairness be stated that the water was boiled after a certain date, and other precautions were taken, so that the vaccination cannot be said to be altogether responsible for the' immunity. Still, the figures are striking" (Lancet, March 1898). In 1899 Wright vaccinated against typhoid more than 3000 of the Indian army, at Bangalore, Rawal Pindi and Lucknow. Government has now sanctioned voluntary inoculation against typhoid, at the public expense, among the British troops. " All regiments leaving for the tropics are offered this inoculation, and each year a larger percentage of the soldiers are accepting it. Here are some of the statistics: In August and September 1905, to men of a single regiment were inoculated: of these, 23 refused to accept a second inoculation. The regiment reached India, September 28. A month later, typhoid fever broke out; and during the following few months 63 cases were observed in the regiment. With but two exceptions, the disease attacked only the men who had not been inoculated, and both of these exceptions were men who had refused a second inoculation. Careful experiments were made with the second battalion of Royal Fusiliers in India in 1905 and 1906. The average strength of this regiment was 948 men. During the two years, 284 were inoculated with Wright's anti-typhoid vaccine. The regiment had a total of 46 cases of typhoid. Thirty-five of these were men who had not been inoculated; 9 had been inoculated. Five of the uninoculated died; none of the inoculated died. Another Indian regiment, the 17th Lancers, in 1905, 1906 and 1907 inoculated about one-third of its men. During the three years it had 293 cases of typhoid fever. There were 44 deaths, with not a single death of an inoculated man. During the first half of 1908, in the largest seven Indian stations where careful records were kept, out of a total of 10,420 soldiers, 2207 volunteered for inoculation. Typhoid developed in 2% of the uninoculated, and in less than 1% of the inoculated men. Forty-five deaths occurred. Five per cent of these deaths were among the uninoculated and 1% was among the inoculated men. ... In the United States army, a medical board has strongly recommended anti-typhoid vaccinations, and vaccination is now cffered to those who desire it. Already 2000 soldiers have voluntarily received inoculation. The German army has adopted the same means of prophylaxis, and is pushing it vigorously " (Warbasse, ioc. cit.). Beside the preventive treatment, bacteriology has given us" Widal's reaction " for the early diagnosis of the disease—a matter of the very highest practical importance. A drop of blood, from the finger of a patient suspected to be suffering from typhoid fever, 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 nutrient fluid containing living bacilli of typhoid, and a drop of this mixture is observed 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. This " clumping " is also made visible to the naked eye by the subsidence of the agglutinated bacilli to the bottom of the containing vessel. The amazing delicacy of " Widal's test " is but a part of the wonder. Long after recovery, a fiftieth part of a drop of the blood will still cause clumping: it has even been obtained from an infant whose mother had typhoid shortly before, the child was born. A drop of blood from a case suspected to be typhoid can now be sent by post to be tested a hundred miles away, and the answer telegraphed back. II. Malta Fever (Mediterranean fever).—The Micrococcus Melitensis was discovered in 1887 by Sir David Bruce. The work of discovering and preparing an immunizing serum was done at Netley Hospital. In this fever, as in typhoid and some others, Widal's test is of great value: " The diagnosis of Malta fever from typhoid is, of course, a highly important practical matter. It is exceedingly difficult in the early stages" (Manson). Even in a dilution of I in Iwo, the blood of Malta fever can give the typical reaction with the Micrococcus Melitensis; and this occurred in a case at Netley of accidental inoculation with Malta fever: one of three cases that have happened there. The case is reported in the. British Medical Journal, October 16, 1897: " It appears that he had scratched his hand with a hypodermic needle on September 17, when immunizing a horse for the preparation of serum-protective against Malta fever; and his blood, when examined, had a typical reaction with the micrococcus of Malta fever in I000-fold dilution. The horse, which has been immunized 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." About 5o cases of the fever, by April 1899, had been treated at Netley. The Lancet, April 15, 1899, says that the treatment was "with marked benefit: whereas they found that all drug treatment failed, the antitoxin treatment had been generally successful." Happily, it has now been proved that the usual source of infection with Malta fever is the drinking of the milk of infected goats: thus, by the avoidance, or by the careful and thorough boiling of the milk, the fever may be prevented: and prevention is better than cure. In 1904 a commission was sent out to Malta by the Royal Society, at the request of our government, to discover how the fever is conveyed to man. They found that it is not conveyed by air, or by drinking-water, or by pollution of sewage, or by contact; nor are its germs carried, like those of malaria, yellow fever and sleeping sickness, by insects. They found that it might be conveyed in food. There-fore Bruce examined the milch-goats, since goats' milk is universally drunk in Malta. The goats looked healthy enough, but it was found that the blood of 5o% of them gave the Widal reaction, and that some lo % of them were actively poisonous: monkeys fed on milk from one of them, even for one day, almost invariably got the disease. On the 1st of July 1906, an official order was issued forbidding the supply of goats' milk to our garrison. The year before, there had been 643 cases among our soldiers alone. In 1906, up to the 1st of July, there were 123 cases. During the rest of the year, including the three worst months for the fever, there were 4o cases. In 1907 there were II cases; in 1908 there were 5 cases; in 1909 there was I case; in 1910, by latest accounts, none. 12. Epidemic Meningitis.—The history of the serum treatment of epidemic meningitis affords an admirable example of the place of experiments on animals in the advancement of medical practice. This form of meningitis is one of the worst ways in which a man can die. Dr Robb, who had charge of the Belfast fever hospitals during an epidemic in Belfast, calls it " the most terrible in its manifestations, and the most disastrous in its death-rate, of all the epidemic diseases met with in English-speaking countries." Very little is known as to the way in which it spreads, and the public health authorities cannot prevent its sudden appearance in a town. " Many of those attacked," says Dr Robb, died within a few hours of the onset, and that after terrible suffering; while many of those who survived the acute attack lingered on for weeks and months, going steadily downhill in spite of every effort to save them. Again, many of those who did survive were left permanently maimed.' That is the usual picture of the disease when it is left to the older methods of treatment. By means of inoculation experiments, Dr Flexner and Dr Jobling; of the Rockefeller Institute, proved that the disease is due to a particular kind of germ, diplococcus intracellularis. They obtained these germs from the bodies of patients who had died of the disease; they cultivated the germs all by themselves, in test tubes, apart from all other kinds of germs; and they were able to reproduce the disease in monkeys by injecting under the skin a minute quantity of this pure culture of the germs. It may be worth noting that the disease in monkeys is less violent and less painful than it is in man. By the help of these experiments, Flexner and Jobling were able to prepare a serum for the treatment of the disease, in the same way as the serum is prepared which has been such a blessing to the world in cases of diphtheria. This serum for the treatment of epidemic meningitis was first used in the spring of 1907. The contrast between cases without serum treatment and cases with serum treatment is very plain. We may first give the records before the use of the serum. Of 4000 cases in New York in 1904, 75% died; Baker reports from Greater New York 2113 cases with 1636 deaths, giving 77.4% mortality; Chalmers reports from Glasgow (1907) 998 cases with 683 deaths, giving 68.4% mortality; Bailie reports in Belfast (1907) 623 cases with 493 deaths, giving 79.2 % mortality; Ker reports that in the Edinburgh epidemic there was 78% mortality; Robertson reports from Leith (1907) 62 cases with 74.4% mortality; Tumour reports from the Transvaal 200 cases with 74 % mortality. Amongst patients treated in hospitals the death-rate was no better. Of 202 cases in Ruchill Hospital, Glasgow, 79.2 % died ; of 108 cases in Edinburgh Fever Hospital, 80.5% died ; of 275 cases in Belfast Fever Hospital, 72.3% died ; and Dunn reports that in the Boston Children's Hospital, during the eight years 1899-1907, the mortality varied from 69% to 8o %o. Contrast with these the results in cases treated with Flexner's and Jobling's Serum: Cases. Died. Mortality per cent. City Hospital, Cincinnati. 45 14 31.1 Dr Dunn, Boston 40 9 22.5 Johns Hopkins Hospital, Baltimore . 22 4 18.1 Rhode Island Hospital 17 6 35-2 Lakeside Hospital, Cleveland 29 II 37'7 Edinburgh Fever Hospital 33 13 43'3 Mount Sinai Hospital (Children) 15 2 13'3 Municipal Hospital, Philadelphia 21 9 42.7 Belfast Fever Hospital 98 29 29.6 I These figures speak for themselves. Similar results have been obtained with similar treatment in France and Germany. " From these figures," says Dr Robb, " it will be seen that the death-rate in cases not treated with serum averaged some 75 %. This has been reduced in cases treated with the serum to less than half, and in many instances much below that figure." " My own experience has been that of 275 cases under my care in hospital, before the use of the serum was commenced, 72.3%. died; while of the 98 cases treated with serum 29.6% died. No selection of cases was made: every case sent into hospital since September 1907 has been treated in this way. No change in the severity of the attack was observed: in the three months immediately before the serum arrived with us 45 cases came under treatment, of whom 37, or 82 %, died; and in the first four months after we began its use in hospital 30 cases were treated, of whom 8 died, a mortality of 26.6%; while of the 34 cases occurring in the city in the same period, but not sent into hospital, and not treated with the serum, over 8o% died. Great as this change in the death-rate has been, it is not more striking than the improvement in the course run by the cases; for whereas it was common to have cases running on into weeks and even months, such cases are no longer met with " (R. D. S. pamphlet, 1909). 13. Malaria.—Laveran, in 188o, discovered the Plasmodium malariae, an amoeboid organism, in the blood of malarial patients. In 1894 Manson took, as a working%heory of malaria, the old belief that the mosquito is the intermediate host of the ,parasite. In 1895 came MacCullum's observations on an allied organism, Halteridium. In 1897, after two years' work, Ross found bodies, pigmented like the Plasmodium, in the outer coat of the stomach of the grey or " dapple-winged " mosquito, after it had been fed on malarial blood. In February 1898 he started work 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—(I) the Halteridium, (2) the Proteosoma of Labbe. Both have flagellate forms, and both are closely allied to the Plasmodium malariae. 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 " (Manson, 1898). These pigmented cells give issue to innumerable swarms of spindle-shaped bodies, " germinal rods "; and in infected mosquitoes Ross found these rods in the glands of the proboscis. Finally, he completed the circle of development, by infecting healthy sparrows by causing mosquitoes to bite them. It would be hard to surpass Ross's work, and that done in Italy by Grassi and others, for fineness and carefulness. He says, for instance, " out of 245 grey mosquitoes fed on birds with proteosoma, 178, or 72%, contained pigmented cells; out of 249 fed on blood containing halter-idium, immature proteosoma, &c., not one contained a single pigmented cell. . . . Ten mosquitoes fed on the sparrow with numerous proteosoma contained 1009 pigmented cells, or an average of lot each. Ten mosquitoes fed on tli'e sparrow with moderate proteosoma contained 292 pigmented cells, or an average of 29 each. Ten mosquitoes fed on the sparrow with no proteosoma contained no pigmented cells." By these and the like observations it was made practically certain that malaria is transmitted from man to man by a special kind of mosquito. Then came the final experiments on man. In -1900 Sambon, Low and Terzi made their famous experiment on them-selves in the neighbourhood of Ostia. They put up a little mosquito-proof hut in a neighbourhood " saturated with malaria." In this little hut they Iived through the whole of the malaria season, without taking a grain of quinine, and not one of them had a touch of the fever. Then another experiment was made. A consignment of mosquitoes containing blood from a case of malaria was sent from Rome to the London School of Tropical Medicine. Dr Manson and Dr Warren then submitted themselves to being bitten by these mosquitoes, and in due time suffered malarial fever. On these proven facts was founded the whole plan of campaign against malaria. The nature, habits and breeding-places of the mosquito of malaria (Anopheles maculipennis) have been studied with infinite care, and are now thoroughly recognized. The task is to destroy its eggs and its larvae, to break the cycle of its life, and to do away with its favourite breeding-places. 14. Yellow Fever. — A special mosquito (Stegomyia) conveys yellow fever from man to man. The germ, like the germ of rabies, has not yet been made visible under the microscope. It is probably a very minute spirochaete, which undergoes a slow evolution in the body of the mosquito told off for that purpose. The earlier experiments (1810-20) made on themselves by Chervin, Potter, Firth and others were truly heroic, but proved nothing. Finlay (188o-1900) experimented with mosquitoes on himself and other volunteers, and certainly proved the transmissibility of the fever through mosquitoes. Sanarelli (1898) prepared an immunizing serum which gave good results: but the germ which he took to be the specific cause of the fever, having found it in cases of the fever, is not now accepted by bacteriologists as specific. But the great work, which proved to the world the way of infection of yellow fever, was done by the Army Commission of the United States (1900). This Commission was sent to Havana, and the experiments were carried out by Drs Walter Reed, Carrot, Lazear and Agramonte in the Army Camp in Havana. A hut was constructed with two compartments, divided from each other by a wire mosquito-proof screen. In one compartment they placed infected mosquitoes, which had bitten a yellow fever patient within the first three days of the fever. More than twenty volunteers offered themselves for experiment. In one set of experiments, clothing and other material, soiled by' the vomit or blood or excretions from cases of the fever, were placed in one of the rooms, and some of the experimenters slept for 21 consecutive nights in contact with these materials, and in some cases in the very sheets on which yellow fever patients had died. Not one of these experimenters took the fever. In another set of experiments, 22 of the experimenters submitted themselves to be bitten by the infected mosquitoes, and in each instance they took the disease. It was thus proved, past all reasonable doubt, that yellow fever cannot be conveyed by ordinary infection, but must be transmitted from man to man through the agency of the mosquito. It might be said, by the opponents of all experiments on animals, that the discovery of these facts has nothing to do with " vivisection." But, as Professor Osier said in his evidence before the Royal Commission (vol. iv. p. 158), these experiments would never have been thought of if it had not been for previous experiments on animals. " The men who made these investigations spent their lives in laboratories, and their whole work has been based on experimentation on animals. They could not otherwise, of course, have ventured to devise a series of experiments of this sort." Out of this work came the wiping out of yellow fever (q.v.) from Cuba after the Spanish-American War, and from the area of the Panama Canal. 15. Sleeping-Sickness.—Experiments on animals have proved that sleeping-sickness is due to specific germs carried by tse-tse flies from man to man. By measures taken to prevent this way of infection, legions of human lives have been saved or safeguarded. 16. Infantile Paralysis.—Flexner, of the Rockefeller Institute, has proved, by experiments on animals, the infective nature of this disease, and its transmissibility by inoculation: a discovery of the very utmost value and significance. - - 17. Myxoedema.—Our knowledge of myxoedema, like our know-ledge of cerebral localization, began not in experimental science but in clinical observation (Gull, 1873; Ord, 1877). In 1882-1883 Reverdin and Kocher published cases where removal of the thyroid gland for disease (goitre) had been followed by symptoms such as Gull and Ord had described. In 1884 Horsley, by removal of the thyroid gland of monkeys, produced in them a chronic myxoedema, a cretinoid state, the exact image of the disease in man: the same symptoms, course, tissue-changes, mental and physical hebetude, the same alterations of the excretions, the temperature and the voice. In 1888 the Clinical Society of London published an exhaustive report, of 215 pages, on 119 cases of the disease, giving all historical, clinical, pathological, chemical and experimental facts; but out of 215 pages there is but half a page about treatment, of the useless old-fashioned sort. In 1890 Horsley published the suggestion that a graft of thyroid gland from a newly killed animal should be transplanted beneath the skin in cases of myxoedema: " 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. 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." In 1891 George Murray published his Note on the Treatment of Myxoedema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep. Later, the gland was administered in food. At the present time tabloids of thyroid extract are given. We could not have a better example how experiments on animals are necessary for the advancement of medicine. Now, with little bottles of tabloids, men and women are restored to health who had become degenerate in body and mind, disfigured and debased. The same treatment has given back mental and bodily growth to countless cases of sporadic cretinism. Moreover, the action of the thyroid gland has been made known, and the facts of " internal secretion " have been in hart elucidated. (Claude Bernard, speaking of the thyroid, the thymus and the suprarenal capsules, said: ' 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.") 18. The Action of Drugs.—Even in the 18th century medicine was still tainted with magic and with gross superstition : the 1721 Pharmacopoeia contains substances that were the regular stock-in-trade of witchcraft. Long after 172I neither clinical observation, nor anatomy, nor pathology brought about a reason-able understanding of the action of drugs: it was the physiologists, more than the physicians, who worked the thing out—Bichat, Magendie, Claude Bernard. Magendie's study of upas and strychnine, Bernard's study of curare and digitalis, revealed the selective action of drugs: the direct influence of strychnine on the central nerve-cells, of curare on the terminal filaments of motor nerves. Two instances may be given how experiments on animals have elucidated the action of drugs. A long list might be made—aconite, belladonna, chloride of calcium, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics—all these and many more have been studied to good purpose by this method; but it must suffice to quote here (I) Sir Thomas Fraser's account of digitalis, and (2) Sir Thomas Lauder Brunton's account of nitrite of amyl: "1. Digitalis 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... . It was not until the experimental method was applied in its investigation, in the first instance by Claude Bernard, and subsequently by Dybkowsky, Pelikahh, Meyer, Bohm 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 of the blood vessels. The indications for its use in disease were thereby revolutionized, and at the same time rendered more exact; and the striking benefits which are now afforded byy the use of this substance in most (cardiac) diseases were made avail-able to humanity." ' 2. 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 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." 19. Snake Venom.—Sewall (1887) showed that animals could be immunized, by repeated injection of small doses of rattlesnake's venom, against a sevenfold fatal dose. Kanthack (1891) immunized animals against cobra venom: afterward Fraser, Calmette and many others worked at the subject. Fraser's work on the anti-dotal properties or the bile of serpents is of the very highest interest and value, both in physiology and in sero-therapy. Calmette's work is an admirable Instance of the delicacy and accuracy of the experimental method. The different `venoms were measured in decimal milligrammes, and their action was estimated by the body-weights of the animals inoculated ; but of course this estimate of virulence was checked according to the susceptibility of the animals; guinea-pigs, rabbits and especially rats being more susceptible than dogs. " The following table gives`the relative toxicity, for z kilogramme of rabbit, of the different venoms that I have tested ": 1. Venom of Naja . 0.25 milligramme per kilogramme of rabbit. One gramme of this venom kills 4000 kilogrammes of rabbit : activity = 4,000,000. 2. Venom of Hoplocephalus . . 0.29 . 3.450,000. 3. Venom of Pseudechis . . . 1.25 . 800,000. 4. Venom of Pelias herus . . 4.00 250,000. By experiments in vitro Calmette studied the influence of heat and chemical agents on these venoms; and, working by various methods, was able to immunize animals: " I have got to immunizing rabbits against doses of venom that are truly colossal. I have several, vaccinated more than a year ago, that take without the least discomfort so much as forty milli-grammes of venom of Naja tripudians at once. Five drops of serum from these rabbits wholly neutralize in vitro the toxicity of one milligramme of Naja venom. . . . It is not even necessary that the serum should come from an animal vaccinated against the same sort of venom as that in the mixture. The serum of a rabbit immunized against the venom of the cobra or the viper acts in-differently on all the venoms that I have tested." In 1895 he had prepared a curative serum: " If you first inoculate a rabbit with such a dose of venom as kills the control-animals in three hours; and then, an hour after injecting the venom, inject under the skin of the abdomen fcur to five cubic centimetres of serum, recovery is the rule. When you interfere later than this, the results are uncertain; and out of all my experiments the delay of an hour and a half is the most that I have been able to reach." In 1896 four successful cases were reported in the British Medical Journal. In 1898 Cahnette reports:-- " It is now nearly two years since the use of my antivenomous serum was introduced in India, in Algeria, in Egypt, on the West Coast of Africa, in America, in the West Indies, Antilles, &c. It has been very often used for men and domestic animals (dogs, horses, oxen), and up to now none of those that have received an injection of serum have succumbed. A great number of observations have been communicated to me, and not one of them refers to a case of failure " (Brit. Med. Journ., May 14, 1898; see also Boston Medical and Surgical Journal, April- 7, 1898). It is of course impossible that " antivenene "' should be always at hand, or that it should bring about any great decrease in the number of deaths from snake-bite, which in India alone are o,000 annually; but at least something has been accomplished with It. The account given above of the chief discoveries that have been made by the help of experiments on animals, in physiology, pathology, bacteriology and therapeutics, might easily have been lengthened if we added to it other methods of treatment that owe less, but yet owe something, to these experiments. Nevertheless the facts quoted in this article are sufficient to indicate the great debt that medicine owes to the employment of vivisection. (S. P.)

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